27 December 2005

Vioxx litigation

By JOHN CURRAN Associated Press Writer
December 26,2005 | ATLANTIC CITY, N.J. -- For someone mired in judicial purgatory, Superior Court Judge Carol Higbee is remarkably upbeat. She doesn't want pity -- many judges work as hard, she says. She doesn't want publicity -- it makes her uncomfortable, and she grants interview requests grudgingly. She just wants justice -- and she's ready to dispense it, one Vioxx case at a time, even if it takes a lifetime.

And at the current rate, it could, assuming the cases are not settled or withdrawn.

Higbee, 55, is the New Jersey judge assigned to thousands of cases brought in state court against Merck & Co. over its now-withdrawn painkiller Vioxx. The lawsuits -- all 4,333 of them -- blame the Whitehouse Station-based pharmaceutical company for heart attacks and strokes suffered by users.

Merck has acknowledged links between Vioxx and heart attacks and strokes in clinical studies, but only after 18 months' use.

If they all go to trial and take as long as a recent, seven-week case, Higbee would need 583 years to hear them all.

"I don't foresee that that's the way things will happen," she said in a recent interview with The Associated Press. "I'm going to be a judge for X many more years and during those years, I'll be trying cases. Maybe they're Vioxx cases, maybe they're others."

The way things are going, they'll be Vioxx cases. With 9,200 cases filed nationwide and former users still streaming into courthouses with new claims, the litigation shows no signs of slowing.

Merck & Co. has said it plans to fight the lawsuits, one by one. In New Jersey, the responsibility for trying them all falls to Higbee, a soft-spoken former medical malpractice attorney known for cutting through the cant without playing favorites.

Higbee says patience isn't one of her strong points. But she has shown plenty of it so far, refereeing battling lawyers in the recent trial -- which ended Nov. 3 with a Merck victory -- and meeting with lawyers for Merck and the plaintiffs to schedule the trials to come.

On Feb. 27, it's back to the courtroom for the next Vioxx trial. As in the first, Higbee will spend her days on the bench and her nights at home reviewing trial transcripts in preparation for the next day's session. And when she isn't dealing with a Vioxx issue, she'll be tending to the 375 non-Vioxx cases on her docket.

"Vioxx is important. Every other piece of litigation I have is important. Even though it's more high-profile, it's not more important than any other case," Higbee said.

A native of Mishawaka, Ind., Higbee attended Temple University and its law school before spending 17 years in private practice, working as a plaintiffs attorney on behalf of victims of slip-and-falls, bad drugs and negligent doctors. In 1993, she was appointed to the bench by then-New Jersey Gov. James Florio, a position that now pays $141,000 annually.

When it became clear that Vioxx litigation was going to tax New Jersey courts, the state Administrative Office of the Courts looked to Higbee.

"Judge Higbee was an obvious choice," spokeswoman Winnie Comfort said. "She's experienced and she can manage the incredible workload that comes with some of these mass tort cases."

When she's off the bench, Higbee spends her time at home tending to her rose bushes and tomatoes, reading mystery novels and -- with her husband, a high school English teacher and part-time actor -- raising their 5-year-old granddaughter.

For now, though, her eyes are squarely on the mountain of work ahead of her.

Will the Vioxx workload ever ease up?

"It depends on the participants," she said. "They can choose what they want to do. And what they want to do today may be different from what they want to do later. Litigation, it's just like the rest of life. You never know what's around the corner."
© 2005 The Associated Press. Link

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Tylenol tragedies

I've railed about acetaminophen here before. It really is ugly: People who just need more pain-relief; attempted suicides (often first-attempts involving people who aren't really trying to kill themselves); and recreational drug users who don't know that its the acetaminophen that's more dangerous (to them) than the hydrocodone or oxycotin.

December 26,2005 | WASHINGTON -- Think popping extra pain pills can't hurt? Think again: Accidental poisonings from the nation's most popular pain reliever seem to be rising, making acetaminophen the leading cause of acute liver failure.

Use it correctly and acetaminophen, best known by the Tylenol brand, lives up to its reputation as one of the safest painkillers. It's taken by some 100 million people a year, and liver damage occurs in only a small fraction of users.

But it's damage that can kill or require a liver transplant, damage that frustrated liver specialists insist should be avoidable.

The problem comes when people don't follow dosing instructions -- or unwittingly take too much, not realizing acetaminophen is in hundreds of products, from the over-the-counter remedies Theraflu and Excedrin to the prescription narcotics Vicodin and Percocet.

"The argument that it's the safest sort of has overruled the idea that people cannot take any amount they feel like," says Dr. William Lee of the University of Texas Southwestern Medical Center, who laments that acetaminophen is popped like M&Ms.

Acetaminophen bottles currently recommend that adults take no more than 4,000 milligrams a day, or eight extra-strength pills.

Just a doubling of the maximum daily dose can be enough to kill, warns Dr. Anne Larson of the University of Washington Medical Center.

Yet, "if two is good, 10 is better in some patients' minds," she says with a sigh.

The Food and Drug Administration has long wrestled with the liver risk, warning two years ago that more than 56,000 emergency-room visits a year are due to acetaminophen overdoses and that 100 people die annually from unintentionally taking too much.

A study published this month by Larson and Lee has agency officials weighing whether to revisit the issue.

Over six years, researchers tracked 662 consecutive patients in acute liver failure who were treated at 22 transplant centers. (Acute liver failure is the most severe type, developing over days, unlike chronic liver failure that can simmer for years because of alcohol abuse or viral hepatitis.)

Almost half were acetaminophen-related. More remarkable was the steady increase: Acetaminophen was to blame for 28 percent of the liver poisonings in 1998, but caused 51 percent of cases in 2003.

That makes acetaminophen the most common cause of acute liver failure, the researchers report in the journal Hepatology.

While most patients pulled through with intensive care, 74 died and 23 others received a transplant.

Some 44 percent of the cases were suicide attempts.

But more, 48 percent, were unintentional overdoses, which "isn't hard to do," Larson says.

Say you take Tylenol Cold & Flu Severe for the flu's aches and stuffiness -- 1,000 mg of acetaminophen, every six hours. A headache still nags so between doses you pop some Excedrin -- 500 mg more of acetaminophen. Switch to Nyquil Cold/Flu at bedtime, another 1,000 mg.

Maybe you already use arthritis-strength acetaminophen for sore joints -- average dose 1,300 mg.

Depending on how often they're taken, the total acetaminophen can add up fast.

That's the nonprescription realm. Surprisingly, 63 percent of unintentional overdoses involved narcotics like Vicodin and Percocet that contain from 325 mg to 750 mg of acetaminophen inside each pill.

Some were chronic pain sufferers taking more and more narcotics as their bodies adjusted to the powerful painkillers, not knowing they were getting ever-higher acetaminophen at the same time. Or they added over-the-counter products for other complaints.

Just this month, Larson treated an 18-year-old whose liver crashed after using Vicodin for three or four days for car-crash injuries. "She was just taking too much because her pain was bothering her."

Led by Tylenol manufacturer McNeil Consumer & Specialty Pharmaceuticals, most over-the-counter products now voluntarily list acetaminophen on front labels.

McNeil also runs ads about the risk, saying "if you're not going to read the label, then don't buy our products," says spokeswoman Kathy Fallon.

But how strongly labels warn varies by product. A rule to standardize warnings, urged by FDA's scientific advisers in 2002, still is working its way through the agency.

While FDA runs a consumer education campaign about the liver risk, nonprescription drugs chief Dr. Charles Ganley says the new study suggests the agency may need to further target narcotic-acetaminophen combinations.

Lee wants to copy Britain, which saw a 30 percent drop in severe liver poisonings after restricting how much acetaminophen could be bought at once.

That's unlikely. Meanwhile, the advice is simple: Read drug labels and add up all your acetaminophen, avoiding more 4,000 mg a day. For extra safety, Lee advises no more than 2,000 to 3,000 mg for more vulnerable people, who regularly use alcohol or have hepatitis.Link

It's not that I think acetaminophen should be discouraged or even removed from OTC. But I do think we need some more effective education campaigns.
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08 December 2005

Starting off, and update

For you new readers of PFP, let me entice you with my two favorite (apparent) facts about pain:
Pain hurts less when it is inflicted by a woman, researchers have found.
Students were asked to put their fingers in a clamp which was tightened until the pain was unbearable. Researchers from the University of Westminster found that people allowed women to turn the clamp much further than men.

Dr David Williams, who led the research said the study suggested people do not expect women to inflict as much pain. He said: "This effect is likely to be a result of what participants subconsciously expect, based on socially acquired gender stereotypes - people feel that they are less likely to experience intense pain from a stimulus given by a woman rather than a man.

"This effect is less likely to be down to males trying to appear macho in front of a female - a conscious and deliberate act - as the result applied to both genders." He said the fact there were no differences in how men and women responded to the test suggested women do not actually handle pain better.

Dr Williams said people's sensitivity to pain was also shown to depend on their surroundings. In the study, people appeared to suffer more if there was a poster on the wall which might trigger negative feelings, such as a chart of wounds or a poster calling for blood donors.

Dr Williams, who carried out the research for his PhD, said: "People subconsciously evaluate their environment. "This evaluation can result in identical stimuli being perceived as more or less painful for the same participant or, in some cases, an innocuous stimulus being perceived as painful or a relatively intense stimulus perceived as innocuous."

He said the finding could have implications for how patients are given potentially painful treatments. "Individuals can be 'primed' for pain by qualities of their environment and, as a result, may suffer unnecessarily during acutely painful clinical procedures. "Awareness of these principles may be useful in developing methods of reducing suffering in those situations." Link

I originally posted about this here,
and for the past year I've been waiting for the study to show up in a peer-reviewed journal, and for some corroboration. It's time to go to the source. More soon.

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07 December 2005

Another pain blog

Here's a very, very, very good blog on pain:
Hope posting this doesn't drive me out of business.

Biofeedback and pain modulation

From Wired:
Pain can be mysterious, untreatable and debilitating, and its causes can be unknown. But if you could see the pain -- or, at least, your brain's reaction to it -- you might be able to master it.

A study from researchers at Stanford University and MRI technology company Omneuron suggests that's possible, and the results could lead to better therapies for those suffering from crippling chronic pain.

The researchers asked people in pain to try to control a pain-regulating region of the brain by watching activity in that area from inside a real-time functional magnetic resonance imaging, or fMRI, machine. Initial results showed subjects could reduce their pain, some quite dramatically.

It's the first evidence that humans can take control of a specific region of the brain, and thereby decrease pain, said Stanford professor Sean Mackey, who co-wrote the paper, which was published last week in Proceedings of the National Academy of Sciences.

"(Similar to) going to a gym and working muscle using weights, here we're using the real-time fMRI technology to exercise a certain brain region," he said.

Study co-leader and Omneuron CEO Christopher deCharms said for many people with chronic pain, available treatments like medication or surgery simply don't work. But this exercise, which researchers have termed "neuroimaging therapy," could one day help some of the millions of Americans who suffer from untreatable chronic pain.

In the study, eight healthy subjects who'd been subjected to a painful stimulus and eight chronic pain patients underwent a series of fMRIs. The images tracked activity in the brain's rostral anterior cingulate cortex -- an area deCharms said is related to pain. Subjects watched this area on a monitor in real time during the procedure. Prompted by researchers' suggestions of trying to lessen their own pain by ignoring it or imagining it as benign, they set out in a mental game of hot-and-cold to lessen their discomfort.

Twenty-eight healthy subjects and four pain patients were also put into control groups that tried to control pain by viewing other patients' brain data or using other mental strategies, but no fMRIs. These tactics didn't show a significant reduction in pain, deCharms said.

The pain patients reported that the fMRI helped them decrease their overall pain 64 percent. Healthy subjects said they saw a 23 percent increase in their ability to control the strength of their pain, and a 38 percent increase in their ability to master its unpleasantness.

"I think most people found it very exciting to be able to watch the activity in their own brain, moment by moment, as it took place," deCharms said.

Vera A. Gonzales, a pain psychologist in League City, Texas, said she thinks the study lends scientific data to what scientists already knew empirically -- that people can decrease their own pain by focusing on certain thoughts.

It probably also helped that subjects could watch their brain activity unfold on a screen, she said. For years, some therapy methods have allowed patients to monitor and try to control their biofeedback by concentrating on things like skin temperature and heart rate.

Mackey and deCharms cautioned it will be some time before such therapy could be available for commercial use. They're investigating the process of getting Food and Drug Administration approval, and right now they're focusing on a study to investigate the effects of long-term neuroimaging therapy, deCharms said. One day, patients may even be able to think away other problems like depression, anxiety and dyslexia.

"We don't yet have a good answer to what happens if you keep practicing and practicing," he said.

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06 December 2005

Another resource

Just found this website on pain geared toward patients:
Haven't looked into who underwrites it so caveat lector.


Merk deleted data on Vioxx

[ed: I'm going to post new stuff below the welcome post for a bit. Thus some articles will magically appear in posts before they were written.]
From Forbes.com:
Merck's Deleted Data
Robert Langreth and Matthew Herper, 12.08.05, 8:10 PM ET
A top editor of The New England Journal of Medicine says that he was stunned to find out that data linking Vioxx to cardiovascular risk was deleted from a major study his journal published five years ago--and that it appears that Merck researchers may have deleted that data.

"I was somewhere between surprised and stunned," Dr. Gregory Curfman, executive editor of The Journal, says. "They allowed us to publish an article that was just incomplete and inaccurate in some respects and was misleading and may have contributed to the detriment to the public health."
Merck recalled Vioxx after its own study linked long-term use of the drug to an increased risk of heart attacks and strokes. Now, the question is if that alarm should have been sounded much earlier.

Just days after Merck recalled Vioxx from the market, editors at The Journal discovered....early versions of the manuscript [that] contained a blank table entitled "CV events"--which is standard jargon for cardiovascular events. Time stamps in the software indicated that the table was deleted two days before the manuscript was submitted to The New England Journal on May 18, 2000. "When you hover the cursor over the editing changes, the identity of the editor pops up, and it just says 'Merck,'" Curfman says.
The editors weren't sure what to make of the finding, so they kept quiet. It wasn't clear that the information that had been in the table would have changed the conclusions of the study...."We talked internally. Should some action be taken? We did not feel we had sufficient evidence to act on it," Curfman says.
an internal Merck document dated July 5, 2000--after the VIGOR manuscript was submitted to the journal, but well before the study went to press....it indicated that two Merck authors on the VIGOR study knew of three additional heart attacks among Vioxx patients in the study, which had not been disclosed to The New England Journal of Medicine. The heart attacks occurred in the final five weeks of the trial and in patients at low risk for heart problems.
Curfman says the editors had assumed that the VIGOR manuscript only included limited data on heart attacks because that was all that was available at the time. "It turns out that they had quite a bit more already worked up," he says. He raced back to the office and spent the next few weeks analyzing all the VIGOR drafts, raw data and correspondence.
Curfman says he called lead author Claire Bombardier of the University of Toronto, on Monday, indicating that the statement [noting the potential trouble] would be published. She told him that she would begin working on a correction.....Bombardier said that the VIGOR paper appropriately disclosed the data and that the authors were working on finalizing a response to the editorial.
Hints that Vioxx might cause heart attacks had existed for years, as basic research pointed to a mechanism by which the drug might cause more clots. When VIGOR was published in The New England Journal of Medicine, there were already questions among scientists about the potential of Vioxx and related drugs
In a statement, Merck disputed The New England Journal analysis. "The VIGOR publication, which was peer-reviewed, fairly and accurately described the results of the study as of the prespecified cutoff for analysis. The additional events referred to in the editorial were events that were reported after the prespecified cutoff date and, therefore, these were not included in the primary analysis reported in the article.

"Nevertheless, the additional events were disclosed to the FDA in 2000, presented publicly to the FDA's Advisory Committee in February 2001 and included in numerous press releases subsequently issued by Merck. We also note that these additional events did not materially change any of the conclusions in the article."

Curfman responded, "We're not buying into that."

Here's a bit of hearsay: when these stories came out last year, a close friend and former Pfizer statistician told PFP that her department had been warning management for quite awhile that their studies on Celebrex and heart trouble were using the wrong endpoints and potentially distorting the conclusions.
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03 November 2005

Self-injurious behavior

A number of cases have been reported in which patients are said to have damaged or destroyed areas of body afflicted by neuropathic pain and sensory deficit (the latter being an inevitable accompaniment of the former) (see Mailis, 1996).

In 30 years of pain clinic practice with a particular emphasis on neuropathic pain, I have seen two only patients in whom ‘self-injurious behaviour’ (Mailis, 1996) has occurred. Patient 1 was one of 160 patients with central post-stroke pain (CPSP) personally seen and examined by myself; Patient 2 was one of 282 patients with postherpetic neuralgia (PHN) personally seen and examined by myself.

Patient 1 was a right-handed man who had a stroke at age 66 affecting the left side of his body, including the face. He was aphasic, and remained so for 6 weeks; he had hiccoughs which persisted for 2 or 3 months. There was severe loss of power in his left arm and leg.

Burning and shooting pain appeared in the left side of his face some 3 months later.

He was first seen in the Pain Clinic 2 years after the stroke. By this time his motor deficit was almost imperceptible. He still complained of burning and shooting pains in the left side of the face, particularly at the tip of his nose; he also had occasional pins and needles in his left arm and even less frequently in his left leg. He stated that his facial pain was exacerbated by drinking hot liquids; that the left side of his face always felt hot, and sometimes went red for 3 or 4 weeks at a time. On examination, tactile and sharpness sensations were diminished on the left side of the face, particularly on the outer lower left side of his nose, and to a lesser extent in his left arm. There was no clinically evident deficit of temperature sensation.

The ala nasae of the left nostril was absent, leaving a half-moon-shaped gap extending about 7.5 mm up the nose in comparison with the right side. He said that he had ‘picked and pulled’ at his nostril ever since the pain came on, because that was where the pain was worst. His GP confirmed that this self-inflicted mutilation had occurred since the central post-stroke pain came on. The patient averred that he still felt pain in the ‘missing part’ of his nose.

He had had a stellate ganglion block and an intravenous infusion of lignocaine in another hospital before being referred to us; neither had had any effect on his pain. We prescribed nortriptyline, rising to 75 mg nocte. This also had no effect, and the patient discharged himself after 3 months.

Patient 2 was an apparently phlegmatic male farmer born in 1912 who had herpes zoster affecting his right ophthalmic nerve (V1) in 1984, at the age of 72. When seen in the Pain Clinic 2 years later, aged 74, he had some mild backache but was otherwise an extremely healthy man, still working. He complained of a pain on the right side of his forehead which he described on his McGill Questionnaire as "Throbbing, boring, pressing, pulling, and hot". He had some mild dynamic tactile allodynia. Amitriptyline, rising to 50 mg nocte, was prescribed. When next seen in a follow-up clinic, a few months later, he stated that he felt ‘much better’. However, the following year he had a mild stroke, which resulted in him being treated with Madopar® 62.5 mg b.d.

He was next seen in the Pain Clinic 9 months later (now aged 75). There were no evident symptoms or signs of stroke; he was then taking a proprietary drug containing both an anticholinergic and a calcium channel blocker. His forehead pain was still described as ‘much better’.

Beginning 3 months later, he complained that he ‘couldn't feel the right side of his forehead’. He had begun to scratch the area, resulting in red scratchmarks. When asked why he did this, he denied that there was any pain or itching, but said that as he couldn't feel anything, he wanted ‘to make sure it was still there’. Clinical testing confirmed the absence of tactile and sharpness sensations, and severe diminution of temperature sensation; an area about 3 cm wide and 4 cm wide centred above the middle of the right eyebrow could be said to be virtually anaesthetic.

He was seen at frequent intervals over the next 4 years. Within 18 months, he had scratched his forehead down to the bone in circular area of about 1.5 cm diameter about 2.5 cm above the middle of the right eyebrow, surrounded by a rectangular area in which injury changed centripetally from down to periosteum to more superficial cutaneous layers. He prevented the process of healing by repeated scratching. He repeatedly denied that he felt any pain, but said that there was some ‘irritation’. As he was clean-shaven, he was asked whether or not he didn't think that seeing his forehead in a shaving mirror every morning confirmed that it was indeed present. He admitted this, but said it had become a habit during the day to touch and subsequently scratch, harder and harder, to see if he could elicit any sensation which would confirm its presence. Medical treatment with both external applications of benzydamine and lignocaine creams, and systemically with tricyclics, carbamazepine, baclofen, and buprenorphine had no effect; neither did transcutaneous nerve stimulation, stellate ganglion or supraorbital nerve blocks.

Neither of our patients was assessed by a clinical psychologist. However, both appeared to be of normal intelligence; both were married men doing responsible jobs. They may well have been exogenously depressed by their illness, but showed no obvious clinical signs of endogenous depression at interview. They thus did not overtly exhibit two of the criteria listed by Mailis (1996) for self-injurious behaviour (SIB): low intelligence and depressive personality.

Many of the cases of SIB reported in the literature (which has been extensively reviewed by Mailis, 1996) were of ‘ulcers’ and ‘excoriations’. Injury of this sort is undoubtedly under-reported. However, both the cases reported here had extensive and unequivocal injuries. It is interesting, and perhaps significant, that both involve the face, for by far the greatest number of reported self-inflicted injuries are facial, in patients with anaesthesia dolorosa following destructive procedures of the trigeminal ganglion.

Prima facie, it would seem that the first patient reported herein was a genuine case of autotomy; he destroyed a painful part, in which he subsequently continued to have phantom pain.

The second patient, however, mutilated an area from which he had no apparent sensory input. This is an extreme case of a much commoner clinical phenomenon: following peripheral nerve injury resulting in an anaesthetic area of skin, most patients take no notice of it, except to remark, if directly questioned, that they have an area in which there is no feeling. A small number, however, become obsessed with a perfectly painless but anaesthetic area. The patient reported here is such a case, although the only one in our experience who has injured himself as a result.

However, another case involving a patient with HZ-PHN has been reported to me anecdotally by Dr R.W. Johnson (Bristol). This concerns an elderly man who had facial zoster, and subsequently had violent itching in his analgesic right ala nasae. Because he could feel no pain, scratching the itch eventually resulted in excavation of the lower outer border of the nose.

These cases are clearly not autotomy as commonly defined (the term is not included in either the first (Merskey, 1986) or second ( Mersky and Bogduk, 1994) edition of the IASP Classification of Chronic Pain). The term as now used in neurological/pain medicine appears to have been introduced by Wall et al. (1979), although they did not limit it to a phenomenon occurring only in supposed neuropathic pain, as now is the case.

There is an implication for experimental animal work, in which it is well-known (but rarely reported) that of animals subjected to nerve ligation and other subtotal nerve injuries, only a proportion exhibit signs of neuropathic pain, and of this proportion, only a few perform autotomy. If an animal chews off an extremity, how do we know whether it is doing so because the extremity hurts, or because it regards an anaesthetic part as a foreign body, and rids itself of it? This would appear to be the conclusion from the work of Shir et al. (2001), who found that autotomy only occurs in rats with completely denervated hindlimbs. The best argument against such an interpretation has been put forward by Blumenkopf and Lipman (1991) on the basis of animal studies, but cannot be justified by experience with human patients. The present case 2 had no pain in the mutilated area, and I do not regard it as a case of autotomy, whereas case 1 not only had pain in the mutilated area, but continued to experience such pain in the missing ala nasae after SIB, thus raising the interesting question of the relationship between pain in an area of partial sensory deficit and phantom pain.


Congenital insensitivity to pain

From a very nice overview of the research on the subject:
5. Congenital indifference to pain

With these insights into the basis of pain insensitivity, stoics will patiently await the unravelling of the genetic basis of the clinically less pressing, but philosophically more interesting problem of congenital indifference to pain. – John Wood, 1996

Congenital indifference to pain, also referred to as congenital universal insensitivity to pain, has been reported since the early 1930s (Dearborn; Ford; Boyd; McMurray; Ogden; Landrieu and Davis). These individuals typically have painless injuries beginning in infancy, but normal sensory responses on examination. Perception of passive movement, joint position, and vibration is normal, as are tactile thresholds and light touch perception. The ability to distinguish sharp and dull stimuli and detect differences in temperature seems to be intact ( McMurray and Ogden). Reflexes and autonomic responses are also normal.

Peripheral nerve samples were obtained from several of the earlier cases of congenital indifference to pain, and no abnormalities were observed (Ogden et al., 1959). Because of their seemingly normal neurologic examinations, these individuals were considered to have a deficit in the affective response to pain rather than in the sensory discrimination of painful stimuli. However, because morphometric analysis of nerve fiber size density had not been performed, it is unclear whether selective loss of nerve fibers was present. There have been mixed results with some biopsies reported as abnormal ( Low and Dyck) and it is possible that some cases are HSAN V. Because of the possibility of peripheral neuropathy, these cases are therefore not considered definitive examples of indifference to pain ( Dyck and Thomas).

A case of congenital indifference to pain with normal nerve morphology has been described by Landrieu et al. (1990). The patient was a 5-year-old girl with painless fractures and indifference to ‘casual injuries’. Withdrawal reflexes and grimacing were present to pinprick and hot water (43°C), but she was indifferent to prolonged or repeated application of the painful stimuli anywhere on her body. Subcutaneous injection of histamine yielded normal results. She had an otherwise normal neurological examination. She detected pinprick, heat, and cold, and responded normally to light touch, joint position, vibration, and pressure. Her reflexes were normal, no autonomic abnormalities were observed, and cortical sensory evoked potentials were normal. A sural nerve biopsy appeared normal using electron microscopy, and the size density distributions appeared normal for both myelinated and unmyelinated fibers. In addition, she was reported to have normal psychomotor development.

The normal electron microscopic nerve morphometry rules out the possibility of a selective absence of unmyelinated nociceptors, although it does not exclude the possibility of other structural or neurochemical abnormalities. This patient demonstrates that congenital indifference to pain does not require the same type of peripheral nerve abnormalities associated with the hereditary sensory neuropathies. As Thomas (1993) has suggested, such patients ‘could represent a disturbance affecting neurotransmitters that did not involve loss of nerve fibers, or … the differences could be due to an abnormality of the central sensory pathways or processing’. Additionally, the case suggests that abnormal pain responses can occur even though pain discrimination, affect, and withdrawal responses appear preserved.

Davis et al. (1998) described a subject with normal perception of pinprick, light touch, and vibration. In addition to lifelong lack of pain perception with accompanying painless injuries, she had gait disturbance and spasticity. Sural nerve biopsy and electrophysiologic studies were normal. At age 56, she had progressive decline in cognitive abilities. Autopsy conducted at age 62 showed evidence of Alzheimer's disease and thalamic gliosis at multiple levels, including both ventral and midline nuclei. The amount of gliosis exceeded that found in age-matched normal brains and in an Alzheimer's disease control brain. Other family members were reported to have similar symptoms, including a lack of response to painful stimuli. Although complicated by the presence of other neurologic symptoms, this report suggests that deficits present in hereditary pain insensitivity and indifference disorders can have central as well as peripheral origins.
6. Asymbolia for pain and related conditions

When lesions occur in the areas of the brain that subserve the processing of painful stimuli, deficits in one or more of the components of pain perception can occur, and disorders similar to congenital pain insensitivity can result. Lesions in the anterior cingulate cortex or insular cortex impact the medial pain system and, thus, might be expected to cause a loss of the affective-motivational component. Lesions in the primary and secondary somatosensory cortex affect the lateral pain system; their expected major effect would be loss of sensory-discriminative components of pain.

Loss of the affective-motivational component of pain has been called ‘asymbolia for pain’. An early report described a patient who showed a lack of responsiveness to strong electrical currents and physically threatening gestures (Schilder and Stengel, 1931). Although there was some reaction to pain, no withdrawal responses occurred, and the patient at times ‘even seemed to derive some pleasure’ from the painful stimuli. The authors described both the ‘pain reaction’ and the ‘appreciation of pain’ as inadequate, and attributed pain asymbolia to findings of parietal lobe lesions in this patient and two others who were studied.

Later authors restricted use of the term ‘asymbolia for pain’ to patients with deficits in the affective-motivational component of pain but preserved sensory discrimination. Such patients perceive painful stimuli but lack emotional responses and withdrawal movements (Berthier et al., 1988). As in the earlier descriptions, some patients reportedly smiled or laughed in response to noxious stimuli. Computed tomography demonstrated insular cortex lesions in all patients in a series of six such patients ( Berthier et al., 1988). Lesions in the secondary somatosensory cortex could have explained a lack of response to painful stimuli, but no such abnormalities were found in two of these patients.

It is also possible that central lesions could impair the sensory-discriminative components of pain while sparing affective-motivational components. Ploner et al. (1999) describe a patient with a lesion in the primary and secondary somatosensory areas subserving the left hand. He had normal heat pain thresholds in the right hand, but did not perceive pain in the left hand, even at temperatures much higher than those used on his unaffected side. He showed deficits in the assessment of both stimulus localization and quality in the left hand. When offered a list of prompts including both painful and non-painful thermal descriptors, the patient would not use any of them to describe the stimulus, nor could he locate the stimulus more specifically than ‘between fingertips and shoulder’.

However, when stimulus intensities equal to and greater than what he considered painful on the unaffected side were administered to the left hand, the patient described a ‘clearly unpleasant’ feeling that he wanted to avoid. This finding suggests that the affective-motivational component of pain was intact and is consistent with the lateral pain system, which includes the somatosensory cortex, being more involved in the sensory-discriminative component of pain than in pain affect. This case also illustrates that it is possible for pain responses to occur without an intact sensory-discriminative system.
7. Conclusions

The deficits present in the different pain insensitivity syndromes provide insight into the complex anatomical and physiological nature of pain perception. Reports of pain asymbolia and related cortical conditions illustrate that there can be losses that independently involve either the sensory-discriminative component or the affective-motivational component of pain perception, thus highlighting their different anatomical localization. The presentations of congenital indifference to pain and pain asymbolia overlap, which suggests that indifference to pain – whether congenital or acquired – may involve one or more deficits preferentially affecting the components of the medial pain system, which includes the anterior cingulate cortex.

By affecting both the lateral and medial pain systems, the peripheral nerve abnormalities observed in individuals with the various types of HSAN cause deficits in both components of pain perception. The case of Ploner et al. (1999) demonstrates that the affective-motivational component can be retained even in the absence of the sensory-discriminative component. Importantly, this suggests that the absence of affective responses in individuals with HSAN is not simply a consequence of loss of sensory discrimination but also involves loss of input to the medial pain system caused by the peripheral neuropathy.

It has been proposed that the affective component of pain is not unitary and consists of at least two stages, an immediate primary stage and a cognitively-mediated second stage (Price, 1999). In the cases reviewed, it is unclear at which stage the observed deficits originate. Careful assessment of the separate components of pain sensory intensity and unpleasantness in patients with various congenital pain insensitivity and indifference disorders will help to further clarify the pathways underlying the different components of pain perception. In addition, mapping genetic defects in HSAN patients will provide important clues about molecular mechanisms of pain, and the promise of new, more effective and selective therapies.


02 November 2005

Blind men and the elephant

In my dissertation I argue that the traditional account of pain's intrinsic badness --i.e., pain is bad because disliked; because unpleasant; because represents damage, et cetera-- are like the famous three blind men and the elephant. When we have the correct conception of what pain is, we can see that all of these (and other quasi-motivational states like fear) are the source of pain's intrinsic badness. For my reference, and your pleasure, here's
John Godfrey Saxe's ( 1816-1887) version of the famous Indian legend,
It was six men of Indostan
To learning much inclined,
Who went to see the Elephant
(Though all of them were blind),
That each by observation
Might satisfy his mind.

The First approached the Elephant,
And happening to fall
Against his broad and sturdy side,
At once began to bawl:
"God bless me! but the Elephant
Is very like a wall!"

The Second, feeling of the tusk
Cried, "Ho! what have we here,
So very round and smooth and sharp?
To me `tis mighty clear
This wonder of an Elephant
Is very like a spear!"

The Third approached the animal,
And happening to take
The squirming trunk within his hands,
Thus boldly up he spake:
"I see," quoth he, "the Elephant
Is very like a snake!"

The Fourth reached out an eager hand,
And felt about the knee:
"What most this wondrous beast is like
Is mighty plain," quoth he;
"'Tis clear enough the Elephant
Is very like a tree!"

The Fifth, who chanced to touch the ear,
Said: "E'en the blindest man
Can tell what this resembles most;
Deny the fact who can,
This marvel of an Elephant
Is very like a fan!"

The Sixth no sooner had begun
About the beast to grope,
Than, seizing on the swinging tail
That fell within his scope.
"I see," quoth he, "the Elephant
Is very like a rope!"

And so these men of Indostan
Disputed loud and long,
Each in his own opinion
Exceeding stiff and strong,
Though each was partly in the right,
And all were in the wrong!


So oft in theologic wars,
The disputants, I ween,
Rail on in utter ignorance
Of what each other mean,
And prate about an Elephant
Not one of them has seen!


12 October 2005

Latency of acute pain onset

Features of acute pain were examined in patients at an emergency clinic. Patients who had severe, life-threatening injuries or who were agitated, drunk, or ‘in shock’ were excluded from the study. Of 138 patients who were alert, rational and coherent, 51 (37%) stated that they did not feel pain at the time of injury. The majority of these patients reported onset of pain within an hour of injury, although the delays were as long as 9 h or more in some patients. The predominant emotions of the patients were embarrassment at appearing careless or worry about loss of wages. None expressed any pleasure or indicated any prospect of gain as a result of the injury.

The occurrence of delays in pain onset was related to the nature of the injury. Of 46 patients whose injuries were limited to skin (lacerations, cuts, abrasions, burns), 53% had a pain-free period. Of 86 patients with deep-tissue injuries (fractures,next term sprains, bruises, amputation of a finger, stabs and crushes), only 28% had a pain-free period. The McGill Pain Questionnaire was administered to patients who felt pain immediately after injury or after a delay, and revealed a normal distribution of sensory scores but very low affective scores compared to patients with chronic pain. The results indicate that the relationship between injury and pain is highly variable and complex.


Bone Pain

The pathophysiological mechanism of pain in patients with bone metastases in the absence of a fracture is poorly understood. The presence of pain is not correlated with the type of tumor, location, number and size of metastases, gender or age of patients (Oster et al., 1978). While about 80% of patients with breast cancer will develop osteolytic or osteoblastic metastases, about two-thirds of demonstrated sites of bone metastases are painless (Front et al., 1979). The resorption of bone due to the increased osteoclastic activation decreases bone density and disrupts skeletal architecture, either at focal sites or generally throughout the skeleton. Many nerves are found in the periosteum and others enter bones via the blood vessels. Microfractures occur in bony trabeculae at the site of metastases resulting in bone distortion. The stretching of periosteum by tumor expansion, mechanical stress of the weakened bone, nerve entrapment by the tumor or direct destruction of the bone with a consequent collapse are possibly associated mechanisms (Bjurholm et al., 1988; Campa and Payne, 1992; Foley, 1993). The weakening of bone trabecolate and the cytokines, which mediate osteoclastic bone destruction, may activate pain receptors. The release of algesic chemicals within the marrow probably accounts for the observation that pain produced by tumors is often disproportionate to their size or degree of bone involvement. A secondary pain may be caused by reactive muscle spasm (Twycross, 1995). Nerve root infiltration and the compression of nerves by the collapse of osteolytic vertebrae are other sources of pain (Bruera, 1993).


Congenital Insensitivity to Pain and Headache

Congenital insensitivity to pain (CIP) is a rare clinical syndrome characterized by dramatic impairment of pain perception since birth (for a recent review, see Nagasako et al., 2003). As they lack the protective function of pain against dangerous stimuli, patients with this syndrome are prone to potentially life-threatening painless injuries and unnoticed illnesses, especially during childhood. Most often, CIP is a manifestation of hereditary sensory and autonomic neuropathy (HSAN) involving the small-calibre (A-delta and C) nerve fibres, which normally transmit nociceptive inputs along sensory nerves. The sensory loss for pain in HSAN may be either generalized or restricted to some body parts. In many cases, the nociceptive fibres gradually degenerate in a length-dependent manner and sensation is partly preserved proximally. At present, five types of HSANs with different underlying genetic abnormalities have been identified as potential causes of CIP (Dyck et al., 1983 and Thomas, 1993). HSAN I usually begins after the first decade with a distal loss of pain and thermal sensitivity that can progress to impairment across all sensory modalities and ulcerations of extremities. This disease has been shown to be caused by a mutation in the SPTLC1 gene encoding a subunit of serine palmitoyltransferase (Bejaoui et al., 2001 and Dawkins et al., 2001). HSAN II presents with diffuse impairment of discriminative touch and pressure sensation with variable impairment of other sensory modalities in a glove-and-stocking pattern, leading to trophic ulcers in infancy. Mutations of a novel gene termed HSN2 have been identified recently in patients with HSAN II (Riviere et al., 2004 and Lafreniere et al., 2004). Patients with HSAN III (familial dysautonomia or Riley–Day syndrome) show widespread autonomic dysfunction and a severe pansensory disturbance caused by a mutation in the I?B kinase complex associated protein, IKBKAP, gene (Anderson et al., 2001 and Slaugenhaupt et al., 2001). The clinical picture of HSAN IV includes diffuse thermal and pain insensitivity, self-mutilation, anhidrosis and recurrent fevers with preservation of other sensory modalities. Mutations in the nerve growth factor receptor gene TRKA have been found in all cases of HSAN IV analysed so far, implicating the NGF/TRKA pathway in the pathogenesis (Indo et al., 1996 and Indo, 2001). The presentation of HSAN V may be similar to HSAN IV, except for variable autonomic involvement (Donaghy et al., 1987, Dyck et al., 1983 and Low et al., 1978). Recently, a mutation in the NGF beta gene has been identified in a Swedish family with a similar clinical picture (Einarsdottir et al., 2004).

Despite partial or total sensory loss for pain, many patients with CIP can experience pain during their life, especially in HSAN I (Dyck, 1993, p. 1069). Such patients can have phantom pain in amputated extremities, lancinating pains due to inflammation within nerves containing actively degenerating fibres, mechanical allodynia in partially denervated areas and stimulus-independent pain that may be of central origin (anonymous reviewer, personal communication). We report the case of a 32-year-old woman with a severe and generalized congenital insensitivity to pain caused by HSAN, who experienced physical pain for the first and unique time in her life shortly after the sudden loss of her brother.
The patient was an intelligent and communicative woman who worked as a shop assistant. Her parents were algerians and the incidence of CIP in the family suggested an autosomic recessive mode of transmission. The patient had sustained innumerable painless injuries during childhood, including fractures of the nose and of the left radius, severe burns of both buttocks after sitting on a radiator and of the scalp after a hot shower. She had also had her teeth drilled several times at the dentists without anaesthesia, without any pain. At the age of 13, appendicitis was revealed by vomiting and diarrhea without pain. Deliveries of her two children (at the age of 27 and 31) were completely painless despite the lack of anaesthesia. She had no history of self-mutilation, osteomyelitis or joint disease. Unexplained episodes of hyperthermia up to 40 °C were first noted at the age of 12 and recurred during periods of hot weather. The patient had always been anosmic. She was ticklish and remembered having felt intense itch after nettle contact. Sweating was reported to be normal.

When systematically asked about possible previous experiences of physical pain, the patient reported that the only pain she had ever felt consisted of an episode of intense headache, which had taken place 2 years before the interview but, fortunately, had been well documented by her general practitioner. This inaugural headache occurred in a context of strong emotional overload and anxiety, 3 weeks after her younger brother died suddenly in a car accident. She had the sensation of carrying an enormous weight bilaterally on top of her head, which hurt so much that she was no more able to concentrate on her work. The pain was not associated with focal neurological symptoms, photophobia, phonophobia, nausea or vomiting, and was not aggravated by routine physical activity. There was no family history of headache. Standard clinical examination was normal, as was a brain CT scan. Paracetamol and aspirin were ineffective. The pain spontaneously waned after a few days and completely disappeared 2 weeks later. The general practitioner concluded in favor of an episode of tension-type headache as part of an anxious reaction to the loss of her brother.
The clinical picture of this patient, which includes a history of innumerable painless injuries during childhood, deficient pain and temperature sensitivity and autonomic abnormalities, is typical of CIP (Nagasako et al., 2003). The association between CIP, anosmia and ageusia has been described previously in several case reports (Jewsbury, 1951, Losa et al., 1989, Madonick, 1954, Ogden et al., 1959 and Thrush, 1973). Although the lack of neuropathological and genetic data does not allow a definitive classification of the present case, both clinical features and neurophysiological data suggest a selective defect of small-calibre nerve fibres with preserved sweating and with intact large-diameter nerve fibres, which best fit with the diagnosis of HSAN V (Donaghy et al., 1987, Dyck et al., 1983, Low et al., 1978 and Minde et al., 2004). Indeed, the abnormality of the nociceptive flexion reflex indicates a marked loss of A-delta-afferent fibres (Willer and Albe-Fessard, 1983), while the complete lack of neurogenic inflammation after intradermal injection of capsaicin strongly suggests a defect of C-fibre function (Culp et al., 1989, Koltzenburg et al., 1992, Torebjörk et al., 1992 and Schmelz et al., 2000). Moreover, preservation of the sympathetic skin response eliminates the diagnosis of HSAN IV, which is always associated with anhidrosis (Hilz et al., 1999 and Shorer et al., 2001). Altogether, these data clearly demonstrate that the pain insensitivity of this patient is associated with a marked impairment of peripheral (i.e. primary afferent) nociceptive mechanisms. Thus, this patient must be diagnosed as a case of congenital insensitivity to pain, not congenital indifference to pain (for a clear distinction between these terms, see Dyck et al., 1983, Kunkle, 1961 and Landrieu et al., 1990
The patient's report of a single episode of intense headache should be interpreted cautiously. First, as noted previously by Thrush (1973), “there are many semantic difficulties in discussing pain with patients who have no experience of it”. For example, patients with CIP may adopt the same pain language as normal people to avoid being regarded as ‘strange’ or ‘abnormal’ (Losa et al., 1989 and Thrush, 1973). Moreover, there is evidence that the memory for a past pain is often inaccurate and that numerous factors may affect its recall (Brodie and Niven, 2000, Erskine et al., 1990 and Feine et al., 1998). One must also consider that our patient might have re-interpreted afterwards the distressing experience of her brother's death as a physically painful event. However, the clinical data suggest that the episode of headache reported by our patient corresponded to a genuine pain experience: the quality of the pain and its localization were precisely described and fulfilled the diagnostic criteria of episodic tension-type headache (Headache Classification Committee of The International Headache Society, 2004); most importantly, the patient's complain of intense headache had been well documented by her general practitioner, who corroborated her own description.

Interestingly, a few previous case reports mentioned that headache could be the sole (or almost the sole) manifestation of pain in patients with CIP (Cohen et al., 1955, Comings and Amromim, 1974, Dearborn, 1932, Jewsbury, 1951 and Magee et al., 1961). The patient reported by Dearborn could not recall any pain except occasional headaches, which unfortunately were not described in detail (Dearborn, 1932). Jewesbury's case n°3 (aged 76) recalled a single unexplained attack of severe headache and vomiting which had occurred 50 years before (Jewsbury, 1951). Of particular interest is Jewesbury's case n°2: this 38-yo man, who was liable to frontal headaches of 24-h duration, developed no headache after intravenous injection of a high dose of histamine diphosphate (though his face flushed within the first minute) (Jewsbury, 1951). However, this same patient developed a severe and prolonged headache after a lumbar puncture, just like another CIP patient reported by Cohen et al. (1955). Histamine headache has been shown to be caused by dilatation of intracranial vessels (Wolff, 1963), while post-lumbar puncture headache is probably caused by continued leakage of cerebrospinal fluid from the subarachnoid space, leading to lowering of intracranial pressure, withdrawing support for the brain and thus causing traction upon intracranial vessels (Lance and Goadsby, 1998, p. 258). Overall, such occurrence of headache in CIP patients suggests that some forms of headache might bypass peripheral nociceptive mechanisms and be generated directly in the central nervous system. Such a mechanism of centrally generated headache has been demonstrated previously. Indeed, Raskin et al., 1987 and Veloso et al., 1998 have shown that a substantial number of patients treated surgically for uncontrollable chronic pain developed recurrent headaches for the first time after electrodes had been inserted in their periaqueductal gray area. On the other hand, one could postulate that residual intact peripheral nociceptors might also contribute to the triggering of trigeminal pain in some CIP patients. As a matter of fact, toothaches have been reported in a few cases (Comings and Amromim, 1975 (patients DW and WW); Landrieu et al., 1990 (patient 2)). Our patient never experienced dental pain, however, although she had had her teeth drilled several times without anaesthesia. Moreover, she once severely burnt herself on the scalp without feeling any pain. Such a complete lack of trigeminal pain evoked by noxious stimuli suggests a profound loss of peripheral trigeminal nociceptive innervation and pleads in favor of the central origin of her headache.

The originality of the present case lies in the fact that our patient's pain was closely related to an event with strong emotional impact. One could argue that the occurrence of this inaugural headache soon after her brother's death might be coincidental. However, it is well known that psychological factors may play a central role in certain pain syndromes such as tension-type headache (Lance and Goadsby, 1998), and that physical pain may be precipitated or revived by a current emotional illness or event, including bereavement (Merskey, 1975 and Zisook et al., 1982). As a matter of fact, previous studies have underlined the contribution of bereavement to the development of tension-type headache (Kaiser and Primavera, 1993 and Abu-Arafeh, 2001). In this perspective, the inaugural episode of headache in this patient with CIP who had never experienced pain before, strongly suggests that the transcription of the grief of bereavement into physical pain may sometimes occur independently of the peripheral mechanisms of nociception. This observation fits nicely with Sigmund Freud's postulate that “the intense, ever-increasing cathexis of the absent (lost) object (…) creates exactly the same economic conditions as does the pain-generated cathexis of an injured part of the body, and makes it possible for the absence of the usual prerequisite of physical pain - an attack somewhere in the periphery—to be disregarded” (Freud, 2003). In agreement with such a psychodynamic view, experimental data suggest that the same neural mechanisms that regulate physical pain may also control the expression of separation distress in mammals. Some of the brain areas, which are the most responsive during separation distress, such as the anterior cingulate cortex, the dorsomedial thalamus and the periaqueductal gray area (Herman and Panksepp, 1981 and Panksepp, 2003), are also involved in pain processing and modulation (Peyron et al., 2000, Tracey et al., 2002 and Craig, 2003). Moreover, a recent fMRI study performed in human volunteers showed that activity in the dorsal anterior cingulate cortex—which is known to be linked to pain unpleasantness (Tolle et al., 1999)—was associated with increased distress after social exclusion, providing further evidence that the experience of social and physical pain share a common neuroanatomical basis (Eisenberger et al., 2003). These results have led to the challenging hypothesis that the social attachment system of mammals may have adopted the neural computations of the physical pain system to promote survival (Panksepp, 1998 and Panksepp, 2003). Such an evolutionary perspective may indeed help to understand why some patients may feel physically hurt after the loss of someone they love.


Palliative care and dementia

Advanced dementia patients may be at substantial risk for undetected or undertreated pain. To examine the treatment of pain following hip previous termfracture,next term a prospective cohort study was conducted in an academic teaching hospital. Fifty-nine cognitively intact elderly patients with hip previous termfracturenext term and 38 patients with hip previous termfracturenext term and advanced dementia were assessed daily. The cognitively intact patients rated their pain on a numeric scale ranging from 0 (none) to 4 (very severe). Analgesics prescribed and administered were recorded and compared to hip previous termfracturenext term patients with advanced dementia. The advanced dementia patients received one-third the amount of morphine sulfate equivalents as the cognitively intact patients. Forty-four percent of cognitively intact individuals reported severe to very severe pain preoperatively and 42% reported similar pain postoperatively. Half the cognitively intact patients who experienced moderate to very severe pain were prescribed inadequate analgesia for their level of pain. Eighty-three percent of cognitively intact patients and 76% of dementia patients did not receive a standing order for an analgesic agent. These data reveal that a majority of elderly hip previous termfracturenext term patients experienced undertreated pain. The fact that advanced dementia patients received one-third the amount of opioid analgesia as compared to cognitively intact subjects-40% of whom reported severe pain postoperatively-suggests that the majority of dementia patients were in severe pain postoperatively. This study and others suggest that directed interventions to improve pain detection and alter physician prescribing practices in the cognitively impaired are needed.


29 September 2005


Let's see. I'm (a) writing a dissertation; (b) writing a dissertation on pain; and (c), not leaving the house enough. Sounds about right...
the Adamites, as the members of a heretical sect flourishing about A.D. 200 called themselves... Practised self-flagellation reserving the discipline...for their private gatherings in connection with the religion they professed. In any public processions, the shoulders only were bared, and flagellation was not practised.
--Scott's A History of Torture p.256*

*Sidenote: Scott's book really isn't historically very informative. It's mostly violence-porn masquerading as polemic. For a much, much, much, better resource see Edward Peters's Torture. While Scott's thesis is roughly 'people in societies torture each other and always have', Peters's book is a sober history and exploration of the relationships between torture, criminal law, and class.

24 September 2005

New Nocicepters

Now pain REALLY can't be C-fibers firing...
We all know that if you put your hand over an open flame it's very painful. What you may not know is that, for some people, just lying under a blanket is painful as well. They have neuropathic pain--annoying, chronic pain that comes from a diseased nerve cell rather than a specific stimulus. Feeling phantom pain in a missing limb is another, more famous, example.

Experts say up to two percent of the U.S. population suffers from neuropathic pain. But this pain generally responds poorly to analgesics and other standard treatment and get worse over time, causing permanent disability in some people. Now there may be new hope for these pain sufferers.

Scientists at the University of Virginia Health System have identified a new type of pain-sensing neuron in rats, which are unusually dense in a subtype of calcium channels called T-type channels. It is possible that these "T-rich cells" could be targets for future therapies to treat neuropathic pain as well as acute onset pain, which can happen after invasive surgery or inflammation.

A UVa anesthesiologist, Dr. Slobodan Todorovic, and his colleagues identified these novel cells and believe that the T-type calcium channels in them may serve as a volume control for pain impulses. "We hope that this new type of neuron will be amenable to new therapies. The next step will be to find a drug to block the action of these calcium channels," Todorovic said.

It was once thought that calcium channels were only important for brain function. But, Todorovic and his team show that the T-type channels are important to the functioning of peripheral nerves, especially when the nerves are injured.

A PhD student in UVa's neuroscience graduate program, Mike Nelson, discovered these T-rich nerve cells in Todorovic' lab. "It's very exciting to make an initial observation like this," Nelson said. "It's one reason we go to grad school in the first place." There are no drugs now that effectively treat neuropathic pain, Nelson added.

"Hopefully, observations like this will lead to new and more efficacious drugs in the future. Our findings are another piece of evidence that these calcium channels are excellent targets for new analgesic development."


16 August 2005

Bullimia nervosa and the opioid system

Ok, so its not strictly about pain, but there are many important connections between disorders like bulimia and self-injurious behaviour (SIB), and pain.
RESTON, Va.— The role of the brain’s opioid receptor system—or endorphin system—may hold the key to understanding and treating bulimia nervosa, according to research reported in the Society of Nuclear Medicine’s August issue of the Journal of Nuclear Medicine.

"Involvement of the opioid system may explain the addictive quality of this behavioral disorder," said Angela Guarda, M.D., assistant professor of psychiatry at Johns Hopkins School of Medicine in Baltimore, Md. The first imaging study to implicate the opioid system in bulimia nervosa shows differences in women with bulimia compared to healthy women, added J. James Frost, M.D., Ph.D., professor of radiology and neuroscience at Johns Hopkins and co-author of "Regional ?-Opioid Receptor Binding in Insular Cortex Is Decreased in Bulimia Nervosa and Correlates Inversely With Fasting Behavior." In the study, eight women with bulimia were compared to healthy women of the same age and weight. Their brains were scanned using positron emission tomography (PET) after injection with the short-acting radioactive compound carfentanil, which binds to mu-opioid receptors in the brain, explained Frost. PET is a powerful medical imaging procedure that noninvasively uses special imaging systems and radioactive tracers to produce pictures of the function and metabolism of the cells in the body. He noted, "We found that mu-opioid receptor binding in bulimic women was lower than in healthy women in the left insular cortex. The insula is involved in processing taste, as well as the anticipation and reward of eating, and has been implicated in studies of other driven behavioral disorders, including drug addiction and gambling.”

Bulimia nervosa is a serious eating disorder marked by a destructive pattern of recurrent dieting, binging and vomiting to control one's weight. "Patients feel trapped by this behavioral cycle suggesting something about it is rewarding,” said Guarda, “and, as with substance abuse, the course of bulimia is frequently chronic and relapsing."

Bulimia nervosa, which is 10 times more common in females than in males, affects 1–2 percent of adolescent girls and young women in the United States. Bulimia may become chronic and lead to serious health problems, including seizures, irregular heartbeat, dental erosion, swollen salivary glands, gastrointestinal irritation and electrolyte imbalances. In rare cases, it may be fatal. While the cause of bulimia nervosa is still unknown, research shows that certain brain chemicals may function abnormally in bulimia patients. This research may point to a molecular target for development of more effective treatments than those currently available. Frost indicated that medications that affect the brain’s opioid receptor system and approaches to treatment for substance abuse disorders may be helpful in treating bulimia.


Gender and pain in the Economist

From the Economist.
Men and women seem to perceive pain in different ways. That may mean they sometimes need different pain-relief drugs

MALES and females respond to pain differently, even as children. In most places, boys are expected to show a stiff upper lip when they get hurt, while in girls wailing is, well, girlie. In part, this difference is learnt—or, at least, reinforced by learning. But partly, it is innate. It is hard, for instance, to blame upbringing for the finding that boy and girl babies show different responses to pain six hours after birth, or that male rats are more long-suffering than females. It is also life-long. Ed Keogh of the University of Bath, in England, and his colleagues have found that women report feeling pain in more bodily areas than men, and also feel it more often over the course of their lives.

Many researchers are therefore concluding that genetics underpins at least some of the difference, and that females really do feel pain more than males. Indeed, some go further. They think that the way men and women experience pain is not only quantitatively different, but qualitatively different, too. In other words, men's and women's brains process pain using different circuits. Some pain scientists therefore think it is only a matter of time before painkillers are formulated differently for men and women in order to account for this difference.

Jeffrey Mogil, director of the pain genetics laboratory at McGill University in Montreal, is one of the leading advocates of such “pink and blue” painkillers. Pick a disease at random, he says, and the chances are that females and males will handle the pain associated with it differently. That seems to be true in mice, at least. When new mouse “models” of human disease are created by genetic engineers, Dr Mogil and his colleagues are often asked to test the engineered mice for their responses to pain. They consistently find differences in the way the mutant, diseased mice and their non-mutation-carrying brethren respond to painful stimuli. But, generally, those differences are seen more strongly in one sex than the other.

A prescribing headache

The latest example of such a difference is in migraine, a condition that is three times more common in women than in men. In 2004, a group of researchers led by Michel Ferrari of Leiden University in the Netherlands reported that they had created what they believed to be the first mouse model of migraine. Since some researchers argue that migraine is associated with heightened sensitivity to pain, they sent their creation to Dr Mogil for testing. He stresses that his data are preliminary. However, he does find a lowered pain threshold in the mouse migraine model compared with healthy mice—but only in females.

Dr Mogil is now convinced that the pain response in men and women is mediated by different brain circuits—and not only because of his own observations. Obstetricians and gynaecologists have long known that certain drugs are particularly effective in women. Mothers in childbirth prefer nalbuphine to morphine, for instance. Men, however, report the opposite preference when they are in pain.

Both nalbuphine and morphine work by stimulating the brain's endogenous-opioid receptors (endogenous opioids are the molecules that opium-derived drugs mimic). But opioid receptors come in several varieties, two of the most important of which are known as mu and kappa. Morphine binds to the mu receptors, while nalbuphine stimulates the less well-studied kappa receptors. Kappa-receptor agonists, as molecules such as nalbuphine are known, appear to have little or no pain-relieving effect in men.

Two years ago, Dr Mogil identified the first gene known to be involved in modulating pain thresholds in women. Variations in this gene have no effect on men's responses to a kappa-receptor agonist called pentazocine, but they do affect the response in women. The protein produced by this gene, melanocortin-1 receptor, also affects hair and skin colour. Working in collaboration with Roger Fillingim of the University of Florida, Gainesville, Dr Mogil found that redheaded women with fair skin—who have a particular version of the receptor—have a heightened response to pentazocine.

Jon Levine and Robert Gear, of the National Institutes of Health Pain Centre at the University of California, San Francisco, also think that there are fundamental differences between the sexes when it comes to pain. They have explored the effects of nalbuphine on post-operative pain in men and women who have had their wisdom teeth removed. The results suggest that kappa-opioid agonists not only fail to alleviate pain in men, they can actually make it worse.

Dr Gear and Dr Levine believe that as well as an analgesia (ie, pain-suppression) circuit, the brain contains what they call an anti-analgesia circuit—one which, when activated, pumps pain up. They have shown that which circuit is activated depends not only on the type of receptor a drug acts on, but also the dose given. Among their dental patients, low doses of nalbuphine had a short-lasting analgesic effect in the women, but profoundly enhanced pain in the men. However, when they added a low dose of naloxone—a drug that blocks all types of opioid receptor—to the nalbuphine, the sex difference disappeared and pain relief was significantly enhanced in everyone. After refining the relative proportions of the two drugs in the mixture, they have succeeded in finding (and patenting) a combination that is effective in both sexes.

Nor is it only the mechanism of pain perception that differs between the sexes. Dr Keogh and his colleagues argue that there are significant differences in the ways men and women cope with pain, as well.

This conclusion is based on studies involving hospital patients, as well as others on volunteers who were exposed to a painful stimulus, such as an ice-water arm-bath. Using this, the researchers were able to measure the point at which people first notice pain, as well as their tolerance—the point at which they can no longer stand it. Men were able to minimise their experience of pain by concentrating on the sensory aspects—their actual physical sensations. But this strategy did not help women, who focused more on the emotional aspects. Since the emotions associated with pain, such as fear and anxiety, tend to be negative, the researchers suggest that the female approach may actually exacerbate pain rather than alleviating it.

Dr Keogh, a psychologist, sees this difference as an effect of social conditioning—and uses it to point up the dangers of under-estimating social influences in favour of those of the genes. But it is not obvious why such male and female “coping strategies” should not be underpinned by genetics, in the same way that perceptions are..

Yes another great example of a science writer tackling research on sex/gender and x. Here, the survey of the research is decent but clear. But then we get a final paragraph like this:
The evolutionary reason why men resist pain better than women is, however, a mystery. After all, pain is there to stop you doing bad things to yourself. Perhaps it is because males and females are exposed to different sorts of pain. Males, for instance, get into fights much more often than females do, and thus get wounded more often. On the other hand, they do not have to undergo the visceral pain of childbirth. And perhaps a willingness to tolerate less pain than men do helps to explain why women live longer than their menfolk


From Roxanne

10 August 2005


MONTREAL 27 July 2005--Scientists at the MUHC have made progress in understanding what causes migraines. The research, published in the new issue of the Proceedings of National Academy of Sciences (PNAS), reveals how gene mutations known to cause a form of inherited migraine--the kind that cause debilitating headaches and light flashes known as auras--target a cellular process involved in brain cell communication.

"A number of mutations have been shown to result in familial migraines," says Dr. Rhoda Blostein--a medical scientist at the Research Institute of the MUHC, professor in the Department of Medicine and Biochemistry at McGill University, and author of the new study. "Discovering genetic mutations that cause disease is important, but in order to develop treatments we must understand what these mutations do." By engineering several genetic mutations known to cause inherited migraines (type 2), and incorporating them into human cells, Dr. Blostein and her team showed several genotypes damage the operation of a tiny cellular mechanism commonly known as the Sodium Pump (Sodium/Potassium ATPase enzyme).

"Much of what happens in your brain--from memory to basic movement--is the result of the transmission of electrical impulses along nerve cells," says Dr. Blostein. "This is a basic process by which our brain cells communicate." By expelling sodium from the cell, and drawing potassium from outside, the sodium pump maintains a gradient of potassium, which is critical for the propagation of electrical signals along nerve cells. Like an air conditioner in the heat of summer, the sodium pump is a massive energy hog, consuming around 30% of the energy produced by the cell in order to perform this vital cellular process.

Of particular interest in this study is that some mutations cause migraines by reducing sodium pump efficiency--akin to reducing the power supply. "This is the first time that a genetic mutation of the sodium pump has been shown to cause disease by changing the properties of this biochemical process, rather than completely turning it off," notes Dr. Blostein. This new understanding of how genetic mutations cause migraines takes us one step closer to the development of improved treatments, providing hope to millions of migraine sufferers.


20 July 2005

More on pain and drug law

As a followup to the last post. Here's an earlier comment from Lindsay. I mentioned this here.
NYT article
There's been a lot of talk about medical malpractice "reform" lately. Bush says that OB-GYNs are unable to practice their "love" because they're afraid of getting sued. Nobody is talking about the much worse legal injustice facing the medical profession: doctors who are going to jail for practicing good medicine.

Pain specialists who prescribe large quantities of opiates to patients with chronic pain are being harassed by law enforcement. Some are losing their licences, some are even being sent to jail. The physicians are being flagged, charged, and convicted by law enforcement who want to keep drugs off the street.

The irony is that the doctors most likely to be targeted are those who deliver the standard of care for patients with severe pain. There are a lot of sanctimonious pronouncements in medical journals and in the mainstream media about how serious pain is and how important it is to treat pain aggressively.

[...] Last August, the D.E.A. publicly acknowledged the need for a "principle of balance" to address the necessity of access to pain medications and the approaches to containing abuse, addiction and diversion. It published "Prescription Pain Medications: Frequently Asked Questions and Answers for Health Care Professionals and Law Enforcement Personnel," which thoughtfully explained the concepts, and offered clear descriptions of the circumstances under which the D.E.A. may prosecute a doctor. Mysteriously, however, in early October the agency pulled the document from the Web site, saying it had "misstatements."

The D.E.A. declined to elaborate on its reasons for pulling the document. Some people have speculated that the agency was worried that the information could be used to help clear physicians charged with trafficking.[...]

The current climate is forcing doctors to practice bad medicine:

"We are unable to refer patients to doctors who will treat pain, if only because once a name gets out there, patients understandably flock, and then the doctor is targeted," said Siobhan Reynolds of Pain Relief Network, a patient advocacy group based in New York. The Association of American Physicians and Surgeons, based in Tucson and dedicated to the concerns of private practitioners, has gone so far as to warn doctors against managing chronic pain, lest they face of years of harassment and legal fees, even prison. "If you do," the association enjoins, "first discuss the risks with your family."

Scattered evidence confirms these impressions. A 1998 survey of more than 1,300 physicians by the New York State Medical Society found that 60 percent were moderately or very concerned about the possibility of being investigated by regulatory authorities for prescribing opiates for noncancer pain.

A third said they prescribed lower quantities of pills and lower dosages "frequently" because of the possibility of eliciting an investigation. When asked how often they avoided prescribing a preferred drug for noncancer pain, because doing so required triplicate forms, half said "frequently."

Brings a whole new meaning to "evidence based medicine", doesn't it?


Pain and drug law

I've mentioned cases like this before. Its nice to see it broached so directly in a major newspaper.
The New York Times
July 19, 2005
Punishing Pain

Zephyrhills, Fla.

When I visited Richard Paey here, it quickly became clear that he posed no menace to society in his new home, a high-security Florida state prison near Tampa, where he was serving a 25-year sentence. The fences, topped with razor wire, were more than enough to keep him from escaping because Mr. Paey relies on a wheelchair to get around.

Mr. Paey, who is 46, suffers from multiple sclerosis and chronic pain from an automobile accident two decades ago. It damaged his spinal cord and left him with sharp pains in his legs that got worse after a botched operation. One night he woke up convinced that the room was on fire.

"It felt like my legs were in a vat of molten steel," he told me. "I couldn't move them, and they were burning."

His wife, Linda, an optometrist, supported him and their three children as he tried to find an alternative to opiates. "At first I was mad at him for not being able to get better without the medicines," she said. "But when he's tried every kind of therapy they suggested and he's still curled up in a ball at night crying from pain, what else can he do but take more medicine?"

The problem was getting the medicine from doctors who are afraid of the federal and local crusades against painkillers. Mr. Paey managed to find a doctor willing to give him some relief, but it was a "vegetative dose," in his wife's words.

"It was enough for him to lay in bed," Mrs. Paey said. "But if he tried to sit through dinner or use the computer or go to the kids' recital, it would set off a crisis, and we'd be in the emergency room. We kept going back for more medicine because he wasn't getting enough."

As he took more pills, Mr. Paey came under surveillance by police officers who had been monitoring the prescriptions. Although they found no evidence that he'd sold any of the drugs, they raided his home and arrested him.

What followed was a legal saga pitting Mr. Paey against his longtime doctor (and a former friend of the Paeys), who denied at the trial that he had given Mr. Paey some of the prescriptions. Mr. Paey maintains that the doctor did approve the disputed prescriptions, and several pharmacists backed him up at the trial. Mr. Paey was convicted of forging prescriptions.

He was subject to a 25-year minimum penalty because he illegally possessed Percocet and other pills weighing more than 28 grams, enough to classify him as a drug trafficker under Florida's draconian law (which treats even a few dozen pain pills as the equivalent of a large stash of cocaine).

Scott Andringa, the prosecutor in the case, acknowledged that the 25-year mandatory penalty was harsh, but he said Mr. Paey was to blame for refusing a plea bargain that would have kept him out of jail.

Mr. Paey said he had refused the deal partly out of principle - "I didn't want to plead guilty to something that I didn't do" - and partly because he feared he'd be in pain the rest of his life because doctors would be afraid to write prescriptions for anyone with a drug conviction.

If you think that sounds paranoid, you haven't talked to other chronic-pain patients who've become victims of the government campaigns against prescription drugs. Whether these efforts have done any good is debatable (and a topic for another column), but the harm is clear to the millions of patients who aren't getting enough medicine for their pain.

Mr. Paey is merely the most outrageous example of the problem as he contemplates spending the rest of his life on a three-inch foam mattress on a steel prison bed. He told me he tried not to do anything to aggravate his condition because going to the emergency room required an excruciating four-hour trip sitting in a wheelchair with his arms and legs in chains.

The odd thing, he said, is that he's actually getting better medication than he did at the time of his arrest because the State of Florida is now supplying him with a morphine pump, which gives him more pain relief than the pills that triggered so much suspicion. The illogic struck him as utterly normal.

"We've become mad in our pursuit of drug-law violations," he said. "Generations to come will look back and scarcely believe what we've done to sick people."

For Further Reading:

For more information on Richard Paey's case and others like it, visit the Pain Relief Network.

Treating Doctors as Drug Dealers: The DEA’s War on Prescription Painkillers (pdf) by Ronald T. Libby. Cato Institute, 28 pp., June 2005.

Cartoons by Richard Paey.
* Copyright 2005 The New York Times Company

Thanks Lindsay for the pointer.

10 July 2005

Cox-2's in Canada

A roundup of recent developments.


Arthritis and accupuncture

There has been no doubt for a good long while that accupuncture does have analgesic effects on certain types of pain. Though, as in the last graf here, its usefulness as a treatment is more dubious (though my sense from an admittedly superficial understanding of the literature is that, Dr. Moore's comment is a bit too strong).

Results of a randomised trial in this week's issue of The Lancet suggest that acupuncture could reduce pain and improve joint functioning in the short-term for people with osteoarthritis of the knee.

Osteoarthritis most frequently affects the knee joint. Despite a limited evidence base, arthritis patients are increasingly turning to acupuncture, especially as side-effects of non-steroidal anti-inflammatory drugs are common and wide-ranging.

Around 300 patients with chronic osteoarthritis of the knee were randomly assigned to acupuncture, minimal (sham) acupuncture (superficial needling at non-acupuncture points), or a waiting list control.

Patients were allowed to use non-steroidal anti-inflammatory drugs throughout the study. Physicians administered acupuncture and minimal acupuncture in 12sessions over 8 weeks.

Patients completed questionnaires at the start of treatment, and after 8 weeks, 6 months, and 1 year. Analgesic use was similar for patients in the three groups. After 8 weeks, patients given acupuncture had a substantially lower score on an established osteoarthritis index than patients in the control group (26 points and 50 points, respectively).

Minimal acupuncture also had short-term benefit compared with no acupuncture (36 points on the osteoarthritis index). However, at 1-year follow-up there was no significant difference in scores between the three groups. Lead investigator Claudia Witt (Charite University Medical Center, Berlin, Germany) comments:

“Acupuncture treatment had significant and clinically relevant short-term effects when compared to minimal acupuncture or no acupuncture treatment in patients with osteoarthritis of the knee. We now need to assess the long-term effects of acupuncture, both in comparison to sham interventions and to standard treatment.”

In an accompanying Comment, Andrew Moore (Pain Research, University of Oxford, UK), states: “The bottom line from Witt and colleagues' large, long, and high-quality study of acupuncture for knee osteoarthritis is that doing something is better than doing nothing.”

However he cautions that it is too soon to draw firm conclusions from the current study: “We are still some way short of having conclusive evidence that acupuncture is beneficial in arthritis or in any other condition, other than in a statistical or artificial way. There is limited evidence of effect and, with exceptions, of cost-effectiveness. Most importantly, the need for needles is still in doubt.”

The more data on accupuncture's usefulness we have, the clearer its mechanism may become. This is, in part, because the sites where an accupuncture regime is indicated for a particular pain turns out to vary greatly between conditions --sometimes its on the spot of the pain, other times it is applied elsewhere on the body in accordance with a traditional theoretical constellation of points (in such cases the relevant neuroanatomy can be less clear).

Along with certain kinds of transcutaneous electrical nerve stimulation, accupuncture is a 'counter-irritation analgesia'. We know that these forms of analgesia involve both opioid and non-opioid systems (for example, naloxone --an opioid antagonist-- has been shown to reduce accupuncture's analgesic effects). The mechanisms of the notorious placebo effect and hypnotic analgesia also play some role in the effects of accupuncture.

See Price and Mayer's 1995, "Evidence for endogenous opiate analgesic mechanisms triggered by somatosensory stimulation (including accupuncture) in humans." Pain Forum 1995, 4(1) 40-43.

Hypnotic analgesia and the placebo effect do have a good deal of theoretical importance for us philosophers (the former is especially useful in understanding why pain is bad). Thus the more light accupuncture sheds on these topics, the better for us.

Oh, and the empirical explanations are always nice for smacking down those who claim it involves 'mind-over-matter' in some metaphysical sense. Though you, gentle reader, don't believe that should be necessary. Right?

07 July 2005

Daily Mail: Gender and pain

Of course, you, diligent reader of PFP, already knew all this, right?

Women feel the pain more than men

Women feel pain more than men, more often and for longer periods of time, researchers claim.

Despite the popular belief that men are wimps when it comes to dealing with pain and the female experience of childbirth gives women the upper hand, scientists found that the opposite was true.

Several studies have now concluded that not only do women report more pain during their lives, they also experience it in more parts of the body, more often and for a longer duration compared to men.

Researchers from the University of Bath said there appeared to be a difference in how men and women thought about pain, and anxiety may affect them in different ways.

The different strategies that men and women have in coping with pain may also actually make their experience worse.

Dr Ed Keogh, a psychologist from the university's Pain Management Unit, said men may take a more problem-solving approach to pain, meaning that they think about what they can do to deal with the pain and get on with their lives.

Women, on the other hand, may be more emotional and focus on the pain and how it is making them feel, rather than thinking about how they can deal with it and get back to work, for example.

Much to learn

But scientists admit that there is still much more to learn about gender differences in coping with pain.

Dr Keogh said: "Yes, there are important differences between men and women, but that is only half the story.

"What we have to start thinking about is why are there these differences and what are the treatment implications?"

One study carried out by the university involved asking volunteers to place their arm in a bath of warm water before plunging it into a container of ice water.

The researchers measured the pain threshold - the point at which the participants first noticed pain - and pain tolerance - the point at which they could no longer stand the pain.

Women were found to have both a lower pain threshold and tolerance.

"Until fairly recently it was controversial to suggest that there were any differences between males and females in the perception and experience of pain, but that is no longer the case," Dr Keogh said.

"Research is telling us that women experience a greater number of pain episodes across their lifespan than men, in more bodily areas and with greater frequency.

"Unfortunately, all too often the differences between males and females are not considered in pain research or practice and instead are either ignored or statistically averaged."

Genetic differences

Dr Keogh said most explanations for the gender variation concentrated on biological mechanisms, such as genetic and hormonal differences.

But he said it was becoming increasingly clear that social and psychological factors were also important.

The researchers suggested that while women tended to focus on the emotional aspects of the pain they experienced, men tended to concentrate on the physical sensations.

"Our research has shown that whilst the sensory-focussed strategies used by men helped increase their pain threshold and tolerance of pain, it was unlikely to have any benefit for women.

"Women who concentrate on the emotional aspects of their pain may actually experience more pain as a result, possibly because the emotions associated with pain are negative," Dr Keogh said.

The university is also investigating chronic pain in children.

The researchers said that as many as one in 50 children and adolescents live with severely debilitating and recurrent pain, but there is little information on how best to treat them.

Professor Chris Eccleston, director of the Pain Management Unit, said: "Many people used to think that chronic pain was a uniquely adult problem, but recent studies have shown that a number of children are severely affected by pain.

"There can be a significant effect on the child's family and our studies have shown that many parents of children who suffer with chronic pain report higher than normal levels of anxiety, as well as martial and financial problems."

Find this story at http://www.dailymail.co.uk/pages/live/articles/health/womenfamily.html?in_article_id=354638&in_page_id=1799
©2005 Associated New Media