The Pain Chronicles (31 page)

PAIN PERCEPTION AND PAIN MODULATION

Most people still think of pain the way Descartes did—as rising from the body to the brain. Perhaps the most important revision of the Cartesian model in the contemporary understanding of pain is that pain pathways are
bidirectional
: ascending to
and
descending from the brain.

The network of pain areas in the brain includes two different pain systems—one of pain perception and one of pain modulation, which involve both distinct and overlapping brain structures. The pain-modulatory system interacts constantly with the pain-perception system and can inhibit its activity. Much chronic pain is thought to involve either an overactive pain-perception circuit or an underactive pain-modulation circuit.

The brain can send “on” signals that amplify nervous impulses in the spinal cord, so that more signals flood into the brain and become pain, or the brain can send “off” signals that arrest those impulses. For example, at the time of acute injury, signals traveling up the spinal cord to the brain stem and brain evoke
counter-signals
traveling downward that have an analgesic effect by inhibiting the incoming signals. After several hours, however, the brain releases neurotransmitters into the spinal cord that actually amplify the incoming signals, augmenting pain. Thus, acute injuries always hurt more later, a feature that serves the adaptive purpose of enabling flight at first and later enforcing rest.

Although acute injuries provoke some pain modulation, under certain circumstances the modulatory system is dramatically activated. There is no existing practical pharmacological analgesia that can match the brain’s innate pain-control system. It is the secret spell that occasionally allows soldiers, athletes, martyrs, and pilgrims to engage in battles, competitions, or acts of devotion without being distracted by the pain of injury. Electrical stimulation of parts of the brain involved in the pain-modulatory system (the periaqueductal gray matter and raphe magnus nucleus) produces not simply some pain relief, but
complete
analgesia in both humans and animals.

The modulatory and perception circuits are activated by various cognitive and affective states, the two most important of which are
attention
and
expectation.
Although the brain is quite busy, as a matter of course, with input from multiple sensory systems, the limbic system stamps pain with a valence sufficiently negative to give it priority. The greater the attention the brain pays to pain, the more pain one feels (readers, beware!). Dread of impending pain (a state of mind involving both attention and expectation) augments the perception of pain. In studies at Oxford University, Dr. Irene Tracey has shown that
simply asking subjects to think about their chronic pain
increases activation of their pain-perception circuits.

Many rituals surrounding torture involve forcing the victim to examine instruments of torture. As one survivor put it, “Torture isn’t having your leg bit off by a shark, torture is being slowly lowered into the pool.” Different kinds of fear have opposite effects on pain: fear of pain itself generates pain (via expectation). But fear of any other threat
besides
pain can reduce pain (by distraction). One of the most robust activating signals for pain modulation is a threat to survival. A rat exposed to a cat will become analgesic, just as did Bethany Hamilton (the young surfer who felt no pain when her arm was bitten off by the shark).

Perhaps the quenching effect of fear on pain was the hidden neural mechanism that helped some of the accused pass trials by ordeal in ancient times. For example, when Queen Emma of Normandy walked over red-hot plowshares without realizing it, had her fear distracted her brain from registering pain as she watched the judges like prey eyeing a predator? Although the details of her case may be mythical, presumably if
none
of the accused ever passed an ordeal, faith in the system would not have endured for so long. Conversely, in a society with widespread belief in ordeals, one might speculate that the guilty among the accused would expect to feel pain during the ordeal and that expectation would lead them to experience greater pain.

Ordinary distraction can be an effective analgesic. When Dr. Tracey’s subjects performed a demanding counting task while receiving a painful heat stimulus, many parts of the pain-perception matrix became less active, while the cognitive parts of the brain required for the counting task became more active. Music also helps; listening to tones while receiving a painfully hot stimulus actually decreases activity in the pain-perception circuit. Even smells influence pain; Dr. Catherine Bushnell at McGill University demonstrated that pleasant smells decrease pain perception and unpleasant odors enhance it.

The corollary is that expectation of pain relief creates pain relief—an example of the placebo effect. The brain can lull itself and won’t bother to create pain if it expects that a god or a medication will dispense with that pain anyway. Placebo may have played a role in ordeals, as those who were falsely accused but believed in the ordeal system would be convinced that they would be divinely protected from pain during the trial—and the placebo effect could make that belief true.

Placebo
is a Latin word meaning “I shall please.” Stemming from the word used in the first line of the vespers for the dead (“I shall please the Lord in the land of the living”), the placebo effect is like a prayer that is granted if the beseecher has faith that it will be. Yet the etymology of the word reflects the sense of fraudulence with which the placebo effect is popularly—and wrongly—linked. Chaucer disparaged those who “sing placebo,” referring to the sycophants who show up at funerals insincerely reciting vespers and faking grief for the dead in order to partake in the lavish feasts that followed. In
The Canterbury Tales
, he gave the name Placebo to a character prone to false flattery.

But placebo is not false. People once speculated that the placebo effect is psychological—patients want to please the doctor so much that they either feign feeling better or convince themselves that they feel better. Yet when patients believe they are getting an opioid but actually get a placebo, they not only report pain relief, they also unconsciously display the autonomic side effects of opioids, such as respiratory depression.

Placebo is popularly understood as requiring some kind of sham treatment, like a sugar pill. But because the placebo effect is a result of the power of belief, or positive expectation, it can be created through verbal assurances or healing rituals as powerfully as through sham pills or procedures. Neuroimaging studies show that a placebo activates the brain’s pain-modulatory system in a way that is
neurochemically indistinguishable
from treatment with an opioid analgesic.
For example, in a 2005 study led by Dr. Jon-Kar Zubieta at the University of Michigan Medical School, the brains of men were imaged after a stinging saltwater solution was injected into their jaws. The men were then each given a placebo and told that it would relieve their pain. The men immediately felt better, and the screen showed how: in the image, the parts of the brain that release their own opioid-like substances (endorphins, enkephalins, and dynorphins) lit up. In a sense, fake painkillers caused the brain to dispense real ones. Like a New Age dictum—the kind I used to scorn—faith had become chemistry; belief had become reality; the mind had overridden the body.

Even opiate medications require the placebo effect for part of their effectiveness. Studies have found that when morphine or other strong opioids are administered covertly (say, added to an IV), they don’t work nearly as well as when subjects know they are receiving them. The use of a placebo increases morphine’s efficacy by more than a third (with the placebo in this example being simply the positive expectations created by telling patients they have been given morphine and will soon feel great relief). This is also true of other drugs, such as ones that treat anxiety or Parkinson’s disease. The Egyptian Ebers Papyrus was right:
magic is effective together with medicine, and medicine is literally more effective with magic.

One medication requires the placebo effect for
all
of its effectiveness. An intriguing 1995 clinical trial proved an analgesic called proglumide to be a more effective pain reliever than a placebo when both groups were told they were being given an exciting new painkiller. But when subjects were slipped proglumide without their knowledge, thus ensuring they had no placebo effect, they felt no relief at all. None.

I was stumped by what I read about proglumide. When given solely, how could a drug
require
the placebo effect yet be more effective than placebo alone? Does the drug have any mechanism of action besides placebo? If it does, why doesn’t it work like other drugs when given covertly? If it is only a placebo effect, how did it provide greater relief than a sugar pill? The answer seemed to be none of the above. It reminded me of the line in
The Phantom Tollbooth
about the car that went without saying. There had to be a trick to it—but what?

The secret lies in this fact: while the brain’s own endorphins create the placebo effect, there is another substance in the brain (a hormone called cholecystokinin) that dampens that effect by inhibiting endorphins. Proglumide works by blocking the cholecystokinin receptors, thus allowing the brain to create a more vigorous placebo response than it ordinarily would. Proglumide raises the intriguing question of whether drugs should be designed specifically in order to enhance or create a placebo effect. Chronic pain patients often fail to respond to placebo, so drugs that pharmacologically generate a placebo response and activate their sluggish pain-modulation circuits might be of particular benefit to them.

Placebo has a nasty twin:
nocebo
(Latin for “I will harm”), the negative effects of expectation. The brain will generate pain or other adverse responses in people who believe they have been given a harmful substance, even if they haven’t. A patient who is given a fake opiate may feel undesirable side effects, such as itchiness or sleepiness, along with pain relief. Nocebo can even be fatal, as when, for example, people do actually die of fright after being bitten by what turns out to be a harmless snake. Another example is the curious phenomenon, well documented by anthropologists, of death following a voodoo curse (in which those who believe they will die from a voodoo curse in fact perish within a few days). A negative medical prognosis can also cause a fatal nocebo, as in the syndrome of patients dying soon after being told they have terminal cancer but before the malignancy develops further.

EXPECTATION RIVALS NOCICEPTION

I am desperately trying to make a case for the meaningfulness of the scientific literature that shows that expectation can be as powerful as nociception,” John Keltner said. “I just don’t know how to make my patients believe it.”

Dr. Keltner helped to design a study at UCSF that used brain imaging to examine the effects of expectation on pain-perception circuitry. In the study, the brains of healthy Berkeley students were scanned while they received a painful heat stimulus and saw color-coded cues that allegedly indicated whether the temperature of the stimulus was high or low. The pain-perception circuitry in the subjects’ brains turned out to be
as influenced by the cues as by the pain information coming from their skin.

Volunteers were told that the blue cues indicated a low temperature and the red ones indicated a high one. When subjects were shown a blue cue and given a low heat stimulus, their brains generated little pain. When subjects were shown a red cue, but the heat stimulus was actually low, they weren’t fooled: their brain activation remained low. But when subjects were shown a blue cue while the heat stimulus was actually high, they were fooled: their brain activity remained as low as when the stimulus was actually low. In fact, these three different scenarios all produced roughly
the same amount of neural activation
.

“Astonishingly, it turned out we could interchange cue and stimulus and get the same result,” Dr. Keltner said. It turned out “that reducing expectation can be as significant as reducing the pain stimulus itself.”

Only one scenario created dramatically greater brain activation: when the high stimulus was cued with a red cue, it was experienced as much
worse
than when the high stimulus was cued with a blue cue, illustrating the power of nocebo—the “additive” power of negative expectation to augment pain. This last scenario is the one that is most similar to the actual experience of chronic pain, in which the negative experience of being in pain is augmented by negative expectations of pain—one’s own internal cuing. If you expect to enjoy taking a walk but you find that your back hurts, you may notice mild pain (i.e., the blue cue with the high pain scenario), but it will hurt much less than if you have chronic pain and expect to feel pain (i.e., the high pain with the red cue scenario). Moreover, if you feel pain every time you walk, pretty soon your brain will start to generate pain when you take your first step.

In his struggle to bring the insights of the lab into practice, Dr. Keltner has tried explaining the experiment to his pain patients. “When hard-core chronic pain patients come in, I’ve shown them posters of my results, because they make the simple argument in an extremely tangible way,” he said. “I say, ‘Look at the brains of these volunteers. We have demonstrated that expectation can be as powerful as pain. I tell them,
‘You do not have to flat-out succumb to pain.’

“Clinical medicine hasn’t had the opportunity to really figure out the benefits of the placebo effect. If you change people’s expectations, their brain activity should be reduced, but turning basic science into clinical tools is very elusive.”

How can the expectations of chronic pain patients be changed? Of course they expect to be in pain: their pain is chronic.

“That chapter has not been written,” Dr. Keltner said. “We know from the literature that psychological tools can reduce the pain experience by roughly 50 percent in acute pain patients and 30 percent in chronic pain patients. It’s pretty stunning for a therapeutic intervention to come up with a zapper that gets that kind of relief—comparable to the best medications. I’d like to say, ‘I’ve got Zoloft, I’ve got Neurontin, I’ve got steroids, but I’ve also got these other tools, these psychological tools, so you don’t have to be at the whim of pain.’ I have hundreds of patients who are suffering; this is one more tool that could be brought to bear. And you may need that tool because you may have used up all the others.”

How could he get patients to believe in placebo?

“The obvious way is through deception,” he said—that is, assuring the patients that whatever treatment he uses with them is “one of the most effective therapies” and involves “new discoveries” and bolstering his statements with a bogus statistic such as “in most cases—in 90 to 95 percent of cases—it gets real relief” because “if they believe it, it might be true.”

Nevertheless, in his own practice he does not use deception. “It’s a pregnant irony that striving for the placebo effect is a frank contradiction to what clinical practice is all about,” he said. “It’s frustrating that you can’t use this simple tool that works so well in experiments. But a relationship with a doctor is one of the most important human interactions. Doctors are priests! People are more intimate with doctors than they are with anyone. And honesty—simple, straightforward honesty—is the foundation of that experience.”