A royal pain

Much remains to be learned, including by doctors and medical students, about chronic pain. A Hebrew University symposium recently discussed why.

Shoulder pain (illustrative) (photo credit: INGIMAGE)
Shoulder pain (illustrative)
(photo credit: INGIMAGE)
Mounds of prescription and over-the-counter medications are sold and swallowed to relieve chronic pain, but it seems that placebos – pills or procedures that supposedly have no physiological effect – may sometimes be even more effective than “real” drugs.
The placebo effect is probably involved in a lot of complementary medicine techniques and can work even in animals like rodents through training called Pavlovian conditioning. For example, years ago there was a study in which rodents in pain were given a morphine injection every day for four days. Each time the rodents’ suffering was relieved. On the fifth day, saline (salty water) was injected instead of morphine. Remarkably, it also provided relief due to the animals’ conditioned expectation that the injection would reduce the pain.
When general anesthesia was invented to relieve acute surgical pain, England’s Queen Victoria gave birth to Prince Leopold under chloroform. Although her previous deliveries were painful and made her feel “wretched” – a royal pain, Prince Leopold came into the world painlessly. The Church “had long opposed anesthesia because the Bible said that childbirth should be painful.”
But for chronic pain, because few effective new analgesics have emerged from the pharmaceutical companies, the placebo effect is increasingly being researched as an important methodological tool for relieving pain. One can also teach people suffering pain how best to live with it, but it’s better to reduce the pain, even if that means using placebos.
“Pain in Jerusalem” was the name of a symposium on pain science and medicine held recently at the Hebrew University of Jerusalem’s Givat Ram campus that included guest experts from Turin Medical School in Italy and the University of Zurich in Switzerland.
The symposium was organized by HU’s Center for Research on Pain, an interdisciplinary “roof organization” of several scientific labs and medical clinics established in 1977. “Various universities host lectures and conferences on pain, but the HU Center is probably the most active in the country,” said Prof. Marshall Devor, a Toronto-born biologist who is HU’s Alpert Professor of Pain Research. He organized the event together with emeritus Prof. Michael Tal, a veteran dentist and pain expert at the HU-Hadassah Dental Faculty, and Dr. Alex Binshtok, a Ukrainian-born physiotherapist by training who earned a PhD in neuroscience at HU, went on to study and teach at Harvard University and then returned to Israel as a faculty member at the HU’s Faculty of Medicine where he recently earned tenure.
The symposium’s second sponsor was the recently established Jerusalem Brain Community, headed by Prof. Udi Zohary, that promotes a variety of activities for the neuroscience community in the capital. The JBC is an initiative of the HU’s Edmond and Lily Safra Center for Brain Sciences of which Zohary is a member.
Scientists and physicians have regarded placebos as being useful because the patient perceives an improvement in the painful condition, but far inferior to “real” analgesic drugs. Drugs are normally rated by how much better they are than placebos. But every time a drug is taken, the placebo effect is also engaged by virtue of the fact that the patient has personal expectations that the drug will work. The effect of the treatment itself adds to the placebo effect which is due only to the anticipation of pain relief. “But sometimes the placebo effect is even more powerful than the drug effect. We shouldn’t dismiss the effect of expectation as ‘only a placebo’. Placebo can be a very strong element. If we can better harness the power of placebos to relieve chronic pain it will be a very good thing,” Devor told The Jerusalem Post.
“I’M A biologist, not a medical doctor. Doctors in the field of neurology and anesthesiology are trained to use existing pain treatments to help patients, but we biologists try to discover new avenues to relieve pain,” he continued. Experts at the symposium showed charts showing that about 20% of Israelis and Europeans suffer from chronic pain conditions of one sort or another (backache, arthritis, migraine and others). The comparable number is 30% in the US and even higher in other places. Devor said he would “not take the differences in these figures too seriously. Different criteria are used in questionnaires in different countries. But chronic pain – which is usually defined as pain continuing for at least three months – is a major problem around the world that greatly affects the quality of life of millions of people.”
Devor earned his bachelor’s and doctoral degrees from Princeton University and the Massachusetts Institute of Technology and was a postdoctoral fellow with pain research pioneer Prof. P.D. Wall who worked at University College London and also at the HU.
As an undergraduate and doctoral student he studied appetites, the parts of the brain that are involved in feeding and drinking, response to pheromones and the sense of smell. For his scientific career he thought pain was good problem to study. He came on aliya with his wife in 1975, trained as a postdoc with Wall and joined the HU faculty as a research associate in 1977. He then rose to the rank of professor in 1988. He served as chairman of the department of cell and developmental biology three terms and also headed the HU Pain Center. He has contributed considerably to the understanding of the physiological basis of neuropathic pain and more recently to mechanisms involved in loss of consciousness and pain-free surgery.
“Unfortunately, most medical schools give very few class hours on pain except for pain specialists,” Devor said, even though pain is the most common reason that people seek out the help of their family doctor. Palliative medicine, a specialty aimed at relieving pain for the terminally ill, is usually provided by anesthetists. Neurologists treat headache but surprisingly, they often do not know much about neuropathic pain involving nerve injury.” With neuropathic pain, the nerve fibers themselves are damaged and dysfunctional, and damaged nerve fibers send abnormal signals to pain centers of the brain. “Many doctors have to deal with their patients’ pain even though most never learned much about what causes pain or how to treat it. We held our symposium to give more exposure to the subject,” he said.
“WOMEN SUFFER from many chronic pain conditions more than men – ironically even though there is a common belief that they have a higher pain threshold than men because they give birth again and again. “It is not clear why women suffer more. Maybe it’s hormones, but many chronic pains do not follow a monthly cycle, and fibromyalgia – a complicated syndrome with pain felt in the muscles and soft tissue – occurs mostly in older women where hormonal differences between women and men are not so big. There must be psychosocial and genetic influences as well.”
When male and female volunteers are asked to put a hand in ice water until they can’t stand it anymore, men tend to tolerate pain more. Maybe their thicker skin has an effect, but for us to really answer this question, we have to go into their heads. We can know if someone suffered an injury that causes pain, but the amount of pain often doesn’t correlate well with the level of injury,” explained Devor. “Backache is a common complaint, but if you show neurologists and orthopedists a lot of x-rays of the back, they usually can’t say who has a lot of pain and who doesn’t. Then there are times when people exaggerate, saying they are in a lot of pain but really aren’t. People with ongoing lawsuits against insurance companies or medical institutions, seeking compensation for pain, rarely respond well to pain treatments. But much more common are people living with terrible pain who in addition suffer the stigma of others who unfairly accuse them of exaggerating for personal gain. At present there is no objective way of measuring how much pain another person is feeling.”
Pain sufferers show all kinds of stress responses that make things worse, such as poor sleep, but these are quite general, continued Devor. For many painful conditions, headache for example, there is no skin rash you can see. Shingles, also called herpes zoster, shows up as a skin rash that is very painful. But in some people, when the rash goes away, the pain remains.”
Pain sufferers can make life difficult for their loved ones, their friends and even their employers by getting irritable and being absent from work.
“Invisible” pains like migraine and back pain are the easiest to exaggerate for unfair gain, like getting out of doing things. Wives may exaggerate pain so they can get their husbands to do the dishes, and husbands may do the same to get their wives to do something, and we know what headaches are sometimes used for as an excuse in family relations,” he said with a smile.
Still, pain does leave footprints. Functional MRI scans “can show signatures of pain, but this isn’t reliable enough to prove that someone is actually exaggerating his pain,” noted Devor.
When he learned many years ago that surgeons did operations on infants without anesthetics, he was shocked. “One reason given then was that babies don’t remember the pain even if they felt it. Doctors at the time also made the point that there was some risk in using general anesthetics on infants. But even if babies don’t recall the pain, they suffer, and the effects can show up later. Today there is much more awareness of the presence of pain in infants.”
Scientific understanding of physiology has advanced tremendously, the biologist continued. “We know much more about nerve injury and how it causes neuropathic pain. We even know a lot more about phantom- limb pain after an arm or leg is amputated, a classic mystery. Herpes zoster still causes a lot of pain. It’s a serious problem that has not yet been resolved. Much more effort needs to be invested in translating discoveries from basic science into the clinic.”
As for medications, the two mainstays remain aspirin and other non-steroidal anti-inflammatory drugs, and opiates like morphine. Opiates are becoming widely overused in some countries around the world, he said, especially in the US, but not so much in Israel. Medical cannabis is becoming more and more widely used in Israel thanks to legalization by the Health Ministry for specific chronic patients. This subject was not discussed at all at the symposium, but some researchers think that the powerful pain relief it can provides depends more on the placebo effect than actually reducing pain pharmacologically, he said.
“YOU HAVE to believe and expect that it helps. A placebo is not just a sugar pill; it involves ceremony and expectation,” said Devor. Prof. Fabrizio Benedetti of the University of Turin Medical School who delivered a public lecture on “Placebo and Nocebo,” described giving patients a pain reliever by injection. The patients felt better for two or three hours and then the pain returned. But when the injection was given surreptitiously via an intravenous line according to a computer’s schedule, “the same drug had no effect on pain.”
One might argue that giving patients placebos for pain and saying it will help them could be unethical. “If it’s true that a lot of pain relief is gained by giving a placebo with a lot of ceremony, is it really unethical to say this pill will help you?” Benedetti said in his lecture that if a doctor says he believes a placebo pill will reduce the patient’s pain, it would be ethical. But if he lies and says it’s a powerful pain-relieving drug, it is not ethical. There is a problem when a doctor undermines his own authority, telling untruths, the Italian researcher said. He described placebo experiments in which the brain creates an endogenous opiate – endorphins – that relieves pain without the placebo itself actually having any opiate drug effect.
Babies and young children also benefit from the placebo effect, Devor added. “When they fall down and it hurts, the mother gives them a kiss, and they calm down. It’s like having a doctor.”
There have been a number of well-known drugs prescribed for pain that actually had little pharmaceutical effect. It’s important to know the “number needed to treat” of a particular drug. Compared to a placebo, such a drug might have to be given to seven patients before it shows even a moderately better effect at relieving pain in one of them, Devor said. “And any of the seven could suffer side effects not caused by the placebo.”
Nocebo is the phenomenon in which an inert substance is given along with a mere suggestion that the substance may bring about negative effects in a patient or research participant. For some, being informed of a pill or procedure’s potential side effects is enough to bring on reallife symptoms. Like the placebo effect, said Devor, “nocebo is still poorly understood and thought to be produced by conditioning and a reaction to expectations.”
Benedetti operates a lab high up in the Alps where he studies altitude headache. “One time, he told participants in the ascent that they are likely to suffer from a high-altitude headache. Many of them developed the pain. Another group was told that there is such a thing as high-altitude headache, but not here, only on Mount Everest where they were not going. Very few of those developed a headache because they did not expect it.”
As another example of nocebo, Benedetti worked at his lab with a few dozen students. He told only one about high-altitude headaches and monitored all of them, knowing who was friends with whom, and who was in WhatsApp contact with others. The one who was explicitly told about the headaches was the first to get one, but about half of those who were his friends and even friends of friends got a headache in a wave after him, Devor said. “It was an epidemic of nocebo effects.” The Italian found that even Parkinson’s disease tremor can be reduced by placebo.
PROF. HANS Ulrich Zeilhofer of the University of Zurich spoke about benzodiazepine drugs that act through GABA receptors. A well know example is the sedative drug known as diazepam. Many people take it as a sleeping pill. He presented much evidence from lab animals that if the drug is injected into the spinal cord, it’s a very good pain reliever. The trouble is that it puts people to sleep when taken as a pill.
“He argued that diazepam acts on different types of GABA receptors, some causing sleepiness and some causing pain relief. If you could make a drug that specifically activates the pain-reducing GABA receptors in the spinal cord rather than sedative GABA receptors in the brain it should relieve pain without putting people asleep, even if taken in pill form,” Devor commented.
There have been many failures in the last decade by drug companies in developing effective painkillers, recalled Devor. Celebrex, a COX-2 inhibitor, was widely marketed and advertised, but its use was drastically reduced, at great cost to the manufacturer, due to cardiovascular and gastrointestinal side effects. As huge amounts of money are needed to put potential new drugs into clinical trials without being sure that they will be a success, many companies have dropped the development of potential pain relieving products completely. “Some substances work well in rodents but not in humans.”