Ivan Pavlov is alive and well, though forgotten (Essay 22)

Bernard Lown, MD

Clinicians soon learn that many of the problems they confront derive from the rough and tumble of living. This was true for me as well, a cardiologist with a global referral practice. Psychological problems were commonly in the forefront of whatever medical reasons brought patients to Boston. I aimed to fathom the emotional stresses that amplified or even provoked the presenting symptoms.

The lay public grasps that life stresses shape and even cause illness. For example, when questioned why anyone suffers a heart attack, a majority point to stressful living. This understanding is embedded in our language, from “heartache” as a designation of emotional anguish to a “broken heart” as a cause of sudden death. Such an association long antedates modernity and was brilliantly captured in ancient Greek tragedies. It brims in Shakespeare’s plays. A brief two lines in “Macbeth” capture the essence: “Give sorrow words: the grief that does not speak/
 Whispers the o’er-fraught heart, and bids it break.”
(Act IV, Sc. III)

The relation between the “o’er-fraught heart” and symptoms is not always temporally sequential. One does not necessarily follow the other. The ache or dizziness or other troubles may be preceded by some innocuous or inconsequential event. To illustrate: Cardiologists often encounter patients presenting with angina pectoris. This consists of a tightening behind the breastbone provoked by exertion, usually while hurrying outdoors, especially after a meal. It reflects narrowed coronary arteries that limit the transport of oxygen to the heart when the demand for blood flow is increased by exercise. But at times angina is provoked by something seemingly unlikely to deprive the heart of oxygen.

Peter K. consulted me some years ago about what seemed like classical angina, except it did not occur with exertion. As a matter of fact he was quite athletic and lacked any of the classical risk factors for coronary artery disease. He came from a long-lived family free of heart ailments. Blood lipids and blood sugar were well below threatened levels. He was not hypertensive. He had a good marriage and a wholesome family life. When Peter K. was stressed on a treadmill, he went 15 minutes without experiencing angina, a very substantial exercise capacity. Invariably the chest discomfort occurred in the early morning while he worked at his desk. When asked what provoked it, he gave a curious response: a telephone call. Any telephone call. He offered no explanation of this unusual provocation, though I noted that his wife tensed up, with grief sorrowing her face.

When Peter K. went into the examining room, I asked his wife to remain. Without prodding she resolved the mystery. Eight years earlier, at 8:30 in the morning, their 10-year-old daughter was killed by a truck while crossing an intersection on the way to school. A phone call from the police informed her husband of the tragedy.

It seemed astonishing that being reminded of an event that had occurred years earlier could be more burdening to the heart than physical exertion. The fact that a telephone ring could provoke angina pectoris recalled the pioneering work of the great Russian medical physiologist, Ivan Pavlov (1849-1936). He showed that some environmental events could be linked to the neural responses regulating visceral organs such as the digestive system or the heart. One of Pavlov’s breakthroughs involved externalizing a dog’s salivary gland, thereby enabling him to measure the flow of saliva in response to various foods under different circumstances. Pavlov discovered that the repeated ringing of a bell just as food was being delivered elicited the same copious flow of saliva at the mere sound of the bell, even without food. He labeled this learned response the “conditioned reflex.” The effects of the bell ringing on salivary flow were attenuated and ultimately extinguished during multiple repetitions when it was unaccompanied by food.

Pavlov made another observation: When a stimulus was aversive or painful, the conditioned reflex was long lasting and persisted without reinforcement. Thus an innocuous stimulus, when coupled in memory with some hurtful event, can evoke a cascade of neurophysiologic visceral responses that diminish coronary blood flow. I have observed that Pavlovian conditioning can induce palpitations, various cardiac arrhythmias, and even sudden cardiac death.

I have noted that conditioned reflexes commonly develop with the use of medicines. One patient was dependent on nitroglycerine for alleviating exertion-induced angina. When asked how many pills he consumed, he indicated none. It was curious that he never took a pill but could not be without one. He explained that all he had to do was touch the little bottle containing the pills in his pants pocket, and the chest discomfort melted away. Another patient had extremely disabling angina for which, he said, nitroglycerine was the “miracle drug.” One hot summer day while walking on a beach in his bathing suit, he developed angina. The pain was so severe he could not move. Standing, seemingly paralyzed in a growing puddle of sweat, he asked a bystander to fetch the nitro pills in his jacket pocket some 50 yards away. The man raced over, took out the little bottle and waved it in the air to have the patient acknowledge that it was indeed the proper medicine. The moment the patient saw the bottle, the pain abated.

After a number of similar observations, I developed a ritual of instruction when first prescribing nitroglycerine. In part this was compelled by my failure to persuade many patients to use nitroglycerine freely. Reluctance to take the drug was due to the experience by some of a throbbing headache.

When first prescribing nitroglycerine I asked patients to take a pill under the tongue. Patients would remonstrate that they didn’t have any discomfort right then. I indicated that the intent was to observe any adverse effects that might ensue. The moment the pill was placed sublingually, I started a stopwatch and began to intone that the nitroglycerine, a powerful vasodilator, was now increasing blood flow to the brain as well as the heart. I continued, “More oxygen is reaching your heart. You know that by the flushing sensation in your head. This is a nice warm sensation, a good feeling, a very pleasant throb.” I continued this jabber until two minutes had elapsed.

Then I would ask what they had experienced. The consistent response was a “warm, pleasant throbbing.” Not a single patient complained of a headache, and the use of nitroglycerine increased substantially. Results of the positive psychological conditioning extended beyond the use of medication. I learned that when patients are taught how to control troubling symptoms, they are far less likely to seek costly complication-ridden medical interventions. The majority who learned to use nitroglycerine without hesitation were spared the need for cardiac surgery, angioplasty, or stenting.

I would not have had this insight had I not encountered Eugene A. early in my medical career. The impact of our meeting was so profound that I still recall the Thursday afternoon in mid-March, over 65 years ago, when he sought my medical advice. He introduced me to Pavlov and the conditioned reflex, [KS1]  changed my way of doctoring, and revolutionized my thinking about medicine. Those words might evoke the image of a seasoned Harvard professor, a learned sage, or a man astutely tuned to the fragility of the human condition. Eugene A. was none of those things. Though worldly wise, he lacked formal education. He was a high school dropout who described himself as a “working stiff.” His medical condition was puzzling and complex, though the essential facts were straightforward.

Eugene A. was just 40 when he consulted me for oft-recurring chest pain. At age 21, he had been found to have hypertension. At age 32, while working as a meat packer, he had had a heart attack. Thereafter, he had frequent chest discomfort that he could “walk off.” In fact, his avocation was mountaineering. At the beginning of a climb he experienced soreness behind his breastbone that increased in severity and radiated down both upper arms to the elbows. At this point he would become flushed, break into profuse sweating, and be compelled to stop for some minutes. Then he would get a second wind and could climb at a sustained pace for several hours without re-experiencing chest pain. He was frequently the first of his group to reach the top of Mount Washington in New Hampshire. He was not even breathless, although everyone else was winded.

He did not have chest discomfort while working. His job of meat packing was physically demanding. He had to cart 40-pound slabs of beef into a freezer at minus 7 degrees Celsius. Yet walking the streets of Boston could precipitate chest pain. When he engaged in habitual work or undertook activities he relished, especially indoors, his pain threshold was extremely high. Because of these oddities, several experienced cardiologists questioned whether he had angina and advised him to seek psychiatric help.

Aside from nitroglycerin, no drug could diminish the incidence or assuage the severity of the anginal attacks. When these were severe, he would at times pop a dozen or more nitroglycerine tablets sublingually to hasten relief. Looking back I shudder at how few effective medications were then available. Another decade would pass before beta blockers were introduced, followed shortly thereafter by calcium channel blockers, long-acting nitrates, coronary bypass surgery, angioplasty, and stents for widening partially obstructed coronary arteries. These revolutionized the management of coronary artery disease. Eugene A. was unfortunate to have been born a decade too early.

His family was charged with cardiovascular ailments. Parents, uncles, aunts, siblings: All had succumbed to cardiovascular disease at a young age. He was obsessed with heart disease, being well versed in cardiovascular terminology and possessing a veritable encyclopedia of arcane medical information. He was certain that he would not survive beyond his 42nd birthday.

After the lapse of these many years Eugene A. still is a shadowy presence in my life. He had an attractive, easygoing demeanor, with a seemingly buoyant and happy disposition. Perhaps the proximity of death intensified the joy of every lived moment. He was an omnivorous reader, a probing conversationalist, an autodidact who delved widely into science. As a result his speech was filled with allusions to cosmology, biology, Darwinism as well as peppered with eclectic smatterings derived from undisciplined browsing of scientific pop culture.

I relished Eugene A.’s frequent visits, during which I tested various current and ancient drugs. To foster hope I presented him with a long list of every conceivable vasodilator drug that had at one time or another been prescribed for angina. Weekly we would start a new drug and test its efficacy objectively with an exercise stress test. At the time it was the Master’s Two-Step Test, which required a patient to step up and down two steps for three or six minutes. This primitive stress test preceded the structured treadmill protocol now widely employed. These investigations deceived me into thinking that I was being helpful and encouraged him to believe that he might be helped. At times he was philosophic: “If it doesn’t help me, maybe it will help someone else.”

At the fifth week Eugene A. observed that the tests reminded him of his carsick dog, who vomited on every automobile ride. After a time the dog vomited when Eugene A. merely turned the ignition key and started the motor. [KS2] So he discovered that he could lead the dog close to the car, tie the leash to the open front door, and then start the engine. The dog vomited on the sidewalk and could go then for a ride without soiling the backseat.

“What in blazes has this to do with you?””Didn’t you study Pavlov in medical school? Didn’t Pavlov say something about this?”

Even more perplexed: “What did Pavlov say that relates to you?”

“The conditioned reflex!” he spat out triumphantly, probably leaving out the words “you fool” to spare the feelings of his uneducated doctor.

“Please explain,” I humbly asked.

Eugene A. pointed out that his testing on the two-step lacked scientific rigor. It was performed at random times; sometimes it was warm in the laboratory, other times quite cold. Yet each time when I intoned the 40th crossing, he developed chest discomfort, and by the 44th crossing of the two-step the severity of the pain forced him to stop. This reminded him of the conditioned reflex that Pavlov had discovered, like the sound of the auto engine inducing his dog to vomit.

This remarkable insight inspired me to change the way the study was conducted. Upon his next weekly visit, I told him that henceforward, the test would be done without counting out the number of passages across the two-step. However, he would be alerted when he approached the end of the exercise. Counting out loud would be resumed with the 40th trip.

Then the test was performed in the usual manner, except that the number of crossings was not announced. As he reached the 28th crossing, I began to miscount, calling out 40, 41, 42, and so forth. He appeared startled at the seeming speed-up of the count. After the 29th crossing (miscounted as 41), he complained of chest pain, and by the 44th count (actually the 32nd), the pain had increased unbearably, forcing him to stop. The electrocardiographic changes were striking and were indistinguishable from those when he actually did 44 crossings.

For the ensuing six weeks, the tests were conducted in the same way: [KS3] The number of crossings was not announced till the end. Sometimes the countdown was accurate, sometimes not. During these tests, Eugene A. had neither chest pain nor any electrocardiographic changes when he was stopped at 32. In fact, the articulated numbers were the Pavlovian [KS4] signal. Eugene A.’s observation was absolutely on target: He was behaving like his conditioned car-sick dog.

The weekly results were consistent. I was jubilant. The excitement must have resembled that in the Pavlov lab at the turn of the 20th century. My great medical mentor at the Peter Bent Brigham Hospital, Dr. Samuel Levine, though initially skeptical, was impressed with the consistency of the results. When the steps were miscounted, Eugene A. had angina and electrocardiographic changes at a significantly shortened distance; when he stopped at that very point without a miscount, there was neither. To my knowledge, angina pectoris had never before been deliberately conditioned, let alone with the enunciation of a numeral.

During the seventh week the test was again carried out with the miscount of 40 when he had crossed the two-step only 28 times. Eugene A. looked amused and commented, “Doctor, you either don’t know to count or you are finagling – it’s only 28!” Thereafter he experienced no pain at 32 crossings and showed no electrocardiographic alterations. The study was terminated.

One month later he developed congestive heart failure, and his medical condition deteriorated. Shortly thereafter while driving a truck in Boston, he pulled over to a curb and was later found dead. A postmortem examination showed all three major coronary arteries completely obstructed. His heart was one ball of scar tissue. At the time of his death he was just short of a 42nd birthday.

For me this experience was intensely life changing. Eugene A.’s death meant more than loss of a patient; it was the permanent parting from an intimate friend. He alerted me to something I should have known, namely Pavlovian psychobiology. Eugene A. made me aware that innocuous events could provoke serious symptoms. He pointed my thinking to a host of possible triggers that could remain unrecognized by virtue of their seeming irrelevance.

Being unaware of the conditioning psychological process prevents doctors from detecting the signals that provoke troublesome symptoms. Doctors unaware of precipitating triggers necessarily focus attention on treating the presenting symptoms. In a case like Peter K.’s, the usual treatment options range from prescribing long-acting nitrates to some invasive procedures. A majority of cardiologists would resort to inserting a stent into the narrowed coronary artery. The angina would thereby be ameliorated. But such an intervention, though costly and fraught with possible complications, would not necessarily prolong survival.Once a Pavlovian-like mechanism is recognized, deconditioning is the proper approach for expeditious relief. For Peter K. it involved several conversations, after which he remained angina free. Eugene A. became immune to angina during a shortened traverse over the two-step as soon as he detected deception in the countdown.

Triggering of angina by a verbal cue had not been previously recorded. Research cardiologists would probably look askance at the lack of experimental rigor, the scantiness of robust data, and the very subjective nature of the study. However, nine times when the number 44 was called out, the patient was compelled to stop because of disabling pain accompanied by significant electrocardiographic changes. On four occasions, his response was unaltered even though he had traversed the two-step 12 fewer times. During two tests when the counting was precise and the test was stopped at 32 instead of 44 trips, there was neither pain nor electrocardiographic abnormalities.

I did not publish this experience for 20 years. In the age of numeric science, clinical observations have lost their luster, considered to be subjective, anecdotal, unreplicatable, and therefore unscientific. Indeed, the article was rejected by a number of leading medical journals. Even after publication*, I have never seen this study cited.

Pavlovian psychology is not taught in medical schools. This is a serious deficit, since psychological conditioning constitutes the basis of much learned behavior. Yet the process of conditioning is ubiquitous in modern society. Merchandising and PR, let alone politics, which inundate mass communications, largely depend on exploiting conditioning psychology. The basis of all advertisements is a process of conditioning to manipulate the response to a product and associate it with affirmative values. A product name does not provoke any feelings until it is repeatedly coupled visually and verbally with some affirmative emotion such as youth, beauty, success, wealth, or the like. Yet doctors are inattentive to the prevalence of psychological conditioning in their patients. O tempora! O mores!

*Lown B. Verbal conditioning of angina pectoris during exercise testing. Am J Cardiology. 1977:40, 630-634. This article provides extensive discussion of possible mechanisms.

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