The trouble with treating pain

Image: Michael Woloschinow

I hurt, you hurt, we all hurt. Pain is a human constant. Today it's the minor burn suffered while searing last night's pork chops. Tomorrow it's a twinge in the lower back. Or the faint pulse of an incipient headache, the sting of a hangnail, or the constant tormenting aftermath of a neck injury that drains life of all joy. Sore shoulders say, Too much yard work yesterday. A limp for the first 10 steps out of bed says, You are 60 years old. A lightning bolt down your left arm says, You need to go to the emergency room—now. Buddhists believe that 2,500 years ago Gautama Buddha taught that life is suffering, to which someone with arthritis or a surgical wound or 10 years in the National Football League would say, No kidding.

In its 2011 report Relieving Pain in America, the Institute of Medicine of the National Academy of Sciences estimated that 100 million American adults suffer chronic pain, and that suffering costs the U.S. economy between $560 million and $635 million in medical expenses and lost productivity every year. In 2008, the World Health Organization surveyed 10 developed countries and estimated that 37 percent of adults in those countries suffer chronic pain.

None of those numbers includes people suffering from acute pain, defined as pain that disappears when the underlying cause has been treated or healed. Nor do the figures include children. And public health researchers believe the problem is getting worse. A report issued in 2009 by the United Kingdom Department of Health stated, "Chronic pain is two to three times more common now than it was 40 years ago." In the United States, the massive baby boomer generation is aging into its pain years, having lived long enough to develop chronic conditions that make pain a daily fact of life. Well-trained and well-equipped emergency medicine specialists save thousands of people from catastrophic injuries that not long ago would have been fatal. Many of those saved live on with painful daily reminders of their injuries.

Allan Belzberg, a neurosurgeon and an associate professor in the School of Medicine, says, "I hate pain. I think pain is just a terrible thing. I feel ashamed and horrific when I can't help someone who's in pain."

The contemporary science of pain and its alleviation is a sophisticated, multidisciplinary endeavor. At Johns Hopkins, neurologists, psychologists, psychiatrists, surgeons, geneticists, anesthesiologists, electrophysiologists, nursing researchers, and molecular biologists all work on pain. They are figuring out its mechanisms neuron by neuron, organ by organ, patient by patient. But there remains much about pain that mystifies scientists. This makes progress on treating pain, especially chronic pain, agonizingly slow. "Pain biology is really taking off," says James Campbell, a Johns Hopkins professor emeritus of neurosurgery. "But pain therapeutics is limping along. There are too many people walking around who would say their pain level is six, seven, or eight on a zero-to-10 scale. If we can put a man on the moon, why should anyone have to walk around with a pain level of eight?"

That medicine struggles to alleviate pain is testament to pain's complexity. "When I was in medical school, I remember people saying if you understood the visual system, then you understood most of neurology because the visual system has so many complexities to it and crosses over so many parts of the nervous system," Belzberg says. "I would say if you understand the whole pain system, you understand an awful lot of human physiology."

Jab your finger with a pin. The body's first reaction comes when the point of the pin stimulates a nerve fiber in your fingertip. The fiber is part of a pain sensor known as a nociceptor. The activated nociceptor shoots an electrical impulse along the length of your arm to a cluster of cells in the spinal cord called the dorsal horn. There the nerve impulse gets processed into the spinal cord. Neurons in the spinal cord send the signal up to the thalamus, deep in the core of the brain. Finally, the thalamus relays the information that your finger has been pricked to the somatosensory cortex (which senses it), the frontal cortex (which thinks about it), and the limbic system (which reacts to it emotionally). Ouch.

In textbooks and on medical websites, this series of steps is oft represented by an infographic that portrays the nervous system as a sort of electrical circuit. Viewed this way, pain seems simple and straightforward. But the neat diagram doesn't even hint at the baffling complexity of pain, says Jennifer Haythornthwaite, a professor of psychiatry and behavioral sciences in the School of Medicine. It's not that the step-by-step sensory process depicted by the graphic doesn't take place. It does. But so much more is going on. For example, make the wound a bit more severe—say, a cut that requires a few stitches. The sliced tissue hurts at the point of the injury. That makes sense—the knife that slipped while you were cutting carrots damaged nerves in your finger. But the next day, the pain has expanded to an area around the cut, which is inflamed. That tissue was not injured, yet it hurts. Why? Make the injury worse again—now say the finger's been broken in a softball game. The fracture hurts because tissues and nerves around the damaged bone have suffered trauma. Eight weeks later, everything regarding the bone has mended, but pain persists. If the bone and nerves have healed, why do you still hurt?

The complexities do not end there. If you are African-American, you will feel pain more than if you are a non-Hispanic Caucasian. This is not a subjective matter; laboratory research has documented that pain sensitivity is generally higher in blacks. In the same way, women generally are more pain sensitive than men. In demonstrative cultures, people respond to pain with more emotional distress than people in stoic cultures. And that circuit diagram of pain does nothing to represent what happens in the brain, where physical perception becomes pain and often develops into the psychological phenomenon of suffering.

"You can give 10 people in the lab the same stimulus and get 10 different responses and see 10 different brain images," says Haythornthwaite. "That hurts; go get it fixed' is such a complicated idea, it's amazing that sometimes it work."

Johns Hopkins is an important nexus of pain research, much of it done at the Blaustein Pain Treatment Center. The science ranges from study of the very small (neurons, genes, molecules) to the larger (the psychology of pain, comorbidity with conditions such as depression) to the much larger (how cultural factors change pain perception, how doctors are educated about pain, the importance of compassion). A recent addition to Hopkins is the Neurosurgery Pain Research Institute, housed in the School of Medicine and established in 2012 by an anonymous donor intent on better diagnosis and treatment of pain in patients seen by neurosurgeons.

Michael Caterina directs the institute. As a neurobiologist, he works on tiny stuff that could have huge implications, such as looking for molecules that are expressed only in peripheral pain-sensing neurons and nowhere else. Find those molecules and figure out how to block their activity, and it might become possible to block pain. For example, he studies a protein named TRPV1 that is expressed almost exclusively in nociceptors. TRPV1 can be activated by stimuli such as heat, acid, or chemicals like capsaicin, the main spicy ingredient in chili peppers. When activated, this protein acts like a small battery that electrically charges the nociceptor and triggers it to fire. "Pain involves a lot of learning on the part of the nervous system," Caterina says. "A lot of changes happen when you injure a nerve or injure the tissue that the nerve innervates. There are changes in the neuron whose job it is to detect painful stimuli, and in the uninjured neurons running right next to it, and in the neurons in the spinal cord that the first neuron is talking to, and in the neurons in the brain that the spinal neurons are talking to." If the pain stimuli are pronounced and persistent, that experience seems to change the strength of the impulses flowing through the nervous system, like an amplifier, and the change lasts for a long time. If a period of sustained pain can change how your spinal cord functions, an effective therapy will have to do a lot more than just dampen the hurt of the original injury.

Xinzhong Dong, a neuroscientist in the School of Medicine who collaborates with the Neurosurgery Pain Research Institute, has focused his research on the dorsal root ganglia, the clusters of nerve cells along the spine that are the first neurons to detect pain signals from nerves in the skin, muscles, or organs and send those impulses into the spinal cord. Much of his work has been on developing tools to facilitate imaging the activity in DRG neurons. Researchers typically have been able to monitor neurons only by application of electrodes to individual nerve cells, which limits them to listening to neurons one by one. Now they can image a portion of the DRG to look at how an entire cluster of neurons fires and how their behavior might change after injury or periods of chronic pain.

Dong notes that researchers have found that after an injury or inflammation prompts neurons to begin signaling pain, adjacent neurons begin firing in sync with them. Dong suspects that a neuron transmitting a pain impulse "hijacks" adjacent nerve cells, turning them into pain-sensing neurons, too. He's taking a close look at the channel between nerve cells called a gap junction. Dong thinks it's possible that when a neuron fires a pain impulse, chemicals pass through these channels to activate the neighboring neurons and co-opt their function. This could be one of the mechanisms by which pain signals become amplified.

As pain scientists develop an ever more granular understanding of neurons, synapses, and DRGs, they get closer to explaining the baffling inconsistency and seeming illogic of pain as a physiological phenomenon. For example, Belzberg, who is clinical director of the Neurosurgery Pain Research Institute, studies schwannomatosis, a disorder in which multiple tumors called schwannomas grow on or inside nerves. It sounds ghastly, but some people walk around with dozens of these tumors and feel nothing at all. In other people, the tumors cause excruciating pain. Belzberg does not know why only some of his patients with schwannomatosis suffer.

The word "suffer" broadens the discussion to what the mind makes of the nervous system's pain impulses. "Pain is not just a biological experience," says Haythornthwaite. "It is a psychological experience as well as a sociocultural experience." Steven Cohen, a physician in the Blaustein Pain Treatment Center, says, "There are people with normal MRIs of their backs or heads or abdomens, but they still have back pain or headaches or abdominal pain. And there are people who have terrible MRIs and no pain."

Haythornthwaite works on pain-related catastrophizing—a particular cognitive and emotional response to pain. Some people hurt and stoically carry on, ignoring the pain as best they can. In catastrophizers, pain overwhelms them. The condition correlates with other psychological conditions like neuroticism and depression. Children of catastrophizers seem more prone to the condition, perhaps because of a genetic factor, or an epigenetic factor, or learned behavior.

When someone in pain shows up in an emergency room, how physicians and nurses respond to them affects not only their psychological state but their physical sensitivity. People who suffer from sickle cell anemia often report encounters with hospital staff who are skeptical or dismissive of their pain, which can be severe. "Sickle cell patients who report discrimination experience more clinical pain and also are more sensitive in the laboratory," Haythornthwaite says. "People come to pain with a history of experiences that mold and shape their perception of pain at that moment."

Inner-city hospitals like Johns Hopkins see a lot of patients with substance abuse problems in their emergency rooms, and here too the response of clinical staff can exacerbate pain. James Campbell, who helped start the Blaustein Pain Treatment Center at Hopkins, says it is hard to distinguish whether a patient has been abusing drugs and wishes to score pain meds or is truly in pain. "We still don't have a handle on that," Campbell says. "So much of what we do for a patient depends on believing the patient. If you don't believe the patient, it becomes a really, really frustrating encounter. Imagine it from the patient's perspective. You have pain, and your doctor doesn't believe you. What a double whammy that is." Furthermore, an addict has built up a tolerance to opioids, Campbell says, "so you have to give them double, triple, quadruple the normal dose. It's very scary to give a patient triple the normal dose of morphine. This is a real challenge for the medical field. On the one hand, we want to provide humane care, and on the other hand we want to avoid addiction. What it underscores is the enormous need to find alternatives to opioids, which unfortunately still remain the most effective therapy for severe pain."

Michael Clark, the director of pain treatment programs at Johns Hopkins Medicine, observes, "Many emergency departments are now adopting policies that limit opioid prescriptions to all or particular subgroups of patients, like those with low back pain. They are attempting to limit abuse, diversion, and overdose-related deaths." He adds, "We need better bridge services for patients in outpatient care who go to the ED with an acute problem or seeking additional medication. This would improve communication with all prescribers and coordination of chronic care. All states need a prescription monitoring program that is nationally linked so that patients' use can be tracked carefully and accurately."

The sociocultural and emotional component of pain may be one part of the frustrating failure of so many therapeutics that seem to work in the lab on animals, then flop in clinical trials. Researchers can measure the physical response of a mouse to a pharmaceutical compound. Touch the mouse's paw with a filament to see if it retracts the paw because it's painfully sensitive; administer the pain med and touch the paw again, measuring the animal's response after medication. This tells the scientist if a drug has changed the physical response. But the mouse cannot tell the scientist how it feels. It can't describe its mood, can't report that it slept badly the night before, can't express symptoms of depression—aspects of suffering that accompany chronic pain. So a drug gains approval for human clinical trials based on its apparent therapeutic effect on the nociception of pain in animal models. But in some cases, the drug might not have made the animal feel better, it may have just produced a positive change in the outcome according to the research protocol. So sometimes the drug gets moved on to a disappointing clinical trial because a mouse could not tell a scientist, "I don't care what your findings say about how fast I pull my paw away—this drug did not alleviate my suffering."

For this reason, pain researchers at Johns Hopkins and elsewhere have begun to add to their experimental repertoire more sophisticated methods that allow the animal to indicate to the investigator, based on its actions, whether a particular intervention makes it less uncomfortable. Gayle Page, director of the Office of Nursing Research at the School of Nursing, conducts pain research and has been working to refine the methodology of pain investigators who work with animal models. She notes that patients with neuropathic pain hurt all the time, even when lying perfectly still. This means their normal behavior is compromised. But most animal trials rely on a researcher stimulating the animal to exhibit behaviors believed to be evidence of pain—touch the paw and see if the animal retracts it. There are not yet effective lab tests for detecting the experience of constant discomfort, so the effectiveness of drugs for that can't be measured until they go into human clinical trials.

Too many animal trials are blunt instruments for something as complex and nuanced as pain, Page believes. She says it's common for the applied pain stimulus to be too strong to identify subtle differences in physiology that may make one animal more pain sensitive than another. "If you use a hammer, all the animals are sensitive," she says. Page helped develop a technique that allows for subtly graduated applications of a common inflammatory agent, to more finely gauge pain response in animal models. This helped her identify strains of lab rats that seem more susceptible to pain because of the interactions of endocrine glands in what is known as the HPA axis. This, in turn, could help identify people whose systems have a lower pain threshold. Page also found greater sensitivity in female animals, which correlates with greater incidence of chronic pain syndromes in women.

"Different drugs work in different people," James Campbell observes. "What one sees over and over again is that a particular drug therapy works great in one person but fails miserably in another. Drug trials typically measure the average response and miss out on individual responses. As a result, some drugs fail to gain FDA approval even though they may be safe and effective in certain people. What is needed are ways to predict what the best therapy is for a particular individual, rather than simply depending on an empiric trial of a drug."

Campbell tells a story: "One Sunday morning, as I was beginning to get ready to give an address at a national meeting, the phrase 'pain, the fifth vital sign' struck me." In a hospital, staff evaluate four vital signs to monitor a patient's condition: breathing, pulse, heart rate, and temperature. After that bit of Sunday morning inspiration, Campbell started a national campaign to make the presence and degree of pain a fifth component in the routine assessment of a patient's condition; he says the practice has since been widely adopted across the medical landscape. As he stated in his 1996 presidential address to the American Pain Society, "Vital signs are taken seriously. If pain were assessed with the same zeal as other vital signs are, it would have a much better chance of being treated properly. We need to train doctors and nurses to treat pain as a vital sign."

In 2013, Campbell left Johns Hopkins to found Centrexion, a Baltimore-based biotech company that is trying to develop new pain therapeutics. He says, "Some of my most moving moments as a doctor involved helping my patients with particularly difficult pain problems. That's a real joy. On the other hand, there were the many situations where as a clinician you'd do an operation for pain and it would fail to help the patient's symptoms, or the patient might even be worse. Then you're confronted with someone who says, 'Listen, I'm suffering. What are you going to do for me?' And you really don't know what to do."

There is an arsenal of pain medications now, some of them effective for short-term treatment of acute pain. Long-term use for chronic pain is more complicated because the body builds tolerance to drugs like morphine and oxycodone and develops physical dependency. Michael Clark complains that there is an array of alternatives such as tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, and anticonvulsants that providers too often ignore. Physicians need to be better educated about pain therapeutics, he says. "People would benefit from the ABCs, the basics. 'Here are the drugs, here's how you prescribe.' Five hours of that would translate into a lot more patients treated well."

Beth Murinson, an associate professor in the School of Medicine, has done significant work on better education of medical students in pain management. She says, "This is a big topic for us. We have built a much more robust program in pain for Hopkins medical students. Beginning 10 years ago, we assembled a group of Hopkins faculty, including Jim Campbell, Jennifer Haythornthwaite, Myron Yaster, and others to address the question: What should a Hopkins medical student know about pain by the time of graduation? We developed 255 learning objectives. We used these as the foundation for a survey of North American medical schools, and results of this work were included in Relieving Pain in America. We found that most medical schools, over four years of instruction, are devoting less than 10 hours to pain. This is a huge deficit in light of the observation that over 100 million Americans suffer with pain, and the additional observation that about half of medical encounters involve patients with pain."

Sometimes the most effective treatment regimen involves things patients do not want to do. "No matter what, the overall long-term success rate for injections, for operations, for medications, tends to be low," says Steven Cohen, a physician in the Blaustein center. "The things that we know work—if you're obese, losing weight; if you're sedentary, exercise—nobody wants to hear. Nobody wants to come into the pain clinic and hear, 'Lose weight and exercise more.' People want a pill. A lot of them want narcotics."

Amid all the sophisticated science and discussion of pain's remarkable complexity, it is easy to overlook a far more basic form of therapy. Belzberg points to studies that demonstrate the remarkable effect of someone simply asking the patient how he or she feels. "Nurses tell us all the time that if the doctor goes in and holds the patient's hand and asks them how they are, the nurse will have fewer complaints from the patient," he says. "No question. Nurses have been telling us this for years." It doesn't have to be a doctor doing this, Belzberg says. Patients report more satisfaction with their pain management when anybody asks how they're doing, even a member of the housekeeping staff.

"In talking to patients and trying to get a handle on this," Belzberg says, "one thing that becomes very clear is that for somebody who is in pain, they want to know that you are listening to them, that you're willing to help. You're willing to listen and try to understand what it is that they are suffering."

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