The pain paradox

Some people have constant pain. But the reasons why are not always so obvious.

Posted by Synnøve Ressem

The rats are finished chewing on the soft tissue and cartilage, and now they’re starting in on the bone. Suddenly, they jump aside. A screwdriver takes over, drilling in with great force, turning slowly around. Drilling, drilling, and drilling ….

That’s how Merete Kulseth describes the pain that has tormented her day and night, and on every day of the year for years. She was born with her legs incorrectly positioned and has been through eleven operations in total. The operations have saved her from having to use a wheelchair and crutches. But the doctors cannot rid her of her pain.

Inside the brain: These are the kinds of images that come up on the computer screen when a subject is in an MRI. The picture shows the cortex, white matter and ventricles, or the brain cavity. The researchers add a “color map” of brain activity when volunteers are working on different tasks.

She is now a part of an effort to add another small piece to help explain the puzzle that is chronic pain.

Concentration a challenge

Researchers are looking for differences in the brain between people with chronic illnesses and those who are healthy.

The pain and control subjects undergo various tests, and Gemini meets Kulseth after she has just completed the first part of the test. This involved playing a kind of video game while sensors registered sweat (more formally, galvanic skin response, the same measurement used in a lie detector test), along with pulse and breathing rates. The rest of the experiment will be carried out using magnetic resonance imaging (MRI).

Kulseth is rigged up with special eyeglasses. While wearing them, she will watch a computer screen where the tasks she has to solve will be displayed. She will respond by pressing a button using either her right or left hand.

The next thing we see is her disappearing slowly into the MRI machine.

Human genetic material (DNA) is enormously large. While 99.9 per cent of our genetic code is shared in common with other humans, ‘only’ 0.1 percent is unique to each individual. But in this tiny percentage lie three million differences between unrelated individuals. Three million positions in our genetic material may have an impact on our experience of pain. Illustration: ©Image100 Ltd

Behind a glass wall in an adjacent room, two radiographers and the researcher, medical student Nicolas Elvemo, are at work. They are watching what is happening on several computer screens.

On one screen they see Kulseth inside the machine, and they can both hear and talk to her. Another display shows the tasks she must solve, which consist of simple arithmetic problems and recognition of numbers and symbols.

“The goal is for the subjects to concentrate, it doesn’t matter if they answer right or wrong. Although we explain this to them, it is easy for them to feel performance anxiety, which will also affect their concentration.

“Everyone’s experience is individual, but the experimental groups tackle the same challenges,” explains Elvemo.

Measures tiny changes
On the third screen we get pictures of the whole brain that are taken every three seconds. The pictures are generated by the MRI scanner, which measures tiny changes in the level of oxygenated versus de-oxygenated hemoglobin in red blood cells. Neuronal activity increases the local blood flow and blood volume and subsequently the amount of oxygenated hemoglobin increases, which the scan detects. The changes are so small that they have to be collected in a large series, which are stored on the computer.

“How are things in there?” asks Elvemo as the experiment progresses. “Are you okay?”

“A little cramped,” comes the answer. “But it’s going well. The worst is that I itch but I am not going to scratch myself. And it is a bit cold.”

“You can get an extra blanket, hang on a little more, we are almost finished,” says the aspiring doctor in a calming way.

Once out of the machine, Kulseth is feeling pretty battered and asks that we talk another day.

Pain receptors that affect the pain experience may have special abilities in people with a certain type of genes. A Canadian researcher has found that people with red hair and light skin can tolerate more pain than others. But it remains to find out why it is so. Photo: Luth

Poorly studied
This particular experiment was conducted in autumn 2008. Now the material is being analyzed, interpreted and worked with. The study is small, but interesting.

Chronic pain is actually a problem area that is relatively poorly studied. This is true despite the fact that every third patient who seeks medical attention complains of long-term pain. Thirty per cent of Norwegians who visit their primary health care physician come because of chronic pain.

What is pain?
“Pain is an unpleasant sensory and emotional experience associated with actual injury or tissue damage or is perceived as if such injury has occurred.” This is the clinical definition of pain from the International Association for the Study of Pain (IASP).

Simply stated, the definition means that pain is an unpleasant experience that occurs in connection with an illness or injury, but that it can also occur without apparent reason. The brain picks up pain signals through the spinal cord and sorts, processes, and interprets them.

In other words, we can say that the experience of pain is created in the head.

Chicken and egg
Brain imaging methods make it possible to find out more and more about what is going on in the brain. Asta Håberg is a specialist in interpreting brain images and is the principal investigator for the project that Kulseth is involved in. She explains that many different areas of the brain are activated when it receives pain signals from the body.

“A portion of the brain, called the periaquaductal gray region, is central in the processing of pain. This is difficult to investigate because it is very small and is positioned so that it is not easy to image given the limitations of the MRI,” she explains.

She says that brain images have identified structural changes in the brain in chronic pain patients. Detailed pictures show differences in the thickness of certain areas in the cerebral cortex. The pictures show that the pattern of loss of cerebral cortex varies in relation to pain groups.

“For example, we have seen that the brains of people with fibromyalgia may look different than those with back pain,” Håberg says.

Researchers can thus see that changes do occur. But they have not yet identified the importance of and the reasons for the changes: Are there changes in the brain that create pain, or is it pain that leads to change?

It’s another variation on the classic chicken-and-egg question.

Concentration a problem
Next time I meet Kulseth, she explains that she was completely exhausted and mostly slept for two days after her efforts with the concentration study. It’s a price she will pay gladly, as she hopes it will help with new knowledge that can be used for something:

“I have lived so long with pain now that I don’t know any other way. It takes all my strength and affects daily life for the whole family,” she says.

“Concentration problems are among the most difficult to tackle. They prevent me from holding a job and have also meant that I had to give up my studies. I get tired quickly and can only read a few pages before I’m completely knocked out. Here I think the people who work with rehabilitation and as guidance counselors should be more aware of this problem,” she observes.

Kulseth says that professionals who are trying to help those with chronic pain should not recommend a lengthy study program unless they can ensure close follow-up of the patient. The risk is great that someone with chronic pain will have to quit his or her studies. “Then the only thing that you have left is student debt,” concludes Kulseth, who has had bitter experience in this area.

Difficult to classify
Most of the many who have long-lasting pain are able to function in daily life.

Nevertheless, chronic pain is the most common cause of sick leave and payments from disability insurance. Very often there are no exact physical or mental reasons for the pain, but a nebulous mix of both physical and mental factors. These kinds of conditions are commonly called complex disorders.

A little disrespectfully, we can say that the term refers to disease descriptions that medical science has not fully worked out.

Among those who know a lot about this particular diagnosis is the physician and professor Petter Borchgrevink. He is head of the National Centre for Complex Disorders (NKLS) and Pain Centre in Trondheim. Borchgrevink says that the largest patient group has muscle and skeletal problems.

The problem mostly affects women, and mostly those who work in low wage occupations. For example, fibromyalgia is one of the diagnoses that are included under the umbrella of a complex disorder.

…and difficult to treat
“The symptoms are often vague and therefore difficult to treat. We find that the most effective is a combination of mental and physical training. But it is difficult to completely eliminate the pain,” he says. Addictive morphine-like drugs often make matters worse for this group of patients, the professor explains.

He added that the dependency can become so problematic that the patient must be admitted to undergo withdrawal. This is because the body gets so used to the drug that the dose has to be constantly increased to have an effect. Patients can be given large doses of medication and still feel the pain. There are examples where the pain remains the same and does not get worse even when the patient stops taking the painkiller.

Much misuse
With this in mind, NKSL and the Pain and Palliation (pain relief) research team try to closely monitor new drugs when they are launched. One example is a morphine-like patch that was released on the Norwegian market in 2005.

The patch works much like a nicotine patch, with the clear difference that nicotine patches are used to relieve nicotine cravings, while morphine patches are used to relieve pain. The patch releases its active ingredient in regular, small doses over a long period.

This method of medication would be perfect for pain patients who need low and regular doses of pain medicine. It should mean that the medication could be more controlled, drug consumption could be reduced, and the risk of dependence could be reduced.

But a study conducted in cooperation with the Prescription Database of the Norwegian Institute of Public Health revealed much misuse. That suggests the effect was the exact opposite of what was intended.

“The reason is a combination of poor information and lack of knowledge among those who prescribe the drug,” said Borchgrevink.

Looking for connections
The most important study of chronic pain that is currently underway in Norway is related to data collection from the Nord-Trøndelag Health Study, or HUNT.

Nearly 5,000 people will be checked every three months over the course of four years. The purpose is to study the factors that may influence our experience of pain. Pain is considered chronic when it has lasted more than six months. Some of the subjects have chronic illnesses to begin with, while others will likely develop these kinds of illnesses during the four-year period.

Among other things, the scientists will look at the relationship between high levels of pain and ways of thinking. For example, will the pain be worse if the patient worries about the absolute worst?

It is easy to imagine that pain can provoke anxiety: You feel a pain that has not been there before. You go to the doctor, are given all kinds of tests, but they do not show that anything is wrong. The pain persists, and the thoughts begin to churn: This must be something terrible. Maybe a tumor? A tumor that is about to eat me up – I definitely am going to die, and soon!

Solution to the pain puzzle?
Another part of the project is focused on the relationship between pain and physical activity. The project involves expertise in physical medicine and training theory, genetics, and pharmacology. In this way, the project is a good example of how modern clinical research based on complex relationships benefits from an interdisciplinary research group to help solve the problem.

“In the short term, the goal is to become better at prevention and treatment. In the long term, the hope is that we can solve the great pain puzzle: Why and how does pain occur with no apparent reason? Why haven’t we found the cause of prolonged pain that is not caused by damage to body tissue?” asks Borchgrevink.

Cancer pain a challenge
Chronic pain sufferers need treatment that helps them live an active life with minimal problems. At the opposite end of the spectrum are those with advanced cancer, who need help to enjoy the best possible quality of life in the time they have left. This is an area that gets relatively modest attention, compared with research efforts to find a cure for cancer or to prolong life.

NTNU’s Pain and Palliation research group is considered to be among the world leaders in the area of cancer pain. The group includes specialists in anesthesia, cancer, genetics, general medicine, and psychiatry, and is led by Professor Stein Kaasa.

Kaasa says that the group’s close working relationship with St. Olavs Hospital is an important reason for the group’s far-reaching results. The studies include genetic research, methods of measurement of pain, testing of new drugs, and the effect of different treatments.

Cancer pain can be treated with radiation and/or morphine preparations. Radiation, ­however, can be a big strain for patients. Thus, it should come as no surprise that there was a great deal of attention paid to the researchers’ findings that the number of radiation treatments for pain can be reduced radically and still provide good effect. The research group found that a single radiation treatment provides as good an effect as ten treatments. The result was met with skepticism when it was published in 2006. A recently completed follow-up study confirms, however, that the scientists are right.

How painful is painful?
Kaasa is head of the EU project called the European Palliative Care Research Centre (EPCRC), which is being coordinated from Trondheim and involves prominent researchers from six countries.

The project will include trying to come to agreement on an international standard for pain measurement: How intensely is the pain felt and how painful is it?

The challenge is that the experience of pain is individual. Everyone’s pain threshold is different – what is a little difficult for one person may be perceived as intolerable for another. If the treatment is to be as effective as possible, doctors and their patients need reliable measurement methods and tools.

Today, pain is measured using a body map and a pain scale from zero to ten. The body map is in the form of drawings of the body from the front and back. Patients select where on their body it hurts, and check a number on the scale to reflect how strongly they feel pain.

“Now we are working to digitize the body map and design an electronic tool for pain measurement. Patients will be equipped with a touch-screen computer and will be able to mark their pain right on the screen. First, this approach will make our measurements more accurate and easier to undertake and follow up on. Another advantage will be that the patient will not need to come to the hospital or doctor’s office, but can undertake the measurement from home,” explains Kaasa.

The development is in cooperation with Verdande Technology in Trondheim. The company has its origins in NTNU’s computer and petroleum disciplines.

Genetic variations
A great deal of pain research addresses the regulation of medication. Some patients get more benefit from drugs than other patients, and researchers are in pursuit of the reason behind this fact. Currently, they know that the receptors that affect the experience of pain may have special characteristics in people with certain genes.

For example, a Canadian research team found that people with red hair and light skin can withstand more pain than others. But it remains to determine why this is so.

Genetic research is likely to contribute to many breakthroughs, including in the treatment of pain. The hope is that researchers will be able to find the most likely genes and genetic variations that affect how well pain treatment works in the individual patient. Hopefully, the findings will contribute to new insights into the causes and treatment of pain.

Three million differences
Among those participating in the great gene hunt is Frank Skorpen at NTNU’s Department of Laboratory Medicine, Children’s and Women’s Health. He assumes that even if people are ever so close, the experience of pain and pain intensity may still be different. The reason for this is that there are biological processes and genetic variations that we do not know much about yet.

“The volume of human genetic material, DNA, is huge. Humans share 99.9 percent of our genetic material in common, while ‘only’ 0.1 per cent is distinctive for each individual. ‘Only’ has to be in quotes, because between unrelated individuals we are actually talking about three million differences. There are three million variations in human genetic material, each of which may have an impact,” explains Skorpen.

Thus, genetic variation means that we can have different pain thresholds, that we react differently to medication, and that we have different risks of developing diseases. Pain geneticists are working to understand these differences and determine which genes are involved. Over the longer term, the goal is for the research to help tailor treatment and medication to individual needs.

Same pain, different medicine
“Among the things that we are concerned about is pain in cancer patients who are in the final phase of life. Some need more morphine than others for relief from what initially was thought to be the same degree of pain. Although pain management is generally good, between 20 and 30 per cent of all pain patients are in too much pain. Often it is not possible to increase the morphine dose further because of serious side effects or because it does not give the expected effect,” says Skorpen.

Researchers have already discovered genetic variations in the receptor that morphine binds to and acts through in the central nervous system.

“So far, these results cannot be used in the treatment of individuals. But the differences are quite apparent when we compare groups of patients. In the future, more such genetic ‘markers’ will be found, hopefully in many genes that interact. Then we hope the results to a greater extent can be used to give each patient better and preferably optimal pain management,” says Skorpen.

No magic bullet
Pain genetics is a relatively new and extremely complex field. NTNU is home to one of Norway’s few research groups in this area.

“If we are to find more genetic factors, we have to have better research material. The sample has to be bigger than the patient base here in Norway. That means we are totally dependent on international cooperation,” Skorpen says.

The research group has taken the initiative to join the European Pharmacogenetic Opioid Study (EPOS), a study that provides access to blood samples and clinical data from a large number of cancer patients. Trondheim scientists are also cooperating with other genetic research projects. In addition to pain, they see the importance of genetic factors in the development of pathological emaciation (cachexia) and depression, two very severe symptoms in cancer patients.

“Understanding genetic profiles will not solve every problem. But genetics will be an important tool,” says Skorpen.

Just my imagination?
That you feel pain when you cut yourself or when you break your leg is understandable. But what is far worse is when the feeling of pain occurs because the brain believes the body is injured. Psychiatrist and general practitioner Egil Fors has the following story from real life:

A woman fell from a ladder and landed with her foot on a large nail. The nail went right through her sole, and the woman was taken to hospital with severe pain. There, it turned out that the nail had passed between two toes and that her foot was actually unharmed. Still, the woman felt the same pain that would have occurred if the nail had actually injured her foot.

“The shoe is on display in a medical museum in England. A picture of it was exhibited during the World Conference on Pain in Sydney in 2005,” says Fors.

There are other stories of people who are seriously injured without feeling pain. Then there are people who feel pain in limbs they have lost – a phenomenon called phantom pain. And people who are missing a limb when they are born can feel pain in the body part they have never had.

All of these are examples of how the processing and awareness of pain is in the mind.

All pain is real pain
“It is therefore important to emphasize that all pain is real, whether we understand the cause or not,” says Fors. He believes that general practitioners have increased their overall knowledge and understanding of pain. But he would not rule out the possibility that some patients are still not taken seriously enough and are shown the door with a prescription for “something soothing.”

Fors’s experience as a general practitioner and his work at the pain clinic at NTNU / St. Olavs Hospital has enabled him to meet a full range of chronic pain patients. He confirms that women are highly overrepresented in this patient group. The causes can be many: Greater honesty in reporting pain may be one of them. Genetics may be another. Or perhaps women more often express problems through pain, while men also resort to substance abuse or risky behavior?

Thought patterns and behavior
Fors’s daytime job is at the Pain Centre. The staff here works a great deal with pain health and symptom control, but also on coping with pain through mental and physical training. Fors says that a common treatment is cognitive therapy, which focuses on changing thought patterns and behavior.

“For example, we know that anxiety activates and intensifies pain. Then it is useful to be aware of both the cause and effects of fear. A spinal patient may be afraid to move, for fear of ruining something or making the pain worse. The anxiety causes the muscles to tighten up, tensions to rise, and the result is that the pain gets worse,” Fors says.

“These patients can benefit from relaxation techniques. Moreover, they have to be reassured that movement is not dangerous, but on the contrary will ease symptoms. In circumstances like this, you have to do more than talk. You have to go in actively and work with practices and way of thinking,” he adds.

Fors says that anxiety about one’s health and inactivity are common among patients with chronic illnesses. The result is that they have an impaired ability to function and a generally poorer quality of life.

Body and soul
The diagnosis “just psychological” does not exist in modern medical science. Prospective doctors learn early on that pain and anxiety are a result of both biological and mental processes in the body and brain. Moreover, the experience of pain and fear are basic preconditions for self-preservation.

But prejudice against mental ailments is tenacious. The first person to distinguish between body and soul was the thinker Descartes, who lived in France between 1596 and 1650. It is he who can be assigned the blame for the fact that medical science maintained a distinction between mental and somatic diseases right up until modern times.

In many ways, psychiatry is still a stepchild in the Norwegian health care system. It is hardly a coincidence that the last part of the new St. Olavs Hospital in Trondheim to be built – and at an as-yet unspecified future date – will be the psychiatry center.

Suspicious
We return to Merete Kulseth and her life with pain. Her account of the torment that never stops has made an impression. But it’s almost worse to hear her talk about the prejudice and thoughtlessness that she encounters, and that makes her burden even heavier:

“My handicap is not visible in all situations. I want to do as much as possible and be independent. I live a seemingly normal life with my husband, children, and dogs, and we have a comfortable income. For many, it doesn’t make sense that I should get disability payments. They would probably have preferred that I was bedridden. I have also been met with ignorance when I have visited the doctor. Various forms of suspicions, in addition to severe concentration problems, make me feel both infinitely stupid and alone,” she says.

After many rounds of consultations and hospital admissions, Kulseth is now receiving professional treatment and follow-up at the Pain Centre at St. Olavs Hospital.

Victims of our own culture?
Science tells us that the experience of pain is individual and has a biological explanation. But the ability to cope with pain, and the way we manage it, is also socially and culturally determined. This may certainly be part of the reason why Norway is at the top of the list in Europe when it comes to pain. This dubious distinction means that we have the highest number of reported pain patients relative to the population.

This undoubtedly reflects the fact that treatment options have improved. But it also raises questions about how the good life may have made us unable to tolerate any pain at all. Is it now the norm that we fully expect to live a life without pain – in fact, demand a life without pain? Perhaps we have become a bunch of sissies without the least bit of backbone?

For fun you can do the following experiment: Stand up and concentrate to see if you feel pain anywhere. You will probably detect pain in places you never even knew you had. In this case, it may in fact be helpful not to know where it hurts, after all….

In her book An introduction to medical anthropology, Professor Benedicte Ingstad of the University of Oslo has written, “Medicalization is one of our culture’s ways of relating to what is perceived as problematic behavior. But providing the behavior a diagnosis is also a way to allow the pharmaceutical companies the opportunity to make a profit.”

In other cultures pain may be an important part of different rituals, such as during the transition to adulthood. Some experience self-inflicted pain as a means to achieve greater contact with higher powers. And in connection with both sports and sexuality, pain can be perceived as both stimulating and pleasurable.

It certainly sets a mind thinking.

Synnøve Ressem works as a science journalist at GEMINI magazine, and has been a journalist for 23 years. She is employed by the Norwegian University of Science and Technology in Trondheim.

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