Panel Discussion
The Use of Analgesics in Headache MODERATOR: Seymour Diamond, M.D. TOPICS PARTICIPANTS Choice of Analgesics and Avoidance of AbuseRobert S. Kunkel, M.D. Value of Ergots in Aborting Migraine AttackArnold P. Friedman, M.D. Use of Analgesics in Children A. David Rothner, M.D. Complications of Drug Abuse in Relation to the Headache Patient Donald J. Dalessio, M.D. Dr. Diamond: There is a need for expertise in the pharmacology of pain medications, when treating the headache sufferer. At least half the letters I dictate to referring physicians every week include the following: "Dear Doctor, your patient is habituated to the following drugs (I then list the drugs). We will not be able to help him until he is hospitalized or otherwise weaned off the habituating medications." Then I offer the diagnosis and other recommendations concerning headache treatment. The criteria which distinguish analgesic use from abuse in headache are difficult to establish. Where does one draw the line? When do you use narcotics or simple analgesics? Where does ergotamine tartrate come in? We see patients who are taking excessive amounts of Empirin(r) and codeine, Phenaphen(r) and codeine, Demerol,(r) barbiturates, Fiorinal(r) and propoxyphene compounds. But we also see the patient who abuses the common over-the-counter drugs: Excedrin,(r) aspirin and acetaminophen. What are the consequences of all this, and how do we handle this patient? We have gathered a distinguished group of participants to discuss the subject of analgesics and headaches, and give you some ideas on how to handle the problem. In our format, each discussant will spend about six to eight minutes talking about their subject. The panel also will discuss each subject and then open it up to questions from the audience. I would like to call on Dr. Robert S. Kunkel from the Cleveland Clinic to talk about the choice of analgesics and the avoidance of abuse. Dr. Kunkel: Well, Dr. Diamond, I'm sorry you gave me that topic because it's difficult for me to discuss "choices" of analgesics since I don't like to prescribe them in the first place. As you've already mentioned, most of the patients who come to doctors have already tried many analgesics. Many of them are on barbiturates, and we really spend much of our time trying to figure out how to get them off. Nevertheless, analgesics can be useful for the periodic headache. They certainly should not be used for the treatment of chronic, day-in and day-out headaches. In such patients, specific nonanalgesic medications which interfere with the mechanisms of chronic headache should be the drugs of choice. However, for periodic head pain, I think we are all in agreement that nonaddicting preparations, or perhaps analgesics with very low addicting potential, may be indicated. Aspirin is obviously the most widely used analgesic for headache and other pain; yet most patients, who come to doctors because of headache, have found that aspirin is not effective. It should be noted that aspirin is not an innocuous drug. We all know about the GI side effects; some 40%-60% of patients have been found to have occult blood loss of 2-6 milliliters per day. This could cause significant anemia if the diet isn't adequate. A few patients have parenchymal hemorrhage from gastric erosions. Also, idiosyncratic-type hypersensitivity reactions may occur, particularly in asthmatics; 2%-4% of asthmatics are susceptible to such reactions to aspirin. There are, of course, hematologic effects. Aspirin interferes with platelet function resulting in prolonged bleeding time. Aspirin also displaces Coumadin(r)-type anticoagulants from their protein binding sites and, therefore, should be used cautiously by persons on anticoagulants. Interreactions with aspirin have also been reported with antifungal agents, sulfonamides, monamine-oxidase-inhibiting agents, sulfonylurea-hypoglycemic agents, and uricosuric agents.
By contrast, adverse effects with acetaminophen are remarkably uncommon when the drug is used at dosages of 4 grams or less per day. Acetaminophen is relatively free of the gastrointestinal side effects that can occur with aspirin, such as gastric mucosal irritation and erosion and gastrointestinal bleeding. Also, in contrast to aspirin, acetaminophen has little or no effect on platelet aggregation and does not influence hemostasis in the postoperative patient requiring an analgesic. There has been some question about renal and liver damage with the long-term use of acetaminophen, although existing evidence suggests these problems are seen only in the case of acute massive overdoses, most commonly taken with suicidal intent or pretense. Studies indicate that acetaminophen and aspirin, on a milligram-for-milligram basis, have equal analgesic and antipyretic activities. Either one alone is as effective as other over-the-counter analgesic compounds, such as Vanquish,(r) Excedrin, Anacin,(r) Bufferin,(r) and Empirin, which contain various mixtures of aspirin, acetaminophen, caffeine, and antacids. Other analgesics are from the propoxyphene group, Darvon(r) being the most common. Numerous studies demonstrate that this group is no more effective than aspirin or acetaminophen in relieving pain. As far as my personal choice of analgesics is concerned, I do try to use the milder ones alone and in combination with a relaxant or sedative, such as antihistamine. The sedative effects of antihistamine may potentiate the analgesic effect, as may caffeine, through other mechanisms. Percogesic(r) (a terrible name because everybody thinks it's Percodan(r) or related to Percodan) is a mixture of antihistamine and an aspirin compound. Phrenilin(r) and Dialog(r) are mixtures of acetaminophen and barbiturates. Synalgos(r) is a mixture of APC and a phenothiazole. For acute muscle contraction headache, or sprain or injury of neck or shoulder, occasional use of muscle relaxants combined with aspirin or acetaminophen may be worthwhile. Analgesics, especially those combined with sedatives, should not be prescribed for prolonged use in chronic headache conditions. Yet Fiorinal and Darvon are probably the most frequently prescribed analgesics for chronic headache. Remember that Fiorinal contains 50 mg. of a barbiturate; a large dose. It's not unusual to see patients taking 8, 10 or 12 Fiorinal tablets a day. The newer group of nonaspirin, nonsteroidal agents are marketed as Nalfon,(r) Naprosyn,(r) Motrin,(r) and now Clinoril(r) (which everybody wants since reading about it in the paper). Indocin(r) was mentioned this morning. Some of these drugs are quite useful in controlling minor headaches and acute muscle contraction-type headaches. Midrin(r) is a combination of isometheptine, which is a vasoconstrictor, and acetaminophen. Personally, I find this useful in mixed headache of mild intensity; I don't find it helpful in migraine. I'd like to mention a couple of drugs that I don't use and don't think others should use. These are Talwin(r) and Percodan. These narcotics (Talwin is being classified as a narcotic) are classified as analgesics having low addicting potential; but I've seen many problems as a result of their use. Now if narcotics are needed, I prefer to use codeine, in small amounts. I think there have been ample studies which show that it is probably the least addicting, certainly much less, in my experience, than Percodan, and perhaps even less than the propoxyphene group. Now, how does one avoid drug abuse? By not prescribing it to begin with. But our concern is for the patients who are already on the drugs and the problem is how do you get them off. I believe that the thrust must be with the use of other modalities such as psychotherapy, biofeedback training, physical therapy and the use of an antidepressant medication, found to be most useful in chronic headache. As mentioned earlier, the multiple-disciplinary approach is the most helpful. A good history from the patient should alert you to the possibility of drug abuse, and you have to take the patients' history with a little bit of skepticism. They don't like to admit to you that they're taking so many drugs and will often lie about it. I recently saw a patient who had been seeing a headache specialist for some seven years on a regular monthly basis, taking ergotamine and analgesics, and doing fairly well. The doctor was satisfied with her headache control: but when I examined her she had large lumps all over her buttocks and her legs, with a couple of deep folds down to the muscle in her thigh. They weren't draining but they had been. I asked what caused that and she replied that she used a little bit of Talwin. How much? Five or six injections a day. For how long? Seven or eight years. And what did her doctor say about this? He hasn't been told. I asked if she had been examined. No, never. I've seen severe muscle problems, atrophy, and hardening and woodening of the muscles, following repeated injections with Talwin. Dr. Diamond: The second panelist is Dr. Arnold Friedman, who will talk about the value of ergot in aborting migraine attacks. Dr. Friedman: Basically, ergotamine is not a new agent. Well over a hundred years ago, ergotamine was listed as a treatment for headache in the pharmacology encyclopedia. It was used by Thompson, in the United States, in about 1894 (as an enema of ergotamine), and Eulenberg used it in Europe, in 1883. After its use died out, Stohl picked it up again in 1925, and since that time it has been used rather vigorously for the treatment of migraine, with great success and with some failures; and also overused, as most of these drugs have been. The use of ergotamine in the treatment of migraine illustrates an elementary principle of pharmacology, which states that increasing the dose of a therapeutic compound leads to
maximum effectiveness, but on further increase, it would produce toxic side effects. This is very true for ergotamine. I will discuss this briefly on two bases: one, the individual dose; two, the question of overdose and rebound. If you give a high dose of ergot, as indicated in various leaflets, you commonly get toxic effects - which are worse than the original headache. Yet, small doses are equally effective as large doses. Usually a couple of milligrams will do the trick; if not, larger amounts will not. However, administration must be by appropriate methods and means. In recent times, plasma and salivary drug levels of ergotamine have been determined in patients during an attack and in normal subjects. Using a radioimmunoassay method, the effervescent ergotamine (not available in this country but used quite liberally in Europe) resulted in poorly sustained blood levels. Intramuscular injection of ergotamine went rapidly into the circulation and plasma levels were sustained for many hours. Administration of ergotamine by inhalation appeared to be inefficient. Most of the drug had deposited on the oral pharyngeal mucosa and remained unabsorbed. During a migraine attack, oral ergotamine absorption might be impaired, and tablets will not even start to disintegrate after a half hour or an hour. Not infrequently, tablets are regurgitated. The original work that Harold Wolff and John Graham and others have done indicates that when the vessels dilate during migraine, demonstrated as increased amplitude of pulsation, the amplitude of pulsation and the headache are reduced following the administration of ergotamine. But I would also call your attention to the fact that other work done later indicated that this does not occur in all cases of pain, including head pain from migraine (related to the extracranial circulation). Now the problem of drug dependence in migraine must be considered in the management of this disorder. This is particularly noticeable in patients who have taken ergotamine or narcotics daily for many years. Manifestations of withdrawal are possible complications in patients who use the drug daily and use it in increasing dosage for long periods. I've seen in consultation a number of patients who took two to three milligrams of ergotamine daily for 3 to 25 years, and complained of daily headaches. Many of these patients were checked at Columbia Presbyterian by the peripheral vascular people. Surprisingly, the peripheral vascular circulation was intact. But in some of these patients the dosage had to be increased in order to secure continued relief from attacks, plus there can be a rebound reaction of constriction, dilatation and headache from prolonged use. Recognition of ergotamine rebound is essential. The symptoms are, often, increasing frequency of headache, loss of feeling of well-being, fatigue, let-down, periods of anxiety and depression and, in some cases, toxicity. In a few patients one may see early stages of mild chronic ergotism with nausea, vomiting, increased headache and mild peripheral circulatory insufficiency. Moreover, in the patients who report increased headache if ergotamine is not taken, investigation will reveal that the use of the drug bears little relationship to the relief of the headache. Most of these patients also suffer from underlying emotional problems, depression and anxiety, etc. Gradual withdrawal of the drug and management of underlying psychological problems will form the basis of your proper treatment. There have been efforts by some people to refute the efficacy of ergotamine in the treatment of the acute attack in migraine. In my experience ergotamine is a very effective drug. The problem in some unsuccessful cases was, probably, how much was given and by what route. Using an inappropriate route of administration, side effects and toxicity will in many cases reduce or destroy the effectiveness of the drug. Now one or two words on ergotism. Although rare, it's a very frightening experience for the patient and the physician, and there have been some serious effects from ergotism, including loss of a limb. It is not always related to the amount of drug you have given. It can occur in small amounts and in certain phases, and particularly during septic states. Recently, a dermatologist hospitalized a patient because of some skin lesions which were septic. She complained of her usual headache and was given ergotamine and Bellergal(r) at the same time. Over a period of about four days, more headaches occurred and the limbs changed color. The doctor was called at night and reordered the usual medicine (ergotamine). The next morning, the results were catastrophic; the lady lost a leg. Although such events are uncommon, this drug should not be prescribed without careful follow-up of your patient. If you can't see the patient often, prescribe only minimal amounts. With this doleful statement, I will conclude, but I reiterate that ergotamine is an effective drug. Your results will depend on how well you use it. Dr. Diamond: The next speaker is Dr. David Rothner, who will talk about the use of analgesics in children. Dr. Rothner: I think I should say by way of introduction that when it comes to the subject of pain or perceived pain in children, I am a therapeutic nihilist. Dr. Kunkel's address might be entitled How to get them off medication; my address should be subtitled How not to get them on medication, because I think nonuse of medication is probably the wiser course when one deals with children. When one talks about analgesia, one first must define what pain is and what pain represents. Pain is a subjective symptom. It means different things to different people. When a 45-year-old man has fleeting chest pain and his concern is of myocardial infarction or angina, and one reassures him that it's esophageal reflux from his gastrointestinal tract, somehow the pain takes on much less
significance than it had before. So the first considerations are, what does the pain represent, what are the associated anxieties, and what is the social and emotional environment in which this particular pain is occurring? The second thing one must take into consideration is, is the pain acute or is the pain chronic? And lastly, what is the underlying condition causing the pain? Let us talk first about the so-called acute pain that comes with a specific disorder. The first consideration is to alleviate the primary disease. Some of the worst pain that we see in children (especially when I was doing general pediatric practice; and in my own children) is the pain of acute otitis media. This can be a very severe pain. But if one gives antihistamines which sedate the patient, uses possibly a topical anesthetic or drying agent such as Auralgen(r) and above all, treats the primary condition, the pain no longer becomes as significant as it was before. Therefore, in an acute illness, the primary goal should be not the alleviation of the pain per se, but rather the treatment and the alleviation of the primary disease, whatever it is. One should also realize that if the primary disease is neurological, medication which could aggravate the primary neurologic condition should not be prescribed. So, if the patient has increased intracranial pressure, do not use medication which will aggravate anoxia. In addition to pain, most people have anxiety. In children we can deal with the anxiety with soporific agents. The judicious use of a mild analgesic with a soporific agent or with an antianxiety agent can frequently obviate the necessity of using major-league analgesics. It would be a rare situation where I would have to use morphine or Demerol or even codeine. If you have an acute recurrent disease such as migraine headache, I think that you have to be careful in the way you prescribe medication. There are very few if any patients who walk out of my office with refillable prescriptions for analgesic agents: Darvon or codeine or anything of that sort. If the patient is under 10 or 12 years of age, he should never self-medicate. After that age, if they are going to self-medicate, there should be certain restrictions and certain methods of observing how much medication they are permitted to take. In an acute recurrent illness, use an indicated prophylactic agent. Attacks occurring several times a month can be treated with a prophylactic agent, obviating the necessity of using major analgesics. Try to allay anxiety and help induce sleep, especially in the patient with migraine when your prophylactic agent does not work, and, only if necessary, use a mild analgesic. When we talk about chronic pain, we must consider two distinct circumstances. The first is that of significant organic disease that is not going to respond to treatment, for example, metastatic carcinoma. In these cases, you should make the patients as comfortable as possible and use major analgesics, if necessary. The addition of antianxiety agents may be useful. Take into account the circumstances of the patient. I find that you can use fewer analgesic agents if you spend more time with the patients and find out exactly what's going on in their lives. So the more time you spend, the fewer major analgesics you'll have to use. The second type includes such conditions as so-called tension headaches or combined headaches. These occur less frequently in children than in adults. A good rule to abide by in such circumstances is never to give major narcotic analgesics. Never give refillable prescriptions; instead, see the patient frequently and try to work with him and his family to find other methods of dealing with their problem than the pill. It's important to correct the psychological environment and not use medication, and above all, not to make the treatment of the disease worse than the disease itself. Dr. Diamond: The last speaker is Dr. Donald J. Dalessio, who will talk about the complications of drug abuse in relationship to the headache patient. Dr. Dalessio: It has always interested me that patients will abuse ergot and, as Dr. Friedman said, "take ergot on a daily basis." Of course, one wonders whether they're getting some sort of high from the lysergic acid component of ergotamine. Ergotism has a long history. It goes back to the Middle Ages when peasants would ingest rye contaminated by the ergot fungus. They experienced the typical signs of ergotism: vasoconstriction, burning in the extremities, and they became demented (probably related to the formation of LSD from ergot). The ergot fungus itself makes about 50 different kinds of ergot compounds. Methysergide is an ergot derivative: a rather powerful vasoconstrictor. If used over a prolonged period of time, it may lead to fibrosis, occurring in the retroperitoneal space, heart and lungs. If you use this drug, beware of these significant complications. How does excessive ergot produce ergotism? Not only does it produce both arteriolar and venular vasoconstriction but also it damages the endothelium of small blood vessels and capillaries, eventually reducing the circulation and producing gangrene. Sometimes this may occur in situations where the dose of ergot was not excessive. We make it a rule not to use ergot drugs in patients with compromised vascular circulation, or in those over 65 years of age. Common drugs also can cause trouble. Analgesics, particularly phenacetin, may produce acute nephropathy and chronic kidney disease. Our gastroenterologists feel very strongly that about half the ulcer patients they see are common analgesic, particularly aspirin, abusers. Hemopathy may result from chronic analgesic use, particularly aspirin, producing sulfhemoglobin and methemoglobin. We see a lot of patients who are chronic aspirin abusers whose hemoglobins run in the range of 11.5 to 12 gm./100
ml. After stopping aspirin, the hemoglobin increases to 14 and 15 gm. I suspect that aspirin may have interfered with the hemopoietic process, although there may also have been slight or microscopic bleeding from the gastrointestinal tract. And then there are those patients with psychiatric and neurologic disorders who appear to be habituated to the idea of taking medication. The analgesics seem to answer some unfilled need in terms of a personality disorder, and on occasion they produce unexplained neurologic syndromes. Our response to these patients is to employ what we term the Pain Clinic approach. We have a Pain Clinic, as have several people in the audience (Dr. Crue and Dr. Pinsky, from the City of Hope, Dr. Sadove from Chicago), who could probably speak better about this than I. In all of these patients with chronic pain, we get psychological tests, and I want the tests, not just the psychiatric opinion; I want the data. Hence, the psychologist sees the patient initially. Frequently, it's necessary to admit these patients to hospitals for detoxification. Often, we'll make up a compound which we call Scripps Clinic analgesic, which is 50% acetaminophen and 50% sodium salycilate and give it as two teaspoonfuls every four hours while awake, if we're dealing with chronic pain patients who absolutely must have them. It is given on a regular basis rather than on demand, so that the patients do not have to say "I have pain, therefore I need the pill." We frequently employ transcutaneous neurostimulators for some patients with chronic pain, and drugs to change behavior. Rheumatologists are asked to see the patient for instruction on the proper use of physical therapy or local injections. Sometimes we use hypnosis, group therapy and other techniques. We also emphasize activity management. The patient has got to get up and start moving, and not lie in bed. The nursing staff is counselled to avoid prolonged pain discussions with the patient and to stop pushing drugs. If you write "Empirin compound with codeine, every four hours," some nurses who can't wait the four hours, give the medication to shut the patient up. It takes a lot more effort on the part of the nursing service to run this sort of unit than it does on the part of the physician, so you have to indoctrinate them. In any case, for patients who want to get better, their problem is likely to be resolved by your efforts. In those patients who do not want to get better and who simply want their prescriptions refilled, you're going to fail. The patient is going to leave you and go to somebody else who will write the prescription that he wants. Dr. Diamond: Do any of the panelists wish to comment on any of these presentations? Dr. Friedman: Excessive drug use is a real problem, as indicated in Dr. Kunkel's presentation. Many of these patients are psychologically drug-dependent, and in psychiatric jargon, they're oral-dependent individuals. Although there are many who disagree with me, it is my opinion that autogenic and other techniques will not influence their basic oral-dependent problem. Instead, it requires some knowledge of why and what the repeated use of analgesics means to that individual. What is the symbolic significance of having to put something in their mouths, like medicine? Although this is a more difficult approach, it is closer to the root of the problem. As another comment, at Columbia Presbyterian we studied the heavy intake of Fiorinal in some people who had been using 16 to 18 tablets a day. We found only little traces of barbiturate. An explanation may be that liver metabolism tends to increase with increasing drug use, over a period of time, and thereby reduces the effect of the drug. Dr. Rothner: Unfortunately, it's much easier to sit down and write a prescription in 2 minutes than it is to spend 15 or 20 minutes with a patient. Physicians have to be a lot more careful in overprescribing medications. Dr. Diamond: I would like to take the prerogative, as Chairman, to make two comments. First, some patients claim to be allergic to ergotamine. Often this is based on symptoms of nausea, a not infrequent side effect of ergotamine. Secondly, regarding Dr. Friedman's comment on the limitations of autogenic training, I would only say that there is sufficient evidence that this modality of therapy offers considerable benefit. I do agree, however, that it should not be used to replace psychotherapy, where indicated. Remember also that this therapeutic modality is noninvasive and drugless, and has been beneficial in some cases, where drugs had failed. Dr. Friedman: I do want to make it clear that autogenic techniques, and biofeedback, indeed have helped people with headache. But they have not as yet stood up to the test of time. Dr. Jerry E. Wesch, Indianapolis, Indiana: You've all noted that counselling and nonanalgesic approaches are useful. However, the combination of psychotherapeutic treatments, using autogenics and counselling and psychotherapy, is a more complicated process than is ordinarily thought. One should make referrals carefully. Not many specialists can deal with non-narcotic, nonpsychotic populations. Dr. Ninan T. Mathew, Houston, Texas: Will somebody comment on caffeine dependency and caffeine control? I find that to be a common problem in patients with daily headache who abuse or overuse over-the-counter medications. Dr. Friedman: Caffeine withdrawal headache is very common. In such cases, the headache comes on in the morning, following a period of night-time withdrawal. The mechanism is probably vascular. People who have migraine should not use a lot of caffeine. However, in small amounts, used infrequently, caffeine may potentiate the effects of ergotamine, thereby enabling a reduction in ergot. Caffeine-dependent individuals should be taken off the caffeine
over a short period of time, although not in one night. Dr. W.J. Russell Taylor, Philadelphia, Pennsylvania: For the past year I've been directing a federally funded health care live-in facility which started in the Pennsylvania Hospital. A few months ago we decided to computerize our data and activities. We had an opportunity to look at potential drug abusers in a patient population of about 6,000. I was astounded by the number of patients who were being prescribed excessive amounts of analgesics for headaches by my physicians. After an investigation, I found that aside from the expected complications of increased gastritis or ulcers, these people were having disturbances of sleep pattern and early morning headache. Often, they had been receiving large amounts of analgesics, including barbiturates and propoxyphen in combinations. Since I come from the Philadelphia General Hospital, with ten years of drug-abuse experience, I methodically withdrew these people from analgesics and started them on tricyclics. Good headache relief was achieved with either amitriptyline or other anti-depressants. Dr. Rothner: I think the work in Sleep Clinics across the country would bear out that these medications (analgesics) do interfere with normal sleep patterns and don't improve sleep. Patients who are withdrawn from these drugs end up sleeping better. Dr. Max S. Sadove, Chicago, Illinois: I would like to make several comments. In the laboratory, regarding the barbiturate question, we found enzyme reduction appears with the second dose. Over a period of time, many of these drugs have less and less effect, even though blood levels may be very high. Regarding the issue of caffeine, I challenge anyone to show me any good evidence that caffeine augments analgesia in a statistical, careful analytic study. I studied caffeine added to three narcotics, in human subjects. It was always antianalgesic. On the other hand, it may affect mood, thus enabling the patient to accept the pain. I'd like to emphasize a point that was brought out so beautifully. In many instances, the combination of something mild to alleviate the pain plus something to diminish suffering will do a much better total job. Those of you who had the misfortune to be on the shores of Omaha Beach during World War II, or other combat zones, are aware that wounded patients in pain cannot absorb stomach contents. The food lies in the stomach for six, seven and eight hours. Thus, any patient in pain will frequently not absorb oral drugs. Regarding drug dose, it is more effective to administer medication intravenously when treating severe headache. In this manner, the dosage may be reduced by one-third and have a maximum effect in eight minutes. Dr. Jack J. Pinsky, City of Hope, Duarte, California: In the matter of acute versus chronic conditions, the treatment of acute pain does not present a problem to either physicians or patients. The only problem that we and the patients have is the problem of chronic pain. All talk about effective doses and medicine's intravenous peak levels have absolutely nothing to do with the treatment of the "big medical problem": the treatment of chronic pain and suffering. Dr. Diamond: I would like to add that there has been one study showing effectiveness of caffeine. This is the work of Vinegar, which was reported about six months ago. Dr. Packard: I would agree with Dr. Rothner that the more time you spend with the patient, the less medication is needed. Over the past two-year period I've been running a survey on what the headache patient wants. Thus far, the number one item was not related to pain, but rather an explanation of what's causing the pain and suffering. They had all been to many doctors, yet they stated that nobody had taken the time to explain what was wrong with them. Dr. Diamond: In closing, I would like to thank the audience and the panel for their participation.
The Use of Analgesics in Headache MODERATOR: Seymour Diamond, M.D. TOPICS PARTICIPANTS Choice of Analgesics and Avoidance of AbuseRobert S. Kunkel, M.D. Value of Ergots in Aborting Migraine AttackArnold P. Friedman, M.D. Use of Analgesics in Children A. David Rothner, M.D. Complications of Drug Abuse in Relation to the Headache Patient Donald J. Dalessio, M.D. Dr. Diamond: There is a need for expertise in the pharmacology of pain medications, when treating the headache sufferer. At least half the letters I dictate to referring physicians every week include the following: "Dear Doctor, your patient is habituated to the following drugs (I then list the drugs). We will not be able to help him until he is hospitalized or otherwise weaned off the habituating medications." Then I offer the diagnosis and other recommendations concerning headache treatment. The criteria which distinguish analgesic use from abuse in headache are difficult to establish. Where does one draw the line? When do you use narcotics or simple analgesics? Where does ergotamine tartrate come in? We see patients who are taking excessive amounts of Empirin(r) and codeine, Phenaphen(r) and codeine, Demerol,(r) barbiturates, Fiorinal(r) and propoxyphene compounds. But we also see the patient who abuses the common over-the-counter drugs: Excedrin,(r) aspirin and acetaminophen. What are the consequences of all this, and how do we handle this patient? We have gathered a distinguished group of participants to discuss the subject of analgesics and headaches, and give you some ideas on how to handle the problem. In our format, each discussant will spend about six to eight minutes talking about their subject. The panel also will discuss each subject and then open it up to questions from the audience. I would like to call on Dr. Robert S. Kunkel from the Cleveland Clinic to talk about the choice of analgesics and the avoidance of abuse. Dr. Kunkel: Well, Dr. Diamond, I'm sorry you gave me that topic because it's difficult for me to discuss "choices" of analgesics since I don't like to prescribe them in the first place. As you've already mentioned, most of the patients who come to doctors have already tried many analgesics. Many of them are on barbiturates, and we really spend much of our time trying to figure out how to get them off. Nevertheless, analgesics can be useful for the periodic headache. They certainly should not be used for the treatment of chronic, day-in and day-out headaches. In such patients, specific nonanalgesic medications which interfere with the mechanisms of chronic headache should be the drugs of choice. However, for periodic head pain, I think we are all in agreement that nonaddicting preparations, or perhaps analgesics with very low addicting potential, may be indicated. Aspirin is obviously the most widely used analgesic for headache and other pain; yet most patients, who come to doctors because of headache, have found that aspirin is not effective. It should be noted that aspirin is not an innocuous drug. We all know about the GI side effects; some 40%-60% of patients have been found to have occult blood loss of 2-6 milliliters per day. This could cause significant anemia if the diet isn't adequate. A few patients have parenchymal hemorrhage from gastric erosions. Also, idiosyncratic-type hypersensitivity reactions may occur, particularly in asthmatics; 2%-4% of asthmatics are susceptible to such reactions to aspirin. There are, of course, hematologic effects. Aspirin interferes with platelet function resulting in prolonged bleeding time. Aspirin also displaces Coumadin(r)-type anticoagulants from their protein binding sites and, therefore, should be used cautiously by persons on anticoagulants. Interreactions with aspirin have also been reported with antifungal agents, sulfonamides, monamine-oxidase-inhibiting agents, sulfonylurea-hypoglycemic agents, and uricosuric agents.
By contrast, adverse effects with acetaminophen are remarkably uncommon when the drug is used at dosages of 4 grams or less per day. Acetaminophen is relatively free of the gastrointestinal side effects that can occur with aspirin, such as gastric mucosal irritation and erosion and gastrointestinal bleeding. Also, in contrast to aspirin, acetaminophen has little or no effect on platelet aggregation and does not influence hemostasis in the postoperative patient requiring an analgesic. There has been some question about renal and liver damage with the long-term use of acetaminophen, although existing evidence suggests these problems are seen only in the case of acute massive overdoses, most commonly taken with suicidal intent or pretense. Studies indicate that acetaminophen and aspirin, on a milligram-for-milligram basis, have equal analgesic and antipyretic activities. Either one alone is as effective as other over-the-counter analgesic compounds, such as Vanquish,(r) Excedrin, Anacin,(r) Bufferin,(r) and Empirin, which contain various mixtures of aspirin, acetaminophen, caffeine, and antacids. Other analgesics are from the propoxyphene group, Darvon(r) being the most common. Numerous studies demonstrate that this group is no more effective than aspirin or acetaminophen in relieving pain. As far as my personal choice of analgesics is concerned, I do try to use the milder ones alone and in combination with a relaxant or sedative, such as antihistamine. The sedative effects of antihistamine may potentiate the analgesic effect, as may caffeine, through other mechanisms. Percogesic(r) (a terrible name because everybody thinks it's Percodan(r) or related to Percodan) is a mixture of antihistamine and an aspirin compound. Phrenilin(r) and Dialog(r) are mixtures of acetaminophen and barbiturates. Synalgos(r) is a mixture of APC and a phenothiazole. For acute muscle contraction headache, or sprain or injury of neck or shoulder, occasional use of muscle relaxants combined with aspirin or acetaminophen may be worthwhile. Analgesics, especially those combined with sedatives, should not be prescribed for prolonged use in chronic headache conditions. Yet Fiorinal and Darvon are probably the most frequently prescribed analgesics for chronic headache. Remember that Fiorinal contains 50 mg. of a barbiturate; a large dose. It's not unusual to see patients taking 8, 10 or 12 Fiorinal tablets a day. The newer group of nonaspirin, nonsteroidal agents are marketed as Nalfon,(r) Naprosyn,(r) Motrin,(r) and now Clinoril(r) (which everybody wants since reading about it in the paper). Indocin(r) was mentioned this morning. Some of these drugs are quite useful in controlling minor headaches and acute muscle contraction-type headaches. Midrin(r) is a combination of isometheptine, which is a vasoconstrictor, and acetaminophen. Personally, I find this useful in mixed headache of mild intensity; I don't find it helpful in migraine. I'd like to mention a couple of drugs that I don't use and don't think others should use. These are Talwin(r) and Percodan. These narcotics (Talwin is being classified as a narcotic) are classified as analgesics having low addicting potential; but I've seen many problems as a result of their use. Now if narcotics are needed, I prefer to use codeine, in small amounts. I think there have been ample studies which show that it is probably the least addicting, certainly much less, in my experience, than Percodan, and perhaps even less than the propoxyphene group. Now, how does one avoid drug abuse? By not prescribing it to begin with. But our concern is for the patients who are already on the drugs and the problem is how do you get them off. I believe that the thrust must be with the use of other modalities such as psychotherapy, biofeedback training, physical therapy and the use of an antidepressant medication, found to be most useful in chronic headache. As mentioned earlier, the multiple-disciplinary approach is the most helpful. A good history from the patient should alert you to the possibility of drug abuse, and you have to take the patients' history with a little bit of skepticism. They don't like to admit to you that they're taking so many drugs and will often lie about it. I recently saw a patient who had been seeing a headache specialist for some seven years on a regular monthly basis, taking ergotamine and analgesics, and doing fairly well. The doctor was satisfied with her headache control: but when I examined her she had large lumps all over her buttocks and her legs, with a couple of deep folds down to the muscle in her thigh. They weren't draining but they had been. I asked what caused that and she replied that she used a little bit of Talwin. How much? Five or six injections a day. For how long? Seven or eight years. And what did her doctor say about this? He hasn't been told. I asked if she had been examined. No, never. I've seen severe muscle problems, atrophy, and hardening and woodening of the muscles, following repeated injections with Talwin. Dr. Diamond: The second panelist is Dr. Arnold Friedman, who will talk about the value of ergot in aborting migraine attacks. Dr. Friedman: Basically, ergotamine is not a new agent. Well over a hundred years ago, ergotamine was listed as a treatment for headache in the pharmacology encyclopedia. It was used by Thompson, in the United States, in about 1894 (as an enema of ergotamine), and Eulenberg used it in Europe, in 1883. After its use died out, Stohl picked it up again in 1925, and since that time it has been used rather vigorously for the treatment of migraine, with great success and with some failures; and also overused, as most of these drugs have been. The use of ergotamine in the treatment of migraine illustrates an elementary principle of pharmacology, which states that increasing the dose of a therapeutic compound leads to
maximum effectiveness, but on further increase, it would produce toxic side effects. This is very true for ergotamine. I will discuss this briefly on two bases: one, the individual dose; two, the question of overdose and rebound. If you give a high dose of ergot, as indicated in various leaflets, you commonly get toxic effects - which are worse than the original headache. Yet, small doses are equally effective as large doses. Usually a couple of milligrams will do the trick; if not, larger amounts will not. However, administration must be by appropriate methods and means. In recent times, plasma and salivary drug levels of ergotamine have been determined in patients during an attack and in normal subjects. Using a radioimmunoassay method, the effervescent ergotamine (not available in this country but used quite liberally in Europe) resulted in poorly sustained blood levels. Intramuscular injection of ergotamine went rapidly into the circulation and plasma levels were sustained for many hours. Administration of ergotamine by inhalation appeared to be inefficient. Most of the drug had deposited on the oral pharyngeal mucosa and remained unabsorbed. During a migraine attack, oral ergotamine absorption might be impaired, and tablets will not even start to disintegrate after a half hour or an hour. Not infrequently, tablets are regurgitated. The original work that Harold Wolff and John Graham and others have done indicates that when the vessels dilate during migraine, demonstrated as increased amplitude of pulsation, the amplitude of pulsation and the headache are reduced following the administration of ergotamine. But I would also call your attention to the fact that other work done later indicated that this does not occur in all cases of pain, including head pain from migraine (related to the extracranial circulation). Now the problem of drug dependence in migraine must be considered in the management of this disorder. This is particularly noticeable in patients who have taken ergotamine or narcotics daily for many years. Manifestations of withdrawal are possible complications in patients who use the drug daily and use it in increasing dosage for long periods. I've seen in consultation a number of patients who took two to three milligrams of ergotamine daily for 3 to 25 years, and complained of daily headaches. Many of these patients were checked at Columbia Presbyterian by the peripheral vascular people. Surprisingly, the peripheral vascular circulation was intact. But in some of these patients the dosage had to be increased in order to secure continued relief from attacks, plus there can be a rebound reaction of constriction, dilatation and headache from prolonged use. Recognition of ergotamine rebound is essential. The symptoms are, often, increasing frequency of headache, loss of feeling of well-being, fatigue, let-down, periods of anxiety and depression and, in some cases, toxicity. In a few patients one may see early stages of mild chronic ergotism with nausea, vomiting, increased headache and mild peripheral circulatory insufficiency. Moreover, in the patients who report increased headache if ergotamine is not taken, investigation will reveal that the use of the drug bears little relationship to the relief of the headache. Most of these patients also suffer from underlying emotional problems, depression and anxiety, etc. Gradual withdrawal of the drug and management of underlying psychological problems will form the basis of your proper treatment. There have been efforts by some people to refute the efficacy of ergotamine in the treatment of the acute attack in migraine. In my experience ergotamine is a very effective drug. The problem in some unsuccessful cases was, probably, how much was given and by what route. Using an inappropriate route of administration, side effects and toxicity will in many cases reduce or destroy the effectiveness of the drug. Now one or two words on ergotism. Although rare, it's a very frightening experience for the patient and the physician, and there have been some serious effects from ergotism, including loss of a limb. It is not always related to the amount of drug you have given. It can occur in small amounts and in certain phases, and particularly during septic states. Recently, a dermatologist hospitalized a patient because of some skin lesions which were septic. She complained of her usual headache and was given ergotamine and Bellergal(r) at the same time. Over a period of about four days, more headaches occurred and the limbs changed color. The doctor was called at night and reordered the usual medicine (ergotamine). The next morning, the results were catastrophic; the lady lost a leg. Although such events are uncommon, this drug should not be prescribed without careful follow-up of your patient. If you can't see the patient often, prescribe only minimal amounts. With this doleful statement, I will conclude, but I reiterate that ergotamine is an effective drug. Your results will depend on how well you use it. Dr. Diamond: The next speaker is Dr. David Rothner, who will talk about the use of analgesics in children. Dr. Rothner: I think I should say by way of introduction that when it comes to the subject of pain or perceived pain in children, I am a therapeutic nihilist. Dr. Kunkel's address might be entitled How to get them off medication; my address should be subtitled How not to get them on medication, because I think nonuse of medication is probably the wiser course when one deals with children. When one talks about analgesia, one first must define what pain is and what pain represents. Pain is a subjective symptom. It means different things to different people. When a 45-year-old man has fleeting chest pain and his concern is of myocardial infarction or angina, and one reassures him that it's esophageal reflux from his gastrointestinal tract, somehow the pain takes on much less
significance than it had before. So the first considerations are, what does the pain represent, what are the associated anxieties, and what is the social and emotional environment in which this particular pain is occurring? The second thing one must take into consideration is, is the pain acute or is the pain chronic? And lastly, what is the underlying condition causing the pain? Let us talk first about the so-called acute pain that comes with a specific disorder. The first consideration is to alleviate the primary disease. Some of the worst pain that we see in children (especially when I was doing general pediatric practice; and in my own children) is the pain of acute otitis media. This can be a very severe pain. But if one gives antihistamines which sedate the patient, uses possibly a topical anesthetic or drying agent such as Auralgen(r) and above all, treats the primary condition, the pain no longer becomes as significant as it was before. Therefore, in an acute illness, the primary goal should be not the alleviation of the pain per se, but rather the treatment and the alleviation of the primary disease, whatever it is. One should also realize that if the primary disease is neurological, medication which could aggravate the primary neurologic condition should not be prescribed. So, if the patient has increased intracranial pressure, do not use medication which will aggravate anoxia. In addition to pain, most people have anxiety. In children we can deal with the anxiety with soporific agents. The judicious use of a mild analgesic with a soporific agent or with an antianxiety agent can frequently obviate the necessity of using major-league analgesics. It would be a rare situation where I would have to use morphine or Demerol or even codeine. If you have an acute recurrent disease such as migraine headache, I think that you have to be careful in the way you prescribe medication. There are very few if any patients who walk out of my office with refillable prescriptions for analgesic agents: Darvon or codeine or anything of that sort. If the patient is under 10 or 12 years of age, he should never self-medicate. After that age, if they are going to self-medicate, there should be certain restrictions and certain methods of observing how much medication they are permitted to take. In an acute recurrent illness, use an indicated prophylactic agent. Attacks occurring several times a month can be treated with a prophylactic agent, obviating the necessity of using major analgesics. Try to allay anxiety and help induce sleep, especially in the patient with migraine when your prophylactic agent does not work, and, only if necessary, use a mild analgesic. When we talk about chronic pain, we must consider two distinct circumstances. The first is that of significant organic disease that is not going to respond to treatment, for example, metastatic carcinoma. In these cases, you should make the patients as comfortable as possible and use major analgesics, if necessary. The addition of antianxiety agents may be useful. Take into account the circumstances of the patient. I find that you can use fewer analgesic agents if you spend more time with the patients and find out exactly what's going on in their lives. So the more time you spend, the fewer major analgesics you'll have to use. The second type includes such conditions as so-called tension headaches or combined headaches. These occur less frequently in children than in adults. A good rule to abide by in such circumstances is never to give major narcotic analgesics. Never give refillable prescriptions; instead, see the patient frequently and try to work with him and his family to find other methods of dealing with their problem than the pill. It's important to correct the psychological environment and not use medication, and above all, not to make the treatment of the disease worse than the disease itself. Dr. Diamond: The last speaker is Dr. Donald J. Dalessio, who will talk about the complications of drug abuse in relationship to the headache patient. Dr. Dalessio: It has always interested me that patients will abuse ergot and, as Dr. Friedman said, "take ergot on a daily basis." Of course, one wonders whether they're getting some sort of high from the lysergic acid component of ergotamine. Ergotism has a long history. It goes back to the Middle Ages when peasants would ingest rye contaminated by the ergot fungus. They experienced the typical signs of ergotism: vasoconstriction, burning in the extremities, and they became demented (probably related to the formation of LSD from ergot). The ergot fungus itself makes about 50 different kinds of ergot compounds. Methysergide is an ergot derivative: a rather powerful vasoconstrictor. If used over a prolonged period of time, it may lead to fibrosis, occurring in the retroperitoneal space, heart and lungs. If you use this drug, beware of these significant complications. How does excessive ergot produce ergotism? Not only does it produce both arteriolar and venular vasoconstriction but also it damages the endothelium of small blood vessels and capillaries, eventually reducing the circulation and producing gangrene. Sometimes this may occur in situations where the dose of ergot was not excessive. We make it a rule not to use ergot drugs in patients with compromised vascular circulation, or in those over 65 years of age. Common drugs also can cause trouble. Analgesics, particularly phenacetin, may produce acute nephropathy and chronic kidney disease. Our gastroenterologists feel very strongly that about half the ulcer patients they see are common analgesic, particularly aspirin, abusers. Hemopathy may result from chronic analgesic use, particularly aspirin, producing sulfhemoglobin and methemoglobin. We see a lot of patients who are chronic aspirin abusers whose hemoglobins run in the range of 11.5 to 12 gm./100
ml. After stopping aspirin, the hemoglobin increases to 14 and 15 gm. I suspect that aspirin may have interfered with the hemopoietic process, although there may also have been slight or microscopic bleeding from the gastrointestinal tract. And then there are those patients with psychiatric and neurologic disorders who appear to be habituated to the idea of taking medication. The analgesics seem to answer some unfilled need in terms of a personality disorder, and on occasion they produce unexplained neurologic syndromes. Our response to these patients is to employ what we term the Pain Clinic approach. We have a Pain Clinic, as have several people in the audience (Dr. Crue and Dr. Pinsky, from the City of Hope, Dr. Sadove from Chicago), who could probably speak better about this than I. In all of these patients with chronic pain, we get psychological tests, and I want the tests, not just the psychiatric opinion; I want the data. Hence, the psychologist sees the patient initially. Frequently, it's necessary to admit these patients to hospitals for detoxification. Often, we'll make up a compound which we call Scripps Clinic analgesic, which is 50% acetaminophen and 50% sodium salycilate and give it as two teaspoonfuls every four hours while awake, if we're dealing with chronic pain patients who absolutely must have them. It is given on a regular basis rather than on demand, so that the patients do not have to say "I have pain, therefore I need the pill." We frequently employ transcutaneous neurostimulators for some patients with chronic pain, and drugs to change behavior. Rheumatologists are asked to see the patient for instruction on the proper use of physical therapy or local injections. Sometimes we use hypnosis, group therapy and other techniques. We also emphasize activity management. The patient has got to get up and start moving, and not lie in bed. The nursing staff is counselled to avoid prolonged pain discussions with the patient and to stop pushing drugs. If you write "Empirin compound with codeine, every four hours," some nurses who can't wait the four hours, give the medication to shut the patient up. It takes a lot more effort on the part of the nursing service to run this sort of unit than it does on the part of the physician, so you have to indoctrinate them. In any case, for patients who want to get better, their problem is likely to be resolved by your efforts. In those patients who do not want to get better and who simply want their prescriptions refilled, you're going to fail. The patient is going to leave you and go to somebody else who will write the prescription that he wants. Dr. Diamond: Do any of the panelists wish to comment on any of these presentations? Dr. Friedman: Excessive drug use is a real problem, as indicated in Dr. Kunkel's presentation. Many of these patients are psychologically drug-dependent, and in psychiatric jargon, they're oral-dependent individuals. Although there are many who disagree with me, it is my opinion that autogenic and other techniques will not influence their basic oral-dependent problem. Instead, it requires some knowledge of why and what the repeated use of analgesics means to that individual. What is the symbolic significance of having to put something in their mouths, like medicine? Although this is a more difficult approach, it is closer to the root of the problem. As another comment, at Columbia Presbyterian we studied the heavy intake of Fiorinal in some people who had been using 16 to 18 tablets a day. We found only little traces of barbiturate. An explanation may be that liver metabolism tends to increase with increasing drug use, over a period of time, and thereby reduces the effect of the drug. Dr. Rothner: Unfortunately, it's much easier to sit down and write a prescription in 2 minutes than it is to spend 15 or 20 minutes with a patient. Physicians have to be a lot more careful in overprescribing medications. Dr. Diamond: I would like to take the prerogative, as Chairman, to make two comments. First, some patients claim to be allergic to ergotamine. Often this is based on symptoms of nausea, a not infrequent side effect of ergotamine. Secondly, regarding Dr. Friedman's comment on the limitations of autogenic training, I would only say that there is sufficient evidence that this modality of therapy offers considerable benefit. I do agree, however, that it should not be used to replace psychotherapy, where indicated. Remember also that this therapeutic modality is noninvasive and drugless, and has been beneficial in some cases, where drugs had failed. Dr. Friedman: I do want to make it clear that autogenic techniques, and biofeedback, indeed have helped people with headache. But they have not as yet stood up to the test of time. Dr. Jerry E. Wesch, Indianapolis, Indiana: You've all noted that counselling and nonanalgesic approaches are useful. However, the combination of psychotherapeutic treatments, using autogenics and counselling and psychotherapy, is a more complicated process than is ordinarily thought. One should make referrals carefully. Not many specialists can deal with non-narcotic, nonpsychotic populations. Dr. Ninan T. Mathew, Houston, Texas: Will somebody comment on caffeine dependency and caffeine control? I find that to be a common problem in patients with daily headache who abuse or overuse over-the-counter medications. Dr. Friedman: Caffeine withdrawal headache is very common. In such cases, the headache comes on in the morning, following a period of night-time withdrawal. The mechanism is probably vascular. People who have migraine should not use a lot of caffeine. However, in small amounts, used infrequently, caffeine may potentiate the effects of ergotamine, thereby enabling a reduction in ergot. Caffeine-dependent individuals should be taken off the caffeine
over a short period of time, although not in one night. Dr. W.J. Russell Taylor, Philadelphia, Pennsylvania: For the past year I've been directing a federally funded health care live-in facility which started in the Pennsylvania Hospital. A few months ago we decided to computerize our data and activities. We had an opportunity to look at potential drug abusers in a patient population of about 6,000. I was astounded by the number of patients who were being prescribed excessive amounts of analgesics for headaches by my physicians. After an investigation, I found that aside from the expected complications of increased gastritis or ulcers, these people were having disturbances of sleep pattern and early morning headache. Often, they had been receiving large amounts of analgesics, including barbiturates and propoxyphen in combinations. Since I come from the Philadelphia General Hospital, with ten years of drug-abuse experience, I methodically withdrew these people from analgesics and started them on tricyclics. Good headache relief was achieved with either amitriptyline or other anti-depressants. Dr. Rothner: I think the work in Sleep Clinics across the country would bear out that these medications (analgesics) do interfere with normal sleep patterns and don't improve sleep. Patients who are withdrawn from these drugs end up sleeping better. Dr. Max S. Sadove, Chicago, Illinois: I would like to make several comments. In the laboratory, regarding the barbiturate question, we found enzyme reduction appears with the second dose. Over a period of time, many of these drugs have less and less effect, even though blood levels may be very high. Regarding the issue of caffeine, I challenge anyone to show me any good evidence that caffeine augments analgesia in a statistical, careful analytic study. I studied caffeine added to three narcotics, in human subjects. It was always antianalgesic. On the other hand, it may affect mood, thus enabling the patient to accept the pain. I'd like to emphasize a point that was brought out so beautifully. In many instances, the combination of something mild to alleviate the pain plus something to diminish suffering will do a much better total job. Those of you who had the misfortune to be on the shores of Omaha Beach during World War II, or other combat zones, are aware that wounded patients in pain cannot absorb stomach contents. The food lies in the stomach for six, seven and eight hours. Thus, any patient in pain will frequently not absorb oral drugs. Regarding drug dose, it is more effective to administer medication intravenously when treating severe headache. In this manner, the dosage may be reduced by one-third and have a maximum effect in eight minutes. Dr. Jack J. Pinsky, City of Hope, Duarte, California: In the matter of acute versus chronic conditions, the treatment of acute pain does not present a problem to either physicians or patients. The only problem that we and the patients have is the problem of chronic pain. All talk about effective doses and medicine's intravenous peak levels have absolutely nothing to do with the treatment of the "big medical problem": the treatment of chronic pain and suffering. Dr. Diamond: I would like to add that there has been one study showing effectiveness of caffeine. This is the work of Vinegar, which was reported about six months ago. Dr. Packard: I would agree with Dr. Rothner that the more time you spend with the patient, the less medication is needed. Over the past two-year period I've been running a survey on what the headache patient wants. Thus far, the number one item was not related to pain, but rather an explanation of what's causing the pain and suffering. They had all been to many doctors, yet they stated that nobody had taken the time to explain what was wrong with them. Dr. Diamond: In closing, I would like to thank the audience and the panel for their participation.
