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A book by
William H. Calvin
The Throwing Madonna
Essays on the Brain
Copyright 1983, 1991 by William H. Calvin.

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Scanned, OCR'ed, and webbed -- but NOT proofread (14 Jan 97)


Of Cancer Pain, Magic Bullets, and Humor

In another country, I attended a riot out of that curiosity which is not only known to kill the cat but on occasions the man. I was a passive observer on the pavement between rioters and paratroopers, well to one side, talking with a reporter. Suddenly I felt a dull thud on my forehead--a glancing hit had ripped a jagged 4 cm-long slit. For an hour, the injury was totally painless. I began to worry that my family would be worried if they heard that I was injured and later the thought crossed my mind that infection might result. At this stage, I began to feel a minor deep dull headache.
      By the next morning, deep and superficial pain and tenderness were very obviously present, distressing and disturbing. This died down day by day as the wound healed cleanly without problems. In spite of this obviously impending successful end of the episode, and in spite of the good company and interesting work, I found myself unusually listless, sleepy, irritable, unable to concentrate, shunning food and company. This also disappeared over a period of 7--10 days.

Pain is about as pleasant as a fire alarm--and also as useful. It's nice that your leg nerves are wired up in the spinal cord so that stepping on a thumbtack results in an automatic withdrawal reflex that limits the damage, with the foot lifting and the other leg straightening to take the weight. If pain has a bad name, it is because it is sometimes like a fire alarm that can't be shut off--continuing insistently for a long time after it has alerted you that something is awry.
      If you have broken a bone, such continuing pain probably serves a useful purpose. You become reluctant to move the affected part of your body, and this immobilization aids the healing process. In the days before plaster casts when the human nervous system was being shaped by evolutionary pressures, such continuing pain made some sense. Injured animals hole up somewhere while they heal. The late lassitude that Professor Wall experienced may be useful in protecting the healing wounds; similarly, the early pain was merely sufficient to get him to seek care, but not severe enough to immobilize him at the site of the injury (indeed, 37 percent of emergency-room patients report that they did not feel pain until some time after the injury). In looking at some of the disorders of pain behavior, we tend to seek their origins in these normal phases following injury and in how they vary from one person to another.
      There is a lot of needless suffering associated with chronic pain, suffering that serves no useful purpose whatever. Evolution has evidently not worked very well at preventing this, though our scientific ability to understand the pain mechanisms may eventually accomplish that goal. Minimizing suffering is a human, humane goal but apparently not an imperative of evolution.
      The progress report for this humane goal is, however, not one of the success stories of our civilization. We are just starting to recognize that the brain's mechanisms are quite different for the thumbtack pain and the months-long pain, just starting to understand some of the relationships between chronic pain and depression, just starting to develop some tools for sorting out the problems in animal research which have prevented progress in the past.
      Morphine and similar drugs work very well when you break a leg. The problems come when the physician tries to treat chronic pains such as those from neuralgias or headaches or arthritis. It isn't merely the addiction problem with morphine. It's that all the strategies used for dealing with acute pains--bed rest, immobilization, potent narcotics of various sorts--don't work for chronic pains. They often make them worse.
      One of the most important decisions that a physician must make is whether the patient's pain falls into the acute category or the chronic one, because the treatment of chronic pain is usually almost the opposite of that for acute pain. Anything stronger than aspirin is usually avoided. The patient must not hole up like the injured deer with the broken bone. Walking around the block may seem unnatural to us when we are in pain (as our evolutionary heritage in such matters is much like the deer's; we act much as Professor Wall did a week after his injury), but activity must be forced. If the chronic pain is complicated by depression, treating the depression with antidepressant drugs and psychotherapy may help relieve the pain.
      So the natural instincts for dealing with chronic pain must be resisted, again proving that evolution is imperfect. But what really works well? While there are some exceptions like tic douloureux and its very specific medical and surgical therapies discussed in Chapter 11, the therapy of chronic pain is a mixed bag of psychological, medical, and surgical tricks. It is often not done well at all. The patients who filter through to the pain clinics have typically been through a bewildering array of medicines and operations, have literally gone from one doctor to another, tried everything.
      Pain clinics are a recent invention, though their antecedents go back to World War II. My colleague John Bonica founded one in 1961 at the University of Washington in Seattle; during the 1970s many pain clinics sprang up at both university hospitals and private clinics throughout the world. It was an idea whose time had come, but there is no revolutionary technique at its core. Rather it serves to pool the knowledge and techniques of a number of medical and psychological specialists, serves to create full-time specialists in pain therapy among the anesthesiologists, serves to better identify the conditions for which surgery offers effective therapy, and serves to create a practical body of knowledge about what works and what doesn't.
      A proper reductionistic approach seems at the very core of "scientific medicine": one seeks to get at the root causes, not just to try to make the symptoms go away. On this theory, one treats the pain by eliminating its cause. Granted, some symptomatic treatments make about as much sense as using makeup to cover the jaundiced skin color of hepatitis. But sometimes one must step back a minute and consider whether, in human terms, it makes sense to put all your eggs in one basket. There will always be diseases about which we can do nothing; we will all die of something and would prefer to die pain-free and with dignity. Furthermore, there will always be irreversible history--accidental injuries to the nervous system that cannot be undone, scars that cause pain and cannot be removed without making another scar.
      Particularly in chronic pain, the symptom is often more of a problem than the malfunction giving rise to it. The minor alterations in nerves that give rise to neuralgias are not, in themselves, worrisome. The irritations of blood vessels and the brain's covering membranes giving rise to most headaches are benign. The blood vessel that traumatizes the trigeminal nerve in tic douloureux is usually not preventing the nerve from conducting normal nerve impulses; it infrequently causes serious damage. Most disk disease does not threaten the health of the spinal nerves and the spinal cord (though the exceptions can be quite serious indeed). Most arthritis pain is all out of proportion to the need to warn us not to overuse the joint. But the pains associated with such physically minor irritations can disable even the most stoic person, can even lead them to contemplate suicide.
      In the case of cancer pain, the situation is particularly absurd. In evolutionary terms, the pain serves no useful purpose at all. Even in these modern times when something can often be done for the tumor, the pain does not serve a useful warning purpose, to get someone to see a doctor: in most cases, pain is not an early symptom of cancer. It is not even inevitable; many cancer patients never experience serious pain. Yet pain is probably the most feared aspect of cancer, and for good reason too--tumors that invade bone or peripheral nerves or pancreas are especially bad news.
      You might think that, because it is such a widespread problem (perhaps a half-million sufferers in the U.S. at any one time), physicians would be well trained in managing cancer pain. The medical books on oncology are thick tomes, and one might expect to find therein several long chapters on pain problems and their management. But many do not mention the subject at all; others have only a brief mention. One count showed that the number of pages on pain problems constitute less than 0.2 percent of the cancer textbooks. The knowledge base is not as poor as that, but it is often taught poorly, having fallen between the cracks of our medical specialties.
      A similar impression occurs when one looks at the budget for the U.S. government's arm for cancer research, the National Cancer Institute. An analysis of its program in recent [early 1980s] years reveals that of its billion-dollar budgets, only 0.022 percent went toward cancer pain research. Cancer pain researchers are surprised when their grants are assigned to the NCI's Community Relations office for administration--until they look at the NCI's table of organization and can find no more logical home. It might be argued, with some fairness, that few good research proposals are submitted in the area of cancer pain research, but it is also obvious that cancer pain research is an orphan area, overshadowed by the noble quest for the magic bullet that will cure cancer. And hence avoid cancer pain. But our natural tendencies to seek root causes and cures perhaps need to be tempered-- hedging our bets a bit better than the just-quoted percentage. Besides, our knowledge about-how to treat cancer pain might carry over into other noncancer diseases--such as what will replace cancer near the top of the fatal-disease list should that magic bullet ever appear, if the cell growth or immunology researchers strike it rich.
      While much cancer pain is probably due to tissue damage (and is thus "proper" pain rather than "false alarm" pain), there are many clues that cancer also alters the nerves, mangling the messages. There is a form of muscular weakness (known as the Eaton-Lambert syndrome) which may appear at a site distant from a tumor, as when a lung tumor causes hand weakness (nerve endings no longer release as much neurotransmitter in response to an impulse as they normally would, just as in some forms of myasthenia gravis). The pressure from tumors sometimes injures a nerve, causing it to sprout and attempt to regrow--during which time it will be abnormally sensitive to movements and various things circulating in the bloodstream. Sometimes tumors grow along nerves, completely changing the environment of the nerve and making it malfunction. My own pet (but unproven) theory is that much cancer pain is very similar in mechanism to neuralgia pains--that if we learn to prevent one, we will have gained a handle with which to manipulate the other, that cancer pain research will prove relevant to garden-variety low back pains (no pun intended) and vice versa.
      If there is one overwhelming lesson from basic biomedical research, it is that most problems cannot be effectively tackled head-on. You have to find out a lot about many related things and then, some lucky day, a path will open up toward one of those problems easily identified by the public as a major concern. This lesson, as well as the scientific tendency to seek root causes, means that we properly put most of our eggs in a basic research basket. In the case of pain research, this has meant studies of the specialized sense organs embedded in skin, muscle, and viscera. It has meant tracking the pathways taken by pain and other sensations through the spinal cord and brain. It has meant investigating the normal mechanisms which the brain uses to regulate the sensations reaching consciousness, its ways of turning off unwanted messages.
      Many of the neurobiologists I know would bet that the study of peptide hormones (mostly done in moths, snails, and the like) will prove quite relevant to pain research: one of the brain's control mechanisms involves enkephalin. It is a short-chain protein, a mere five amino acids long: tyrosine, glycine, another glycine, phenylalanine, and finally leucine (or sometimes methionine). Some think that it or a close relative may prove to be the brain's own version of morphine, perhaps even a neurobiological "magic bullet" for pain. Certainly placebos suggest that the brain itself has a mechanism for raising pain thresholds in a morphinelike way: in perhaps 30 percent of patients, a sugar pill taken under the impression that it is a potent painkiller seems to work as advertised. And, lest one think that it is all "psychological," consider this: An antimorphine drug (naloxone) will make the placebo become ineffective, this return of the pain suggesting that the placebo stirred up a morphinelike hormone or neurotransmitter in the brain (naloxone blocks morphinelike receptor sites)` The psychological set seems to tap into a normal brain mechanism for regulating pain sensations, at least for a week or two.
      (Placebos raise a problem in these days of the pharmacist labeling pill bottles with their contents. One cannot admit that the pill is nothing but sugar if it is to work, so a fancy brand name is needed. Among the proposals made in the scientist's humor magazine The Journal of Irreproducible Results for what to name a brand-name placebo are Confabulase, Gratifycin, Deludium, Hoaxacillin, Dammitol, Placebic Acid, and my favorite, Panacease. )
      Most research requires intense specialization in order to make progress. Thus most neurobiologists are not familiar with the differences between acute and chronic pain (of course, neither are most of the physicians treating pain). To counter the natural tendencies to a narrower and narrower focus, there have been a series of interdisciplinary research ventures. Groups of researchers from different backgrounds join together, motivated by a common interest in a particular disease. For example, a pain group might include neurophysiologists working on how nerve impulses get started, on how pain messages are handled in the brain, on how pain affects sleep; it might include neuroanatomists tracing the pain pathways in the spinal cord, neuropharmacologists studying how known pain-relieving drugs act upon nerve cells, behavioral neuroscientists trying to modify pain in rats. And besides the basic scientists, there would be the anesthesiologists, psychologists, psychiatrists, and neurosurgeons treating pain and pursuing their own research interests, perhaps even sociologists studying how the news about improved cancer treatments spreads on the medical grapevine. The clinicians and basic scientists may sometimes work together, perhaps looking at cancer patients and wiretapping a nerve, listening in on the messages being sent from the tumor to the spinal cord and brain, trying to see the tell-tale clues of false alarm messages, trying to figure out which "proper pain" messages are being sent.
      Such ventures have their problems, as each scientist may feel somewhat isolated from the parent discipline or feel out of the mainstream of his own field's research thrust into ever deeper layers of reductionism. The ventures are also financially unstable, usually completely dependent upon government grant money doled out for limited two-or three-year periods--at the end of which time the whole venture can fall apart for lack of jobs (the universities, in which most such interdisciplinary ventures are housed, rarely try to guarantee such jobs with tenure, thus creating an academic version of second-class citizens).
      The clinicians, should they have to give up their research activities, are at least comforted by being able to double their academic incomes by going into private practice. Unlike the clinicians, the Ph.D.-trained basic scientists cannot fall back on treating patients; they are in a very exposed, precarious position which periodically causes them to doubt their own rationality. A friend of mine, who trained with several Nobel-class people in neurobiology and whose published work is well-known, is now making his living by selling computers to small businesses that want to automate their bookkeeping. Two other postdoctoral researchers used to support themselves by applying their mathematical knowledge of game theory (remember "tit for tat"?) to card counting, and would make semiannual trips to Las Vegas to cash in on their computer-pretested schemes at the blackjack tables, regularly earning enough money to support themselves for a little longer (in the usual poor graduate-student style, nothing fancy) while they did neurobiology research. (I can tell this story now only because they too have given up on such a chancy existence in favor of well-paid jobs setting up computer installations.) Another talented researcher sells real estate for half the year, then commutes 5000 kilometers to spend the next six months doing neurobiology again. But living on a shoestring gets a little tiresome after a while, especially if there are children to eventually send to college. Unfortunately, the clinician or the basic scientist who leaves research is, for a variety of reasons (such as having to lower their standard of living), quite unlikely to ever return. And so the fits-and-starts of federal funding for biomedical research regularly cause highly trained people to be lost forever to research, however useful their second careers may turn out to be.
      It makes no sense at all--but then, neither does the overall situation. Judging from the low level of investment in research and development, you'd think that biomedicine was a slowly changing industry like an electrical utility. But utility executives probably invest far more of their budgets in R and D than does the health care "industry." The main problem is that, due to the small-business nature of most health care practices, there is very little investment in research except via governments and taxes. One way of tying research expenditures to the overall health care budget would be to tax health insurance premiums to create a biomedical research trust fund, in much the way that the interstate highway system was built through a gasoline tax creating the highway trust funds. That way research would at least keep pace with inflation; it's been downhill since about 1967 as one president after another has proudly announced a 3 percent increase in the biomedical research budget--in a year with 10 percent inflation. The medical definition of starvation is when the patient continuously loses weight, with no end in sight-- which is why we talk about "starvation diets" for biomedical research. It isn't hyperbole: the funds available are absurdly small by business standards for R and D, and they keep declining despite the self-congratulatory press releases.
      On the bright side, it might be said that the psychology of humor may prove relevant to chronic pain. Scientists may not headline a research grant as a study of humor (for fear of losing a year of their time coping with a press release from a headline-grabbing politician), but there are a variety of clues which scientists are convinced need pursuit. The endorphin and enkephalin researchers are looking to see if humor stimulates natural pain defenses. Then there is laugh therapy, such as Norman Cousins (the late editor of the Saturday Review) utilized in coping with a serious illness.
      The other line of thought comes from cognitive psychologists, who talk of the schemata or templates in the brain, to which we are always trying to match up the situations in which we find ourselves. In the days before cognitive psychology, a prominent British neurobiologist, J. Z. Young, expressed it this way:

We laugh together when we agree, when we understand the same rules.... One of the ways of emphasizing a common use of rules is to laugh at someone who does not share them--hence we laugh at mistakes, odd men out, freaks and Ugly Ducklings generally.... [Even in science, researchers exploring new avenues, the doubters] who are trying to find new rules, are always ridiculous, because they are not satisfied with the old ones. Jokes have the same origin, the fact that one sees the disguised or oblique point gives the assurance of understanding the rules of ability to communicate. Jokes about sex are the funniest of all, because they show an agreement about how to achieve the oldest form of communication.
But there is another side to unshared rules or mismatched expectations: under some circumstances they may cause pain. The sensory nerves in the skin and muscles and joints are highly specialized. Some specialize in the length of a muscle, others in the movement of just one hair, some in cold temperatures, others in heat, and some are diffficult to set off except under conditions likely to cause damage to the cells. These latter sensory types are one kind of "pain" neuron, analogous to a fire alarm tripped by high temperature. Other sensory neurons respond to light rubbing of the skin but also to severe tissue-damaging stimuli; just how the spinal cord and brain look at the discharge pattern of that neuron and tell the difference between rubbing and tissuedamage is one of the prime challenges of sensory neurophysiology. They probably compare patterns of activity in a number of sensory neurons--take a poll, as it were--before deciding that it is worth labeling as noxious enough to be what we call "pain." What happens if the poll yields a bizarre pattern (say, activity in the "cold" sensors as well as in the "hot" sensors)? Cold and hot simultaneously may not fit any previous schema, may be outside the experience of that individual's central nervous system. Now, under benign circumstances, such a novel input might be intriguing, even a humorous surprise. But under other circumstances, such a novel combination of inputs may elicit feelings of distress, of pain--just as a young bird crouches down in fear at any unfamiliar shape flying overhead (this was once considered to be evidence for an innate "chicken hawk" template now it is known to be any unfamiliar bird-sized moving shape overhead). Stimulus configurations that do not match any of the usual templates, which are thus not recognized, can give rise to either extreme of emotions.
      This "mismatch" theory of pain, as I am wont to call it, comes to mind when one sees a person in chronic pain from a damaged nerve, who cannot find adequate words (templates) to express the nature of the sensation: it isn't exactly dull aching, or lancinating, or prickling, or warm--rather the patient calls it "weird." And judging from the ways in which damaged nerves spontaneously initiate nerve impulses, it seems likely that they are indeed receiving a barrage from all kinds of sensors simultaneously. Now, under other circumstances, novel patterns of input are funny--the barrage during tickling, for example. The humor of the surprise ending in a joke, to take an example from higher intellectual function. Could we, with some re-education of chronic pain patients, convince them that their disorderly sensations are funny? Or maybe neutral? But at least not painful?
      This variegated view of pain research may seem a bit jumbled, but I assure you that it is representative of the state of things--a touch of clinical improvement, of new research ideas, of improved social organization for providing expert treatment and doing interdisciplinary research, and a sad problem of disproportionately small resources for improving things. It is a period of intellectual growth, even if there is little expansion of facilities and personnel. Still, it is frustrating to see all those patients and friends who suffer needlessly because the good ideas still have not been translated into good techniques for dealing with pain.
The Throwing Madonna:
Essays on the Brain
(McGraw-Hill 1983, Bantam 1991) is a group of 17 essays: The Throwing Madonna; The Lovable Cat: Mimicry Strikes Again; Woman the Toolmaker? Did Throwing Stones Lead to Bigger Brains? The Ratchets of Social Evolution; The Computer as Metaphor in Neurobiology; Last Year in Jerusalem; Computing Without Nerve Impulses; Aplysia, the Hare of the Ocean; Left Brain, Right Brain: Science or the New Phrenology? What to Do About Tic Douloureux; The Woodrow Wilson Story; Thinking Clearly About Schizophrenia; Of Cancer Pain, Magic Bullets, and Humor; Linguistics and the Brain's Buffer; Probing Language Cortex: The Second Wave; and The Creation Myth, Updated: A Scenario for Humankind. Note that my throwing theory for language origins (last 3 essays) has nothing to do with the title essay: THE THROWING MADONNA is a parody (involving maternal heartbeat sounds!) on the typically-male theories of handedness.
Many libraries have it (try the OCLC on-line listing, which cryptically shows the libraries that own a copy), and used bookstores may have either the 1983 or the 1991 edition.

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