Letters
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send three copies of the letter and a transfer-of-copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
monwealth of Pennsylvania may have given the authors the luxury to choose patients with mild disease that would be ideal candidates to enforce the DRG rules with apparent satisfaction. Another suggestion that the study patients had mild disease is that no deaths were recorded. During 1989 and 1990, ten of our patients in the general sickle cell anemia population died of complications. Finally, we wish to emphasize that, contrary to the authors' experiences, we had an average increase in emergency room visits and in hospital admission rates of about 15% and 40% in 1989 and 1990, respectively. Anyone managing unselected patients with sickle cell disease over a long period realizes that there is no panacea for all patients all the time and that the most reasonable approach is to establish protocols targeted to the individual patient or subsets of patients.
Treating Sickle Cell Pain like Cancer Pain
Ronald N. Rubin, MD Temple University Hospital Philadelphia, PA 19140
To the Editors: We read with interest the article by Brookoff and Polomano (1) about treating sickle cell pain like cancer pain. This concept is not new (2). Sickle cell disease is heterogeneous and varies from very mild to very severe. The exact diagnosis of the patients studied and their fetal hemoglobin (Hb F) level were not mentioned by Brookoff and Polomano. Patients with sickle cell anemia or sickle-/3°-thalassemia tend to have more frequent painful crises than patients with sickle cell Hb disease or sickle-0+-thalassemia (3). Moreover, several factors may moderate the severity of sickle cell anemia (3, 4). Patients with high Hb F values, for example, tend to do better (3). The authors point out that the study was not a controlled trial and that patients may have sought treatment elsewhere or may have had a change in crisis frequency. We strongly agree with those criticisms of the study. Our hospitals are close to the Hospital of the University of Pennsylvania (HUP), and we have shared patients over the years. From our perspective, we believe that the authors have selected a biased group of patients with relatively mild disease. Approximately 500 adult patients with sickle cell disease are registered in the Sickle Cell Program of the Commonwealth of Pennsylvania. The Hospital of the University of Pennsylvania is not a participant in this program and hence has the option to retain certain patients but not others. The patients described by Brookoff and Polomano (1) represent fewer than 10% of all adult patients with sickle cell disease in Philadelphia. We follow 370 adult patients in our institutions, and all are supported by the Sickle Cell Program of the Commonwealth of Pennsylvania. Several patients left HUP and joined our programs after the institution of "morphine-only" policy. On several occasions patients with sickle cell disease sought treatment in our hospitals and needed further therapy with parenteral narcotic analgesics possibly because of premature discharge from HUP. We also note that the decrease in number of admissions and length of hospital stay coincided with the implementation of the diagnosis-related group (DRG) system that began nationwide on 1 December 1988. The patients who migrated to our program often related that they were discharged about 5 days after admission, although they were still in pain. Others related that they had to leave HUP against medical advice because of dissatisfaction with the rapid reduction in pain treatment, apparently done to meet the 5-day target of hospital stay. The lack of participation in the Sickle Cell Program of the Com-
Samir K. Ballas, MD Thomas Jefferson University Philadelphia, PA 19107
Thomas C. Gabuzda, MD Lankenau Hospital Philadelphia, PA 19151 References 1. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116:364-8. 2. Ballas SK. Treatment of pain in adults with sickle cell disease. Am J Hematol. 1990;34:49-54. 3. Piatt OS, Thorington BD, Brambilla DJ, Milner P, Rosse WF, Vichinsky E, et al. Pain in sickle cell disease: rates and risk factors. N Engl J Med. 1991;325:11-6. 4. Ballas SK, Larner J, Smith ED, Schwartz E, Rappaport EF. Rheologic predictors of the severity of the painful sickle cell crisis. Blood. 1988;72:1216-23.
To the Editors: Those who treat adult patients with sickle cell disease regularly are always seeking new protocols which can be used in the emergency room and on the wards to relieve the pain which plagues the lives of many of our patients. Unfortunately, the article by Brookoff and Polomano (1) yielded more serious questions than substantive answers. First, sickle cell disease is not cancer, where pain is frequently associated with far advanced, metastatic, or terminal disease. Acute painful episodes (crises) may occur periodically throughout the life of the patient with sickle cell disease. Although in adults and many children narcotic analgesics are required for acute painful episodes, chronic pain such as that from bone and joint disease often responds to other modalities. Second, to suggest that persons cannot become dependent on or addicted to narcotics simply because they have a continuous legal source, a prescribing physician, is to indulge in a potentially dangerous exercise in semantics and is certainly contrary to what most of us have been taught. As to the study itself, was it approved by the Institutional Review Board (IRB)? Was informed consent given? Would the IRB have approved of the transfer to another hospital of the patient who was unwilling to participate? Finally, by analyzing the subset of patients with "high levels of hospital use," it appears that 15 patients accounted for 66.4%, or all but 39 of the 116 admissions in 1988, and for 53.8%, or all but 30 of the
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65 admissions in 1989. It appears that most of the patients were only rarely hospitalized and thus received no benefit from the protocol. Can the trade-off of reduced rate of hospitalization for morphine dependence be considered a benefit? Perhaps the patient who refused to participate and was transferred to another hospital was the one who benefited the most. Jeanne A. Smith, MD, MPH Harlem Hospital-Columbia University New York, NY 10037 Reference 1. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116:364-8.
Rosemary Polomano, MSN Hospital of the University of Pennsylvania Philadelphia, PA 19104 References 1. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116:364-8. 2. Payne R, Max M, Sunshine A, Inturrisi C, Miser A. Principles of Analgesic Use in the Treatment of Acute Pain and Chronic Cancer Pain. 2nd edition. Skokie, Illinois: American Pain Society; 1989. 3. Brookoff D. Controlled-release formulations have less potential for abuse than other opioid medications [Abstractl- Ann Emerg Med. 1992;21:663. 4. Marks R, Sachar EJ. Undertreatment of medical inpatients with narcotic analgesics. Ann Intern Med. 1973;78:173-81. 5. World Health Organization. Cancer Pain Relief. Geneva: World Health Organization; 1986.
In response: Our report (1) described a change in the treatment of painful sickle cell crisis from the use of high-dose, short-acting opioids as needed—the usual treatment in most hospitals—to a strategy that conformed with principles established by experts in pain treatment (2). This strategy involved individualized treatment plans, prevention of pain recurrence, and education of patients and staff about how to communicate about pain. By providing access to safe and effective analgesics, we increased our patients' ability to treat their own pain and reduced their dependence upon the hospital for pain control. The limitations of an uncontrolled, single-institution study were clearly acknowledged in our report. Drs. Ballas, Rubin, and Gabuzda are incorrect in their characterization of our approach as a "morphine-only" policy. We encouraged our patients who needed opioids to use morphine because it is easily managed and available in a control-released form with a lower potential for abuse (3). Our report clearly stated that we used other opioids when the need arose. Our analgesic policy, reviewed and approved by the hematologyoncology section at our hospital, discouraged the use of meperidine, which many believe is not appropriate for treating sustained pain (2). We acknowledged, however, that there was some initial resistance among our patients to abandoning highdose intermittent meperidine. A few patients, who infrequently used our hospital, sought care elsewhere. One established patient (who insisted on intramuscular meperidine) began receiving analgesia elsewhere. However, she continued to participate in our support group (of which she was vice-president) and helped other patients fashion pain control strategies. The implementation of DRGs at our hospital did not affect the length of stay for patients admitted for painful crisis. Most sickle cell patients were covered by a special public insurance plan (HealthPass) that paid for admissions on a per diem basis. As the attending physician (DB) for many of these admissions, I can certify that discharge was based on resolution of pain with no continued need for parenteral therapy. The hospital never applied pressure to prematurely discharge any patient. Dr. Smith points out that a small proportion of patients accounted for a large proportion of admissions. This pattern of hospitalization is common among sickle cell patients with significant chronic pain. We fear, however, that Dr. Smith confuses physical habituation and drug addiction. Disregard for this difference, which is much more than semantic (2), is a major obstacle to the effective treatment of pain (4). According to the World Health Organization, drug addiction is rooted in the use of drugs for other than their intended purposes and rarely arises from the legitimate use of analgesic medications for the treatment of pain (5). Although we did not quantify the opiates used under both pain protocols, the reduction in the number of patient-days on parenteral opioids argues against an increased risk for drug abuse among our patients. The search for rational treatments for sickle cell pain has been clouded by the fear of opioid analgesics. Ironically, this fear has led in some cases to withholding safe analgesic medications from patients with severe chronic pain and promoting the long-term use of cytotoxic drugs with no proven effect upon the clinical course of sickle cell disease.
To the Editors: Brookoff and Polomano (1) suggest that the systematic use of opioid therapy by experienced clinicians can yield substantial benefits for patients with recurrent acute and chronic pain associated with sickle cell anemia. These results, which have profound implications for clinical practice in this patient population, also pertain to the ongoing controversy surrounding the use of opioids in managing other types of nonmalignant pain. Although the authors mention this context in passing, it is critical to the interpretation of this study and deserves greater emphasis. The long-term use of opioids for the management of chronic nonmalignant pain has traditionally been rejected because of doubts about efficacy (usually discussed in terms of the potential for analgesic tolerance) and concerns about adverse pharmacologic outcomes and addiction. The stigma attached to the medical use of a potential drug of abuse, combined with the intensive regulatory scrutiny that this use engenders, further increase clinicians' concerns about the appropriate application of this therapy. In recent years, however, the role of long-term opioid therapy for nonmalignant pain has been reappraised by pain specialists and others in the medical community (2, 3). Numerous surveys have strongly suggested that a subpopulation of patients with chronic nonmalignant pain can achieve sustained benefit from this treatment without developing adverse pharmacologic effects or addiction (4). Controlled, repeated dose trials in patients with arthritis have yielded mixed views on efficacy (5) but reassuring data about the potential for serious adverse effects. Other studies indicate that analgesic tolerance seldom compromises long-term opioid treatment of painful disease and that aberrant drug-related behaviors (which define the addiction syndrome) are rare in those without a previous history of substance abuse (2). In short, a burgeoning experience suggests that some patients with chronic nonmalignant pain respond to opioid therapy as clinicians expect those with cancer pain to respond— with responsible drug use and benefits that are clearly greater than the risks. Although the study by Brookoff and Polomano has acknowledged limitations, the observed outcome suggests that this conclusion may be applicable to some patients with sickle cell anemia. All pain specialists would recommend caution in using chronic opioid therapy for nonmalignant pain, and a controlled clinical trial to confirm the findings of the Brookoff and Polomano study is needed. Nonetheless, the suggested benefits to the sickle cell patients in this study mirror the favorable outcomes reported in other studies of opioid therapy for nonmalignant pain and add to a growing literature calling for a critical re-evaluation of the traditional rejection of this approach. In a narrow sense, the data in this study suggest that chronic opioid therapy administered by knowledgeable clinicians can produce a favorable outcome in a cohort of patients with sickle cell pain. More broadly, these data also support an evolving perspective about the potential role of chronic opioid therapy for diverse types of nonmalignant pain.
Daniel Brookoff, MD, PhD University of Tennessee at Memphis Memphis, TN 38103
Russell K. Portenoy, MD Memorial Sloan-Kettering Cancer Center New York. NY 10021
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References 1. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116:364-8. 2. Portenoy RK. Chronic opioid therapy in nonmalignant pain. J Pain Symptom Management. 1990;5:S46-62. 3. Melzack R. The tragedy of needless pain. Scientific American. 1990; 162:19-25. 4. Zenz M, Strumpf M, Tryba M. Long-term oral opioid therapy in patients with chronic nonmalignant pain. J Pain Symptom Management. 1992;7:69-77. 5. Kjaersgaard-Andersen P, Nafei A, Skov O, Madsen F, Andersen HM, Kroner K, et al. Codeine plus paracetamol versus paracetamol in longer-term treatment of chronic pain due to osteoarthritis of the hip: a randomised double-blind, multi-centre study. Pain. 1990;43:309-18.
Subcutaneous Compared with Intravenous Heparin for Deep Vein Thrombosis To the Editors: The meta-analysis reported by Hommes and colleagues (1) is likely to rekindle a long-simmering controversy about the relative safety and efficacy of subcutaneous compared with continuous intravenous heparin for the treatment of acute venous thromboembolism. Our reading of the extensive literature in this field has led us to conclude that these two (and other) methods of heparin administration appear to be equally safe and effective. Their meta-analysis, however, neglected the role of the activated partial thromboplastin time (APTT) response in monitoring. Their inference that using subcutaneous heparin may allow us to "achieve early ambulation . . . simplify the treatment of patients with venous thrombosis . . . and consider . . . selfadministration in an outpatient or home setting" also raised concern. This conclusion does not appear to be justified by their analysis. First, heparin's therapeutic efficacy in venous thrombosis appears to be related to its anticoagulant effect as reflected by the APTT response rather than to the absolute dose. The APTT response variability among individuals to a given dose of heparin is large. Monitoring of APTT, which appears to be essential during therapy of venous thrombosis, may be difficult to achieve in a non-hospital setting. Second, mobilization, when indicated, can be achieved with intravenous therapy. Third, because heparin does not prevent embolism in the early onset of proximal deep vein thrombosis, it may not be wise to initiate therapy in settings that lack close medical supervision. Fourth, not all patients can or will selfadminister subcutaneous heparin; and even then, some period of instruction is required. Over time, these concerns may be overcome by appropriate investigations, but as residents of a litigious nation—and, more important, as physicians concerned with the potential lethality of poorly treated acute proximal deep vein thrombosis—we advise against premature extrapolations of this meta-analysis. We agree that, properly given, subcutaneous and continuous intravenous heparin are, at the least, probably equally effective and safe. Kenneth M. Moser, MD Peter F. Fedullo, MD University of California, San Diego San Diego, CA 92103-1990 Reference 1. Hommes DW, Bura A, Mazzolai L, Biiller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84.
To the Editors: The advantage of subcutaneous over alternative means of heparin administration in the management of venous thrombosis has long been controversial. Hommes and colleagues' (1) well-constructed meta-analysis establishes the superiority of subcutaneous heparin dosing in the early treatment of deep vein thrombosis. The authors' conclusions support a safer, more rational therapeutic approach for the growing number of patients who need physical medicine and rehabilitation intervention. Those patients receiving frequent rehabilitation therapy are treated with
mobility and endurance exercises, which are abruptly curtailed when proximal thrombus is diagnosed. Because many of these patients show generalized weakness ("deconditioning") as well as coordination and balance deficits resulting from underlying medical and neurologic illness, they are at risk for falls and other exercise-induced mishaps. Hommes and colleagues' data suggest that the diminished risk of major hemorrhage along with the potential for early ambulation are two distinct advantages of the subcutaneous route of administration in these patients. Subcutaneous heparin, however, is not a panacea and has been associated with heparin-associated thrombocytopenia and thrombosis syndrome (HATT syndrome) (2) and numerous other complications, including bleeding, skin necrosis, and allergic reactions (3, 4). Mark A. Young, MD Johns Hopkins University School of Medicine Baltimore, MD 21239 References 1. Hommes DW, Bura A, Mazzolai L, Biiller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84. 2. Young MA, Ehrenpreis ED, Ehrenpreis M, Kirshblum S. Heparinassociated thrombocytopenia and thrombosis syndrome in a rehabilitation patient. Arch Phys Med Rehabil. 1989;70:468-70. 3. Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Arch Intern Med. 1986; 146:147. 4. Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest. 1989;95:515.
To the Editors: We usually think of low-dose subcutaneous heparin as 5000 units twice a day or every 8 hours. The average dose in the articles reviewed by Hommes and colleagues (1) was three times this amount. In using the low-dose schedule, we do not customarily monitor the dose with the APTT. What was done in the studies reviewed, and what is the authors' recommendation? In short, is 5000 units every 12 hours, as we often administer heparin in the United States, as good as continuous drip heparin? In using the low-dose schedule, is it still permissible not to monitor with the APTT? John F. Burnum, MD 400-C Tenth Street, East Tuscaloosa, AL 35401 Reference 1. Hommes DW, Bura A, Mazzolai L, Biiller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84.
In response: Drs. Moser and Fedullo are concerned that the results of our meta-analysis of six randomized trials (1), if prematurely extrapolated, will result in poor treatment of acute deep vein thrombosis mainly because the advantages of subcutaneous over intravenous heparin administration are limited. As always, major changes in treatment policies need to be based on a sufficient number of properly done clinical studies. As we have indicated, heparin, regardless of the route of administration, requires laboratory control, which is best achieved with initial hospitalization. Usually after 2 to 3 days, stable doses are attained, and patients can be discharged. More important, however, the discussed benefits of subcutaneous injections indicate the potential of low-molecular-weight heparins for the treatment of patients with deep vein thrombosis, as was recently supported by the results of other studies (2, 3). We appreciate the comments of Dr. Young concerning the rare but serious complications of heparin therapy. As Dr. Burnum notes, a clear distinction should be made between prophylaxis with low-dose heparin for venous thromboembolism of high-risk surgical patients and treatment with full-dose heparin given subcutaneously for confirmed venous thrombosis. In the latter, the daily dose varies, but is approximately 33 000 units, and APTT control is mandatory.
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Daan W. Hommes, MD Harry R. Buller, MD, PhD Jan W. ten Cate, MD, PhD Academic Medical Center 1105 AZ Amsterdam, The Netherlands References 1. Hommes DW, Bura A, Mazzolai L, Buller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84. 2. Prandoni P, Lensing AW, Buller HR, Carta M, Cogo A, Vigo M, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet. 1992;339:441-5. 3. Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott G, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med. 1992;326:975-82.
To the Editors: The criteria used for including studies in the analysis by Hommes and colleagues (1) were sensible and fair and the conclusions reasonable. The report, however, highlights a potential problem with meta-analysis as a method of influencing clinical decision making. Recent studies have shown that the efficacy of heparin is critically dependent on the patient's anticoagulant response. Yet this important determinant of efficacy could not be incorporated into the evaluation by Hommes and colleagues because such data were not provided in most of the reports. Therefore, the observed findings may reflect inadequacies in the initial heparin dose or in subsequent dose adjustments rather than in the route of administration. I would have more confidence in the clinical significance of results of a single study that provides assurance that the heparin dose regimens used in both groups was appropriate. Jack Hirsh, MD Hamilton Civic Hospitals Research Centre Hamilton, Ontario L8V 1C3, Canada Reference 1. Hommes DW, Bura A, Mazzolai L, Buller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84.
pressure from 21 to 19 cm of water (a decrease slightly greater than 1 mm Hg) and still had long-term control of bleeding? Andres T. Blei, MD Northwestern University School of Medicine Evanston, IL 60201 References 1. Ring EJ, Lake JR, Roberts JP, Gordon LR, LaBerge JM, Read AE, et al. Using transjugular intrahepatic portosystemic shunts to control variceal bleeding before liver transplantation. Ann Intern Med. 1992; 116:304-9. 2. Myers JD, Taylor WJ. An estimation of portal venous pressure by occlusive catheterization of a hepatic venule. J Clin Invest. 1951^30: 662-70. 3. Sarfeh U, Rypins EB, Mason GR. A systematic appraisal of portacaval H-graft diameters: clinical and hemodynamic perspectives. Ann Surg. 1986;204:356-63. 4. Coy DL, Srivastava A, Gottstein J, Butterworth RF, Blei AT. Postoperative course after portacaval anastomosis in rats is determined by the portacaval pressure gradient. Am J Physiol. 1991;261:G1072-8. 5. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology. 1985;5:419-24.
In response: We agree with Dr. Blei that the portosystemic gradient is a much better measurement of shunt function than the absolute portal pressures reported in our article (1). Absolute portal pressure measurements do not take into consideration the often striking increase in inferior vena caval pressure that occurs following TIPS and therefore can underestimate the decompression achieved by the shunt. Unfortunately, we initially did not recognize the importance of the portosystemic gradient and did not record hepatic vein or inferior vena caval pressures in the 13 patients described in our report. However, we now routinely obtain both portal and systemic pressures, and these measurements are available for 83 patients who have had TIPS since our study. In these subsequent cases, the mean preshunt gradient was 25.1 ± 4.2 mm Hg, which fell to 10.2 ± 3.7 mm Hg after TIPS. Ernest J. Ring, MD University of California, San Francisco San Francisco, CA 94143-0628 Reference 1. Ring EJ, Lake JR, Roberts JP, Gordon RL, LaBerge JM, Read AE, et al. Using transjugular intrahepatic portosystemic shunts to control variceal bleeding before liver transplantation. Ann Intern Med. 1992; 116:304-9.
TIPS and Variceal Bleeding To the Editors: I read with interest the article by Ring and colleagues (1) on the potential benefits of transjugular intrahepatic portosystemic shunts (TIPS) for control of variceal bleeding in patients with poor liver function and uncontrollable hemorrhage or for those awaiting liver transplantation. The study, however, lacks precision in that the article does not mention how portal pressure was measured. Values are presented in centimetres of water; how was the pressure device calibrated? Were permanent records made of the pressure tracings? How can values of hepatic vein pressure not have been included when the pressure gradient across the liver is the hemodynamic variable to follow (2)? A key unresolved question is the degree to which the portal pressure needs to be lowered with this procedure. Surgical experience with side-to-side mesocaval shunts in cirrhosis suggests that a gradient of 12 mm Hg may reduce the risk of recurrent hemorrhage while decreasing the emergence of encephalopathy (3). The importance of the gradient has been shown in recent animal studies (4). Of note, gradients of 10 to 12 mm Hg appear necessary for the de novo development of varices in patients with cirrhosis (5). Many centers worldwide have begun using TIPS in such critically ill patients. Accurate and precise measurements of portal pressure must be incorporated in the technical requirements of this procedure. If not, questions may be left unanswered, as in the article by Ring and colleagues (1): How did TIPS work in patient 3, who had a reduction of portal vein 266
Alpha-Interferon-induced Nodular Rheumatoid Arthritis in Renal Cell Carcinoma To the Editors: Ronnblom and colleagues (1) and Chazerain and colleagues (2) reported the development of rheumatoid arthritis-like disease after alpha-interferon therapy. We describe a similar case of seropositive, nodular rheumatoid arthritis, which occurred during interferon therapy. A 64-yearold man developed gross hematuria on 28 December 1990. A large mass in the upper abdomen detected on physical examination was confirmed by abdominal ultrasonography and computed tomography as a 10 x 10 x 10 cm tumor of the right kidney extending to the pararenal space. The leukocyte count was 6800/mm3, and the hemoglobin level was 17.5 g/dL. Rheumatoid factor and C-reactive protein test results were negative. A chest radiograph was normal. Gallium scintigraphy was negative for metastatic lesions. A right nephrectomy was done on 8 January 1991. The pathology specimens showed renal cell carcinoma (clear cell type). Postoperatively, recombinant interferon alpha-2a (Takeda, Roche, Japan), 9 000 000 U, was administered intramuscularly twice weekly. In October 1991, the patient had pain in his wrists and morning stiffness lasting an hour but not the Raynaud phenomenon. On 6 January 1992, he was referred to an arthritis clinic. A physical examination showed tenderness and swelling in the proximal interphalangeal, metacarpophalangeal, and wrist joints. Metatarsophalangeal joints showed prominent synovial
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swelling but no nodules or clubbed fingers. Blood profiles showed an erythrocyte sedimentation rate of 47 mm/h and a ± C-reactive protein level. The rheumatoid factor value was + 2. A radiograph showed periarticular osteoporosis in the fifth metatarsophalangeal heads. He was given nonsteroidal anti-inflammatory drugs and had some symptomatic relief. Interferon therapy was diminished to once weekly with some reduction of joint swelling. The patient reported, however, that morning stiffness was most severe the day after his interferon injection. On February 6, a rheumatoid nodule was palpable over the extensor surface of the right elbow. The rheumatoid factor value was + 3, and C-reactive protein was + 2. Antinuclear antibodies, C3 and C4, were normal. On March 23, he passed bloody stool and came to the emergency room. A barium enema showed a protruded mass lesion in the colonic hepatic flexure. The lesion could not be reached by colonoscopy, but local extension of the tumor was suspected. A chest radiograph showed small metastatic lesions. All medication including interferon was discontinued. His arthritis rapidly resolved in 3 to 4 days. When he was examined on April 2, there was no active synovitis. Rheumatoid nodules were not palpable. Although renal cell carcinoma is known to cause a paraneoplastic syndrome (3), we believe that alpha-interferon induced this patient's nodular rheumatoid arthritis. Yukio Ueno, MD Shichikawa Arthritis Research Center Mie 514-12, Japan Takaomi Sohma, MD Sohma Memorial Hospital Kyoto, Japan References 1. Ronnblom LE, Aim GV, Oberg KE. Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med. 1991; 115:178-83. 2. Chazerain P, Meyer O, Kahn MF. Rheumatoid arthritis-like disease after alpha-interferon therapy. Ann Intern Med. 1992;116:427. 3. Garnick MB, Brenner BM. Tumors of the urinary tract. In: Wilson JD, Braunwald E, Isselbacker KJ; eds. Harrison's Principles of Internal Medicine. 12th edition. New York: McGraw-Hill; 1991:120712. HIV Infection in the Workplace: Protecting the Vulnerable To the Editors: The recent debate about human immunodeficiency virus (HlV)-infected health care workers has overlooked the particular problems facing those medical students, residents, and fellows who are at great risk of acquiring nosocomial HIV infection. These persons are on "the front lines," doing many invasive procedures (blood draws, intravenous insertion, paracentesis, lumbar puncture, and so forth), often in hurried and stressful circumstances. Whereas staff and attending physicians for the most part have disability and longterm health insurance, medical students, residents, and fellows have no or limited disability insurance and marginal long-term health insurance benefits. Medical students, residents, and fellows who sustain a potential parenteral exposure to HIV are strongly encouraged to have serial HIV testing. Yet if they are found to have contracted HIV through work-related exposure, future employment (particularly if it involves invasive procedures) is jeopardized. This problem is, of course, on top of the tens of thousands of dollars of debt that most of them carry as well as the devastating emotional and personal effects of HIV infection. Should we not provide some financial and health insurance assistance to those in the medical profession with HIV infection, and particularly to those with the fewest resources? It would be commendable if such assistance was available regardless of mode of transmission. Yet a particular obligation exists when transmission occurs in the workplace. Such insurance should be established by medical schools and hospitals. The
time to begin is now, when the number of persons is small but their need is great. Timothy P. Flanigan, MD Charles C.J. Carpentery MD Brown University Providence, RI 02912 Michael Close, MD The Miriam Hospital Providence, RI 02906 Covering for I m p a i r e d Residents To the Editors: Our society and our profession emphasize alcohol as an integral part of mainstream social interaction, and as Aach and colleagues (1) observe, "abuse of alcohol . . . is a major societal problem." Shortly after the drinking age in Wisconsin was raised from 18 to 21 years of age, I met one of the deans of the medical school at a Friday afternoon party sponsored by the Alumni Association. He observed that the admissions committee might need to require that all students be 21 years of age at matriculation; otherwise, some students might not be able to attend the Friday afternoon beer parties. When I suggested that social intercourse could take place in the absence of beer, he laughed and predicted that social functions bereft of alcohol would be poorly attended by students and quickly canceled by the medical school. His sentiments were shared by many of my classmates, who regarded those who did not consume alcohol on a regular and frequent basis to be social misfits. Against this backdrop, I found Aach and colleagues' article disturbing. The authors provide an estimable approach to substance abuse during residency, but I disagree with their tacit assumption that other residents in a program should automatically cover for their impaired colleagues during extended treatment programs. Even if one chooses to regard substance abuse as a disease rather than a choice, it is manifestly unfair to thrust the impaired resident's workload onto colleagues who have worked hard during training to manage stress constructively and thus to avoid impairment. I argue that this approach positively reinforces impaired physicians by rewarding unacceptable behavior with resources not otherwise available. Furthermore, the imposition of additional duties upon unimpaired colleagues places them at risk for future impairment caused by the stress of extra duties. If assigning an impaired resident's duties to other residents cannot be avoided, specific program policy, for example, flexible benefits during extended leaves (2), should be developed to protect the other residents from excessive imposition of additional demands. Brian J. Bohlmann, MD 23 Quail Ridge Drive Madison, WI 53717 References 1. Aach RD, Girard DE, Humphrey H, McCue JD, Reuben DB, Smith JW, et al. Alcohol and other substance abuse and impairment among physicians in residency training. Ann Intern Med. 1992;116:245-54. 2. Bohlmann BJ. Pregnant surgical residents: Oh K?! [Letter]. JAMA. 1991;266:2222-3. In response: Dr. Bohlmann accurately points out that the pervasiveness of alcohol use reflects in large measure the inappropriate emphasis placed on it by our society, including the medical profession. The Association of Program Directors in Internal Medicine (APDIM) agrees that additional duties assumed by residents in a training program when one of their fellow residents is impaired must not place them at risk of impairment caused by stress. However, APDIM takes issue with the view that it is "manifestly unfair" for other residents to manage the impaired resident's duties during the period that the resident is not working. We view alcohol and other substance abuse as an illness, with a high probability of successful outcome, if the appropriate measures are taken. As physicians, we have chosen a career to help those who are ill, including
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our colleagues. Residents have long covered for other residents who are ill, providing that the coverage required does not place too heavy a burden on those who are well. The same is true of physicians who have completed their training. The program director should determine whether or not coverage for an impaired resident is reasonable. We do agree that there should be clear program policies about coverage for illness. We recommended developing program policies and making this information known (1). Flexible benefits during an extended leave is one approach that program directors should consider.
haustive peer evaluation. The College's process for guideline development meets both challenges. Dr. Bettigole's apparent conclusion that the dangers of guidelines far outweigh their benefits challenges the premise of the editorial: that a profession must not only set its standards but that they should be written down. This principle is of fundamental importance to the medical profession. Certainly, a program of practice guidelines is at risk of misuse, especially by third party payers. There are far greater risks, however, when our profession remains silent on the great problems of medical practice.
Richard D. Aach, MD Association of Program Directors in Internal Medicine Washington, D.C. 20005
Harold C. Sox, Jr., MD Dartmouth-Hitchcock Medical Center Lebanon, NH 03756
Reference 1. Aach RD, Girard DE, Humphrey H, McCue JD, Reuben DB, Smith JW, et al. Alcohol and other substance abuse and impairment among physicians in residency training. Ann Intern Med. 1992;116:245-54.
Reference 1. Sox HC Jr, Griner P. An invitation to join a controversy. Ann Intern Med. 1992;116:422-3.
ACP Practice Guidelines
Medical Use of Marijuana
To the Editors: When they are good, practice guidelines issued by organizations like the American College of Physicians (ACP) may well be very, very good, but when they are bad, they will, like the little girl in the nursery rhyme, be horrid. The assertion that such guidelines "should become the preferred source for definitive advice" (1) ignores the fact that, because data accumulate continuously, any such guidelines would potentially be outdated before publication. The assertion is also based on a false premise: that the standard of care is based on medical textbooks, which may also be out of date by the time of publication or before the next edition. The ACP position should be that a review of the recent medical literature is appropriate. If not, why publish practice guidelines in Annals'? The consensus of learned physicians was that bed rest was needed after surgery, childbirth, and acute myocardial infarction. The consensus of learned physicians was that a radical mastectomy was the only surgical means of dealing with breast cancer. Today's consensus may differ radically from yesterday's and from tomorrow's. In the end, the risk is that such practice guidelines will become a straitjacket barring prompt use of new information. A consensus also might be influenced by considerations of cost. Adopting practice guidelines issued by organizations like ACP seems like such a good idea, but it has not been tested and has the potential for doing more harm than good. Richard Bettigole, MD 786 Delaware Avenue Buffalo, NY 14209 Reference 1. Sox HC Jr, Griner P. An invitation to join a controversy. Ann Intern Med. 1992;116:422-3.
In response: Dr. Bettigole has taken me to task for asserting that: Physicians in search of an authoritative recommendation have traditionally turned first to medical textbooks. Although physicians still look there for advice, practice guidelines issued by organizations like the ACP should become the preferred source for definitive advice (1). I stand by this position. Dr. Bettigole's letter, however, reveals deeper concerns with practice guidelines. His concerns are appropriate, but I do not agree with his conclusion. He sees danger in the potential for guidelines to become outdated. For just this reason, ACP periodically revisits its earlier recommendations. He also argues that professional consensus can be a dangerous way to form guidelines for practice. Indeed, guidelines based simply on a consensus do not deserve serious attention; they must also rest on a foundation of rigorous analysis of the evidence and ex268
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To the Editors: In a letter reporting the preliminary results of an anonymous survey of members of the American Society of Clinical Oncology (ASCO), Doblin and Kleiman (1) acknowledge the "possibility of response bias" and that their results "only roughly estimate the views of oncologists." In fact, 57% of those surveyed did not return their questionnaires, and the number of questionnaires returned unanswered is not stated. Further, the authors chose not to include respondents who filled out the survey but who indicated no opinion on the question (30% of the respondents); instead they stated that "of the respondents who expressed an opinion, a majority (54%) thought marijuana in the smoked form should be available by prescription." After all the exclusions, I calculate that this "majority" can be no more than 15% to 20% of the original sample and is probably much less. In addition, Annals was not told that the study results were published previously in a book edited by the president of the Alliance for Cannibus Therapeutics (ACT) (2), which sponsored the study and was then engaged in litigation against the Drug Enforcement Administration (DEA) to reclassify marijuana from schedule I to schedule II. In the book, Doblin states in his survey conclusions that "substantial numbers of cancer patients are not getting the medical care that their doctors would prefer to provide them because federal law prohibits marijuana's medical u s e . " This unwarranted overinterpretation of their results is simply not true. My colleagues and I surveyed every twentieth consecutive, board-certified, practicing clinical oncologist member of ASCO nationwide for his or her experience and opinion of cannabis as an antiemetic (3). A parallel, validating survey was mailed to all practicing adult oncologists in the Washington, D . C , metropolitan area (total of two surveys, n = 170). Analysis by an independent biostatistician showed a greater than 95% agreement between the results of both surveys. Our response rate was 78%, almost double that of the Doblin study ( 1 , 2 , 4). In contrast to their survey, we found that cannabis (marijuana or dronabinol) ranked sixth in the management of severe postchemotherapy nausea and vomiting and was used even less frequently for milder symptoms. When used, it was deemed effective in 50% of the cases, but one in four patients had bothersome adverse effects. The availability of combination antiemetic agents, including the newly released serotonin antagonist, ondansetron, suggests that cannabis would not be used more frequently by most oncologists, even if legalized. For the few patients receiving highly emetogenic chemotherapeutic drugs who are not helped by available antiemetics, case-by-case exemptions from the current restrictive marijuana laws would seem more appropriate. Richard H. Schwartz, MD Georgetown University School of Medicine Washington, D.C. 22180
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References 1. Doblin R, Kleiman MA. Medical use of marijuana. Ann Intern Med. 1991;114:809-10. 2. Doblin R. Marijuana: a question of currently accepted medical use. In: RC Randall; ed. Cancer Treatment and Marijuana Therapy. Washington, D.C.: Galen Press; 1990:341-52. 3. American Society for Clinical Oncology. Program proceedings of the American Journal of Clinical Oncology [Abstract no. 12141. Am J Clin Oncol. 1991; 10:342. 4. Doblin RE, Kleiman MA. Marijuana as antiemetic medicine: a survey of oncologists' experiences and attitudes. Am J Clin Oncol. 1991 ;9: 1314-9. To the Editors: In May 1991, Annals published a letter by Doblin and Kleiman (1) that referred to a survey they had conducted on the medical value of the smokeable form of marijuana (as opposed to dronabinol). Others are better qualified to comment on the unscientific nature of the study and its inability to support its conclusions. I want instead to point out that, although the authors stated their association with the John F. Kennedy School of Government of Harvard University, they failed to mention that Mr. Doblin is the founder and president of the Multidisciplinary Association for Psychedelic Studies (MAPS), referred to as the "People's Psychedelic Pharmaceutical Company" in their newsletter head. The organization has advocated research on humans with the street drug Ecstasy and the gradual medicalization and legalization of psychedelics. In MAPS newsletters dated Summer 1990 and August 1991, Doblin outlines a plan to use different scientific forums, including Annals and the press, to lend credibility to the campaign to legalize marijuana use and to bolster a suit against the Drug Enforcement Administration. I believe that the authors' bias and hidden agenda should be made known to your readers.
Sandra S. Bennett Oregon Federation of Parents for Drug Free Youth Milwaukie, OR 97267 Reference 1. Doblin R, Kleiman MA. Medical use of marijuana. Ann Intern Med. 1991;114:809-10. A final order was issued by the administrator of the Drug Enforcement Administration (DEA) effective 26 March 1992, ". . . concluding the plant material marijuana has no currently accepted medical use and denying the petition of NORML {National Organization for Reform of Marijuana Laws] to reschedule marijuana from schedule I to schedule II of the Controlled Substances Act" (1). The Public Health Service also recently concluded after a review of its medical usefulness that "smoked marijuana is potentially more harmful than helpful to patients with compromised immune systems" (2). Because of this and the availability of Marinol (dronabinol; Unimed, Inc., Somerville, New Jersey), which contains the major active substance, tetrahydrocannabinol, they have decided not to provide additional patients with marijuana for medicinal purposes. They will continue to supply the 13 patients already receiving it. There had been 28 other petitions, but by the time of the decision, 10 patients had been convinced to use alternatives and had withdrawn their applications.—The Editors References 1. U.S. Department of Justice, Drug Enforcement Administration. Marijuana scheduling petition: final order. Federal Register. 1992 Mar 26;57:10499-508. 2. Public Health Service denying new requests for medicinal marijuana. Internal Medicine News & Cardiology News. 1992 May 1;25:31.
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The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send three copies of the letter and a transfer-of-copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
monwealth of Pennsylvania may have given the authors the luxury to choose patients with mild disease that would be ideal candidates to enforce the DRG rules with apparent satisfaction. Another suggestion that the study patients had mild disease is that no deaths were recorded. During 1989 and 1990, ten of our patients in the general sickle cell anemia population died of complications. Finally, we wish to emphasize that, contrary to the authors' experiences, we had an average increase in emergency room visits and in hospital admission rates of about 15% and 40% in 1989 and 1990, respectively. Anyone managing unselected patients with sickle cell disease over a long period realizes that there is no panacea for all patients all the time and that the most reasonable approach is to establish protocols targeted to the individual patient or subsets of patients.
Treating Sickle Cell Pain like Cancer Pain
Ronald N. Rubin, MD Temple University Hospital Philadelphia, PA 19140
To the Editors: We read with interest the article by Brookoff and Polomano (1) about treating sickle cell pain like cancer pain. This concept is not new (2). Sickle cell disease is heterogeneous and varies from very mild to very severe. The exact diagnosis of the patients studied and their fetal hemoglobin (Hb F) level were not mentioned by Brookoff and Polomano. Patients with sickle cell anemia or sickle-/3°-thalassemia tend to have more frequent painful crises than patients with sickle cell Hb disease or sickle-0+-thalassemia (3). Moreover, several factors may moderate the severity of sickle cell anemia (3, 4). Patients with high Hb F values, for example, tend to do better (3). The authors point out that the study was not a controlled trial and that patients may have sought treatment elsewhere or may have had a change in crisis frequency. We strongly agree with those criticisms of the study. Our hospitals are close to the Hospital of the University of Pennsylvania (HUP), and we have shared patients over the years. From our perspective, we believe that the authors have selected a biased group of patients with relatively mild disease. Approximately 500 adult patients with sickle cell disease are registered in the Sickle Cell Program of the Commonwealth of Pennsylvania. The Hospital of the University of Pennsylvania is not a participant in this program and hence has the option to retain certain patients but not others. The patients described by Brookoff and Polomano (1) represent fewer than 10% of all adult patients with sickle cell disease in Philadelphia. We follow 370 adult patients in our institutions, and all are supported by the Sickle Cell Program of the Commonwealth of Pennsylvania. Several patients left HUP and joined our programs after the institution of "morphine-only" policy. On several occasions patients with sickle cell disease sought treatment in our hospitals and needed further therapy with parenteral narcotic analgesics possibly because of premature discharge from HUP. We also note that the decrease in number of admissions and length of hospital stay coincided with the implementation of the diagnosis-related group (DRG) system that began nationwide on 1 December 1988. The patients who migrated to our program often related that they were discharged about 5 days after admission, although they were still in pain. Others related that they had to leave HUP against medical advice because of dissatisfaction with the rapid reduction in pain treatment, apparently done to meet the 5-day target of hospital stay. The lack of participation in the Sickle Cell Program of the Com-
Samir K. Ballas, MD Thomas Jefferson University Philadelphia, PA 19107
Thomas C. Gabuzda, MD Lankenau Hospital Philadelphia, PA 19151 References 1. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116:364-8. 2. Ballas SK. Treatment of pain in adults with sickle cell disease. Am J Hematol. 1990;34:49-54. 3. Piatt OS, Thorington BD, Brambilla DJ, Milner P, Rosse WF, Vichinsky E, et al. Pain in sickle cell disease: rates and risk factors. N Engl J Med. 1991;325:11-6. 4. Ballas SK, Larner J, Smith ED, Schwartz E, Rappaport EF. Rheologic predictors of the severity of the painful sickle cell crisis. Blood. 1988;72:1216-23.
To the Editors: Those who treat adult patients with sickle cell disease regularly are always seeking new protocols which can be used in the emergency room and on the wards to relieve the pain which plagues the lives of many of our patients. Unfortunately, the article by Brookoff and Polomano (1) yielded more serious questions than substantive answers. First, sickle cell disease is not cancer, where pain is frequently associated with far advanced, metastatic, or terminal disease. Acute painful episodes (crises) may occur periodically throughout the life of the patient with sickle cell disease. Although in adults and many children narcotic analgesics are required for acute painful episodes, chronic pain such as that from bone and joint disease often responds to other modalities. Second, to suggest that persons cannot become dependent on or addicted to narcotics simply because they have a continuous legal source, a prescribing physician, is to indulge in a potentially dangerous exercise in semantics and is certainly contrary to what most of us have been taught. As to the study itself, was it approved by the Institutional Review Board (IRB)? Was informed consent given? Would the IRB have approved of the transfer to another hospital of the patient who was unwilling to participate? Finally, by analyzing the subset of patients with "high levels of hospital use," it appears that 15 patients accounted for 66.4%, or all but 39 of the 116 admissions in 1988, and for 53.8%, or all but 30 of the
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65 admissions in 1989. It appears that most of the patients were only rarely hospitalized and thus received no benefit from the protocol. Can the trade-off of reduced rate of hospitalization for morphine dependence be considered a benefit? Perhaps the patient who refused to participate and was transferred to another hospital was the one who benefited the most. Jeanne A. Smith, MD, MPH Harlem Hospital-Columbia University New York, NY 10037 Reference 1. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116:364-8.
Rosemary Polomano, MSN Hospital of the University of Pennsylvania Philadelphia, PA 19104 References 1. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116:364-8. 2. Payne R, Max M, Sunshine A, Inturrisi C, Miser A. Principles of Analgesic Use in the Treatment of Acute Pain and Chronic Cancer Pain. 2nd edition. Skokie, Illinois: American Pain Society; 1989. 3. Brookoff D. Controlled-release formulations have less potential for abuse than other opioid medications [Abstractl- Ann Emerg Med. 1992;21:663. 4. Marks R, Sachar EJ. Undertreatment of medical inpatients with narcotic analgesics. Ann Intern Med. 1973;78:173-81. 5. World Health Organization. Cancer Pain Relief. Geneva: World Health Organization; 1986.
In response: Our report (1) described a change in the treatment of painful sickle cell crisis from the use of high-dose, short-acting opioids as needed—the usual treatment in most hospitals—to a strategy that conformed with principles established by experts in pain treatment (2). This strategy involved individualized treatment plans, prevention of pain recurrence, and education of patients and staff about how to communicate about pain. By providing access to safe and effective analgesics, we increased our patients' ability to treat their own pain and reduced their dependence upon the hospital for pain control. The limitations of an uncontrolled, single-institution study were clearly acknowledged in our report. Drs. Ballas, Rubin, and Gabuzda are incorrect in their characterization of our approach as a "morphine-only" policy. We encouraged our patients who needed opioids to use morphine because it is easily managed and available in a control-released form with a lower potential for abuse (3). Our report clearly stated that we used other opioids when the need arose. Our analgesic policy, reviewed and approved by the hematologyoncology section at our hospital, discouraged the use of meperidine, which many believe is not appropriate for treating sustained pain (2). We acknowledged, however, that there was some initial resistance among our patients to abandoning highdose intermittent meperidine. A few patients, who infrequently used our hospital, sought care elsewhere. One established patient (who insisted on intramuscular meperidine) began receiving analgesia elsewhere. However, she continued to participate in our support group (of which she was vice-president) and helped other patients fashion pain control strategies. The implementation of DRGs at our hospital did not affect the length of stay for patients admitted for painful crisis. Most sickle cell patients were covered by a special public insurance plan (HealthPass) that paid for admissions on a per diem basis. As the attending physician (DB) for many of these admissions, I can certify that discharge was based on resolution of pain with no continued need for parenteral therapy. The hospital never applied pressure to prematurely discharge any patient. Dr. Smith points out that a small proportion of patients accounted for a large proportion of admissions. This pattern of hospitalization is common among sickle cell patients with significant chronic pain. We fear, however, that Dr. Smith confuses physical habituation and drug addiction. Disregard for this difference, which is much more than semantic (2), is a major obstacle to the effective treatment of pain (4). According to the World Health Organization, drug addiction is rooted in the use of drugs for other than their intended purposes and rarely arises from the legitimate use of analgesic medications for the treatment of pain (5). Although we did not quantify the opiates used under both pain protocols, the reduction in the number of patient-days on parenteral opioids argues against an increased risk for drug abuse among our patients. The search for rational treatments for sickle cell pain has been clouded by the fear of opioid analgesics. Ironically, this fear has led in some cases to withholding safe analgesic medications from patients with severe chronic pain and promoting the long-term use of cytotoxic drugs with no proven effect upon the clinical course of sickle cell disease.
To the Editors: Brookoff and Polomano (1) suggest that the systematic use of opioid therapy by experienced clinicians can yield substantial benefits for patients with recurrent acute and chronic pain associated with sickle cell anemia. These results, which have profound implications for clinical practice in this patient population, also pertain to the ongoing controversy surrounding the use of opioids in managing other types of nonmalignant pain. Although the authors mention this context in passing, it is critical to the interpretation of this study and deserves greater emphasis. The long-term use of opioids for the management of chronic nonmalignant pain has traditionally been rejected because of doubts about efficacy (usually discussed in terms of the potential for analgesic tolerance) and concerns about adverse pharmacologic outcomes and addiction. The stigma attached to the medical use of a potential drug of abuse, combined with the intensive regulatory scrutiny that this use engenders, further increase clinicians' concerns about the appropriate application of this therapy. In recent years, however, the role of long-term opioid therapy for nonmalignant pain has been reappraised by pain specialists and others in the medical community (2, 3). Numerous surveys have strongly suggested that a subpopulation of patients with chronic nonmalignant pain can achieve sustained benefit from this treatment without developing adverse pharmacologic effects or addiction (4). Controlled, repeated dose trials in patients with arthritis have yielded mixed views on efficacy (5) but reassuring data about the potential for serious adverse effects. Other studies indicate that analgesic tolerance seldom compromises long-term opioid treatment of painful disease and that aberrant drug-related behaviors (which define the addiction syndrome) are rare in those without a previous history of substance abuse (2). In short, a burgeoning experience suggests that some patients with chronic nonmalignant pain respond to opioid therapy as clinicians expect those with cancer pain to respond— with responsible drug use and benefits that are clearly greater than the risks. Although the study by Brookoff and Polomano has acknowledged limitations, the observed outcome suggests that this conclusion may be applicable to some patients with sickle cell anemia. All pain specialists would recommend caution in using chronic opioid therapy for nonmalignant pain, and a controlled clinical trial to confirm the findings of the Brookoff and Polomano study is needed. Nonetheless, the suggested benefits to the sickle cell patients in this study mirror the favorable outcomes reported in other studies of opioid therapy for nonmalignant pain and add to a growing literature calling for a critical re-evaluation of the traditional rejection of this approach. In a narrow sense, the data in this study suggest that chronic opioid therapy administered by knowledgeable clinicians can produce a favorable outcome in a cohort of patients with sickle cell pain. More broadly, these data also support an evolving perspective about the potential role of chronic opioid therapy for diverse types of nonmalignant pain.
Daniel Brookoff, MD, PhD University of Tennessee at Memphis Memphis, TN 38103
Russell K. Portenoy, MD Memorial Sloan-Kettering Cancer Center New York. NY 10021
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References 1. Brookoff D, Polomano R. Treating sickle cell pain like cancer pain. Ann Intern Med. 1992;116:364-8. 2. Portenoy RK. Chronic opioid therapy in nonmalignant pain. J Pain Symptom Management. 1990;5:S46-62. 3. Melzack R. The tragedy of needless pain. Scientific American. 1990; 162:19-25. 4. Zenz M, Strumpf M, Tryba M. Long-term oral opioid therapy in patients with chronic nonmalignant pain. J Pain Symptom Management. 1992;7:69-77. 5. Kjaersgaard-Andersen P, Nafei A, Skov O, Madsen F, Andersen HM, Kroner K, et al. Codeine plus paracetamol versus paracetamol in longer-term treatment of chronic pain due to osteoarthritis of the hip: a randomised double-blind, multi-centre study. Pain. 1990;43:309-18.
Subcutaneous Compared with Intravenous Heparin for Deep Vein Thrombosis To the Editors: The meta-analysis reported by Hommes and colleagues (1) is likely to rekindle a long-simmering controversy about the relative safety and efficacy of subcutaneous compared with continuous intravenous heparin for the treatment of acute venous thromboembolism. Our reading of the extensive literature in this field has led us to conclude that these two (and other) methods of heparin administration appear to be equally safe and effective. Their meta-analysis, however, neglected the role of the activated partial thromboplastin time (APTT) response in monitoring. Their inference that using subcutaneous heparin may allow us to "achieve early ambulation . . . simplify the treatment of patients with venous thrombosis . . . and consider . . . selfadministration in an outpatient or home setting" also raised concern. This conclusion does not appear to be justified by their analysis. First, heparin's therapeutic efficacy in venous thrombosis appears to be related to its anticoagulant effect as reflected by the APTT response rather than to the absolute dose. The APTT response variability among individuals to a given dose of heparin is large. Monitoring of APTT, which appears to be essential during therapy of venous thrombosis, may be difficult to achieve in a non-hospital setting. Second, mobilization, when indicated, can be achieved with intravenous therapy. Third, because heparin does not prevent embolism in the early onset of proximal deep vein thrombosis, it may not be wise to initiate therapy in settings that lack close medical supervision. Fourth, not all patients can or will selfadminister subcutaneous heparin; and even then, some period of instruction is required. Over time, these concerns may be overcome by appropriate investigations, but as residents of a litigious nation—and, more important, as physicians concerned with the potential lethality of poorly treated acute proximal deep vein thrombosis—we advise against premature extrapolations of this meta-analysis. We agree that, properly given, subcutaneous and continuous intravenous heparin are, at the least, probably equally effective and safe. Kenneth M. Moser, MD Peter F. Fedullo, MD University of California, San Diego San Diego, CA 92103-1990 Reference 1. Hommes DW, Bura A, Mazzolai L, Biiller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84.
To the Editors: The advantage of subcutaneous over alternative means of heparin administration in the management of venous thrombosis has long been controversial. Hommes and colleagues' (1) well-constructed meta-analysis establishes the superiority of subcutaneous heparin dosing in the early treatment of deep vein thrombosis. The authors' conclusions support a safer, more rational therapeutic approach for the growing number of patients who need physical medicine and rehabilitation intervention. Those patients receiving frequent rehabilitation therapy are treated with
mobility and endurance exercises, which are abruptly curtailed when proximal thrombus is diagnosed. Because many of these patients show generalized weakness ("deconditioning") as well as coordination and balance deficits resulting from underlying medical and neurologic illness, they are at risk for falls and other exercise-induced mishaps. Hommes and colleagues' data suggest that the diminished risk of major hemorrhage along with the potential for early ambulation are two distinct advantages of the subcutaneous route of administration in these patients. Subcutaneous heparin, however, is not a panacea and has been associated with heparin-associated thrombocytopenia and thrombosis syndrome (HATT syndrome) (2) and numerous other complications, including bleeding, skin necrosis, and allergic reactions (3, 4). Mark A. Young, MD Johns Hopkins University School of Medicine Baltimore, MD 21239 References 1. Hommes DW, Bura A, Mazzolai L, Biiller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84. 2. Young MA, Ehrenpreis ED, Ehrenpreis M, Kirshblum S. Heparinassociated thrombocytopenia and thrombosis syndrome in a rehabilitation patient. Arch Phys Med Rehabil. 1989;70:468-70. 3. Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Arch Intern Med. 1986; 146:147. 4. Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest. 1989;95:515.
To the Editors: We usually think of low-dose subcutaneous heparin as 5000 units twice a day or every 8 hours. The average dose in the articles reviewed by Hommes and colleagues (1) was three times this amount. In using the low-dose schedule, we do not customarily monitor the dose with the APTT. What was done in the studies reviewed, and what is the authors' recommendation? In short, is 5000 units every 12 hours, as we often administer heparin in the United States, as good as continuous drip heparin? In using the low-dose schedule, is it still permissible not to monitor with the APTT? John F. Burnum, MD 400-C Tenth Street, East Tuscaloosa, AL 35401 Reference 1. Hommes DW, Bura A, Mazzolai L, Biiller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84.
In response: Drs. Moser and Fedullo are concerned that the results of our meta-analysis of six randomized trials (1), if prematurely extrapolated, will result in poor treatment of acute deep vein thrombosis mainly because the advantages of subcutaneous over intravenous heparin administration are limited. As always, major changes in treatment policies need to be based on a sufficient number of properly done clinical studies. As we have indicated, heparin, regardless of the route of administration, requires laboratory control, which is best achieved with initial hospitalization. Usually after 2 to 3 days, stable doses are attained, and patients can be discharged. More important, however, the discussed benefits of subcutaneous injections indicate the potential of low-molecular-weight heparins for the treatment of patients with deep vein thrombosis, as was recently supported by the results of other studies (2, 3). We appreciate the comments of Dr. Young concerning the rare but serious complications of heparin therapy. As Dr. Burnum notes, a clear distinction should be made between prophylaxis with low-dose heparin for venous thromboembolism of high-risk surgical patients and treatment with full-dose heparin given subcutaneously for confirmed venous thrombosis. In the latter, the daily dose varies, but is approximately 33 000 units, and APTT control is mandatory.
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Daan W. Hommes, MD Harry R. Buller, MD, PhD Jan W. ten Cate, MD, PhD Academic Medical Center 1105 AZ Amsterdam, The Netherlands References 1. Hommes DW, Bura A, Mazzolai L, Buller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84. 2. Prandoni P, Lensing AW, Buller HR, Carta M, Cogo A, Vigo M, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet. 1992;339:441-5. 3. Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott G, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med. 1992;326:975-82.
To the Editors: The criteria used for including studies in the analysis by Hommes and colleagues (1) were sensible and fair and the conclusions reasonable. The report, however, highlights a potential problem with meta-analysis as a method of influencing clinical decision making. Recent studies have shown that the efficacy of heparin is critically dependent on the patient's anticoagulant response. Yet this important determinant of efficacy could not be incorporated into the evaluation by Hommes and colleagues because such data were not provided in most of the reports. Therefore, the observed findings may reflect inadequacies in the initial heparin dose or in subsequent dose adjustments rather than in the route of administration. I would have more confidence in the clinical significance of results of a single study that provides assurance that the heparin dose regimens used in both groups was appropriate. Jack Hirsh, MD Hamilton Civic Hospitals Research Centre Hamilton, Ontario L8V 1C3, Canada Reference 1. Hommes DW, Bura A, Mazzolai L, Buller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. Ann Intern Med. 1992;116:279-84.
pressure from 21 to 19 cm of water (a decrease slightly greater than 1 mm Hg) and still had long-term control of bleeding? Andres T. Blei, MD Northwestern University School of Medicine Evanston, IL 60201 References 1. Ring EJ, Lake JR, Roberts JP, Gordon LR, LaBerge JM, Read AE, et al. Using transjugular intrahepatic portosystemic shunts to control variceal bleeding before liver transplantation. Ann Intern Med. 1992; 116:304-9. 2. Myers JD, Taylor WJ. An estimation of portal venous pressure by occlusive catheterization of a hepatic venule. J Clin Invest. 1951^30: 662-70. 3. Sarfeh U, Rypins EB, Mason GR. A systematic appraisal of portacaval H-graft diameters: clinical and hemodynamic perspectives. Ann Surg. 1986;204:356-63. 4. Coy DL, Srivastava A, Gottstein J, Butterworth RF, Blei AT. Postoperative course after portacaval anastomosis in rats is determined by the portacaval pressure gradient. Am J Physiol. 1991;261:G1072-8. 5. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology. 1985;5:419-24.
In response: We agree with Dr. Blei that the portosystemic gradient is a much better measurement of shunt function than the absolute portal pressures reported in our article (1). Absolute portal pressure measurements do not take into consideration the often striking increase in inferior vena caval pressure that occurs following TIPS and therefore can underestimate the decompression achieved by the shunt. Unfortunately, we initially did not recognize the importance of the portosystemic gradient and did not record hepatic vein or inferior vena caval pressures in the 13 patients described in our report. However, we now routinely obtain both portal and systemic pressures, and these measurements are available for 83 patients who have had TIPS since our study. In these subsequent cases, the mean preshunt gradient was 25.1 ± 4.2 mm Hg, which fell to 10.2 ± 3.7 mm Hg after TIPS. Ernest J. Ring, MD University of California, San Francisco San Francisco, CA 94143-0628 Reference 1. Ring EJ, Lake JR, Roberts JP, Gordon RL, LaBerge JM, Read AE, et al. Using transjugular intrahepatic portosystemic shunts to control variceal bleeding before liver transplantation. Ann Intern Med. 1992; 116:304-9.
TIPS and Variceal Bleeding To the Editors: I read with interest the article by Ring and colleagues (1) on the potential benefits of transjugular intrahepatic portosystemic shunts (TIPS) for control of variceal bleeding in patients with poor liver function and uncontrollable hemorrhage or for those awaiting liver transplantation. The study, however, lacks precision in that the article does not mention how portal pressure was measured. Values are presented in centimetres of water; how was the pressure device calibrated? Were permanent records made of the pressure tracings? How can values of hepatic vein pressure not have been included when the pressure gradient across the liver is the hemodynamic variable to follow (2)? A key unresolved question is the degree to which the portal pressure needs to be lowered with this procedure. Surgical experience with side-to-side mesocaval shunts in cirrhosis suggests that a gradient of 12 mm Hg may reduce the risk of recurrent hemorrhage while decreasing the emergence of encephalopathy (3). The importance of the gradient has been shown in recent animal studies (4). Of note, gradients of 10 to 12 mm Hg appear necessary for the de novo development of varices in patients with cirrhosis (5). Many centers worldwide have begun using TIPS in such critically ill patients. Accurate and precise measurements of portal pressure must be incorporated in the technical requirements of this procedure. If not, questions may be left unanswered, as in the article by Ring and colleagues (1): How did TIPS work in patient 3, who had a reduction of portal vein 266
Alpha-Interferon-induced Nodular Rheumatoid Arthritis in Renal Cell Carcinoma To the Editors: Ronnblom and colleagues (1) and Chazerain and colleagues (2) reported the development of rheumatoid arthritis-like disease after alpha-interferon therapy. We describe a similar case of seropositive, nodular rheumatoid arthritis, which occurred during interferon therapy. A 64-yearold man developed gross hematuria on 28 December 1990. A large mass in the upper abdomen detected on physical examination was confirmed by abdominal ultrasonography and computed tomography as a 10 x 10 x 10 cm tumor of the right kidney extending to the pararenal space. The leukocyte count was 6800/mm3, and the hemoglobin level was 17.5 g/dL. Rheumatoid factor and C-reactive protein test results were negative. A chest radiograph was normal. Gallium scintigraphy was negative for metastatic lesions. A right nephrectomy was done on 8 January 1991. The pathology specimens showed renal cell carcinoma (clear cell type). Postoperatively, recombinant interferon alpha-2a (Takeda, Roche, Japan), 9 000 000 U, was administered intramuscularly twice weekly. In October 1991, the patient had pain in his wrists and morning stiffness lasting an hour but not the Raynaud phenomenon. On 6 January 1992, he was referred to an arthritis clinic. A physical examination showed tenderness and swelling in the proximal interphalangeal, metacarpophalangeal, and wrist joints. Metatarsophalangeal joints showed prominent synovial
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swelling but no nodules or clubbed fingers. Blood profiles showed an erythrocyte sedimentation rate of 47 mm/h and a ± C-reactive protein level. The rheumatoid factor value was + 2. A radiograph showed periarticular osteoporosis in the fifth metatarsophalangeal heads. He was given nonsteroidal anti-inflammatory drugs and had some symptomatic relief. Interferon therapy was diminished to once weekly with some reduction of joint swelling. The patient reported, however, that morning stiffness was most severe the day after his interferon injection. On February 6, a rheumatoid nodule was palpable over the extensor surface of the right elbow. The rheumatoid factor value was + 3, and C-reactive protein was + 2. Antinuclear antibodies, C3 and C4, were normal. On March 23, he passed bloody stool and came to the emergency room. A barium enema showed a protruded mass lesion in the colonic hepatic flexure. The lesion could not be reached by colonoscopy, but local extension of the tumor was suspected. A chest radiograph showed small metastatic lesions. All medication including interferon was discontinued. His arthritis rapidly resolved in 3 to 4 days. When he was examined on April 2, there was no active synovitis. Rheumatoid nodules were not palpable. Although renal cell carcinoma is known to cause a paraneoplastic syndrome (3), we believe that alpha-interferon induced this patient's nodular rheumatoid arthritis. Yukio Ueno, MD Shichikawa Arthritis Research Center Mie 514-12, Japan Takaomi Sohma, MD Sohma Memorial Hospital Kyoto, Japan References 1. Ronnblom LE, Aim GV, Oberg KE. Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med. 1991; 115:178-83. 2. Chazerain P, Meyer O, Kahn MF. Rheumatoid arthritis-like disease after alpha-interferon therapy. Ann Intern Med. 1992;116:427. 3. Garnick MB, Brenner BM. Tumors of the urinary tract. In: Wilson JD, Braunwald E, Isselbacker KJ; eds. Harrison's Principles of Internal Medicine. 12th edition. New York: McGraw-Hill; 1991:120712. HIV Infection in the Workplace: Protecting the Vulnerable To the Editors: The recent debate about human immunodeficiency virus (HlV)-infected health care workers has overlooked the particular problems facing those medical students, residents, and fellows who are at great risk of acquiring nosocomial HIV infection. These persons are on "the front lines," doing many invasive procedures (blood draws, intravenous insertion, paracentesis, lumbar puncture, and so forth), often in hurried and stressful circumstances. Whereas staff and attending physicians for the most part have disability and longterm health insurance, medical students, residents, and fellows have no or limited disability insurance and marginal long-term health insurance benefits. Medical students, residents, and fellows who sustain a potential parenteral exposure to HIV are strongly encouraged to have serial HIV testing. Yet if they are found to have contracted HIV through work-related exposure, future employment (particularly if it involves invasive procedures) is jeopardized. This problem is, of course, on top of the tens of thousands of dollars of debt that most of them carry as well as the devastating emotional and personal effects of HIV infection. Should we not provide some financial and health insurance assistance to those in the medical profession with HIV infection, and particularly to those with the fewest resources? It would be commendable if such assistance was available regardless of mode of transmission. Yet a particular obligation exists when transmission occurs in the workplace. Such insurance should be established by medical schools and hospitals. The
time to begin is now, when the number of persons is small but their need is great. Timothy P. Flanigan, MD Charles C.J. Carpentery MD Brown University Providence, RI 02912 Michael Close, MD The Miriam Hospital Providence, RI 02906 Covering for I m p a i r e d Residents To the Editors: Our society and our profession emphasize alcohol as an integral part of mainstream social interaction, and as Aach and colleagues (1) observe, "abuse of alcohol . . . is a major societal problem." Shortly after the drinking age in Wisconsin was raised from 18 to 21 years of age, I met one of the deans of the medical school at a Friday afternoon party sponsored by the Alumni Association. He observed that the admissions committee might need to require that all students be 21 years of age at matriculation; otherwise, some students might not be able to attend the Friday afternoon beer parties. When I suggested that social intercourse could take place in the absence of beer, he laughed and predicted that social functions bereft of alcohol would be poorly attended by students and quickly canceled by the medical school. His sentiments were shared by many of my classmates, who regarded those who did not consume alcohol on a regular and frequent basis to be social misfits. Against this backdrop, I found Aach and colleagues' article disturbing. The authors provide an estimable approach to substance abuse during residency, but I disagree with their tacit assumption that other residents in a program should automatically cover for their impaired colleagues during extended treatment programs. Even if one chooses to regard substance abuse as a disease rather than a choice, it is manifestly unfair to thrust the impaired resident's workload onto colleagues who have worked hard during training to manage stress constructively and thus to avoid impairment. I argue that this approach positively reinforces impaired physicians by rewarding unacceptable behavior with resources not otherwise available. Furthermore, the imposition of additional duties upon unimpaired colleagues places them at risk for future impairment caused by the stress of extra duties. If assigning an impaired resident's duties to other residents cannot be avoided, specific program policy, for example, flexible benefits during extended leaves (2), should be developed to protect the other residents from excessive imposition of additional demands. Brian J. Bohlmann, MD 23 Quail Ridge Drive Madison, WI 53717 References 1. Aach RD, Girard DE, Humphrey H, McCue JD, Reuben DB, Smith JW, et al. Alcohol and other substance abuse and impairment among physicians in residency training. Ann Intern Med. 1992;116:245-54. 2. Bohlmann BJ. Pregnant surgical residents: Oh K?! [Letter]. JAMA. 1991;266:2222-3. In response: Dr. Bohlmann accurately points out that the pervasiveness of alcohol use reflects in large measure the inappropriate emphasis placed on it by our society, including the medical profession. The Association of Program Directors in Internal Medicine (APDIM) agrees that additional duties assumed by residents in a training program when one of their fellow residents is impaired must not place them at risk of impairment caused by stress. However, APDIM takes issue with the view that it is "manifestly unfair" for other residents to manage the impaired resident's duties during the period that the resident is not working. We view alcohol and other substance abuse as an illness, with a high probability of successful outcome, if the appropriate measures are taken. As physicians, we have chosen a career to help those who are ill, including
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our colleagues. Residents have long covered for other residents who are ill, providing that the coverage required does not place too heavy a burden on those who are well. The same is true of physicians who have completed their training. The program director should determine whether or not coverage for an impaired resident is reasonable. We do agree that there should be clear program policies about coverage for illness. We recommended developing program policies and making this information known (1). Flexible benefits during an extended leave is one approach that program directors should consider.
haustive peer evaluation. The College's process for guideline development meets both challenges. Dr. Bettigole's apparent conclusion that the dangers of guidelines far outweigh their benefits challenges the premise of the editorial: that a profession must not only set its standards but that they should be written down. This principle is of fundamental importance to the medical profession. Certainly, a program of practice guidelines is at risk of misuse, especially by third party payers. There are far greater risks, however, when our profession remains silent on the great problems of medical practice.
Richard D. Aach, MD Association of Program Directors in Internal Medicine Washington, D.C. 20005
Harold C. Sox, Jr., MD Dartmouth-Hitchcock Medical Center Lebanon, NH 03756
Reference 1. Aach RD, Girard DE, Humphrey H, McCue JD, Reuben DB, Smith JW, et al. Alcohol and other substance abuse and impairment among physicians in residency training. Ann Intern Med. 1992;116:245-54.
Reference 1. Sox HC Jr, Griner P. An invitation to join a controversy. Ann Intern Med. 1992;116:422-3.
ACP Practice Guidelines
Medical Use of Marijuana
To the Editors: When they are good, practice guidelines issued by organizations like the American College of Physicians (ACP) may well be very, very good, but when they are bad, they will, like the little girl in the nursery rhyme, be horrid. The assertion that such guidelines "should become the preferred source for definitive advice" (1) ignores the fact that, because data accumulate continuously, any such guidelines would potentially be outdated before publication. The assertion is also based on a false premise: that the standard of care is based on medical textbooks, which may also be out of date by the time of publication or before the next edition. The ACP position should be that a review of the recent medical literature is appropriate. If not, why publish practice guidelines in Annals'? The consensus of learned physicians was that bed rest was needed after surgery, childbirth, and acute myocardial infarction. The consensus of learned physicians was that a radical mastectomy was the only surgical means of dealing with breast cancer. Today's consensus may differ radically from yesterday's and from tomorrow's. In the end, the risk is that such practice guidelines will become a straitjacket barring prompt use of new information. A consensus also might be influenced by considerations of cost. Adopting practice guidelines issued by organizations like ACP seems like such a good idea, but it has not been tested and has the potential for doing more harm than good. Richard Bettigole, MD 786 Delaware Avenue Buffalo, NY 14209 Reference 1. Sox HC Jr, Griner P. An invitation to join a controversy. Ann Intern Med. 1992;116:422-3.
In response: Dr. Bettigole has taken me to task for asserting that: Physicians in search of an authoritative recommendation have traditionally turned first to medical textbooks. Although physicians still look there for advice, practice guidelines issued by organizations like the ACP should become the preferred source for definitive advice (1). I stand by this position. Dr. Bettigole's letter, however, reveals deeper concerns with practice guidelines. His concerns are appropriate, but I do not agree with his conclusion. He sees danger in the potential for guidelines to become outdated. For just this reason, ACP periodically revisits its earlier recommendations. He also argues that professional consensus can be a dangerous way to form guidelines for practice. Indeed, guidelines based simply on a consensus do not deserve serious attention; they must also rest on a foundation of rigorous analysis of the evidence and ex268
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To the Editors: In a letter reporting the preliminary results of an anonymous survey of members of the American Society of Clinical Oncology (ASCO), Doblin and Kleiman (1) acknowledge the "possibility of response bias" and that their results "only roughly estimate the views of oncologists." In fact, 57% of those surveyed did not return their questionnaires, and the number of questionnaires returned unanswered is not stated. Further, the authors chose not to include respondents who filled out the survey but who indicated no opinion on the question (30% of the respondents); instead they stated that "of the respondents who expressed an opinion, a majority (54%) thought marijuana in the smoked form should be available by prescription." After all the exclusions, I calculate that this "majority" can be no more than 15% to 20% of the original sample and is probably much less. In addition, Annals was not told that the study results were published previously in a book edited by the president of the Alliance for Cannibus Therapeutics (ACT) (2), which sponsored the study and was then engaged in litigation against the Drug Enforcement Administration (DEA) to reclassify marijuana from schedule I to schedule II. In the book, Doblin states in his survey conclusions that "substantial numbers of cancer patients are not getting the medical care that their doctors would prefer to provide them because federal law prohibits marijuana's medical u s e . " This unwarranted overinterpretation of their results is simply not true. My colleagues and I surveyed every twentieth consecutive, board-certified, practicing clinical oncologist member of ASCO nationwide for his or her experience and opinion of cannabis as an antiemetic (3). A parallel, validating survey was mailed to all practicing adult oncologists in the Washington, D . C , metropolitan area (total of two surveys, n = 170). Analysis by an independent biostatistician showed a greater than 95% agreement between the results of both surveys. Our response rate was 78%, almost double that of the Doblin study ( 1 , 2 , 4). In contrast to their survey, we found that cannabis (marijuana or dronabinol) ranked sixth in the management of severe postchemotherapy nausea and vomiting and was used even less frequently for milder symptoms. When used, it was deemed effective in 50% of the cases, but one in four patients had bothersome adverse effects. The availability of combination antiemetic agents, including the newly released serotonin antagonist, ondansetron, suggests that cannabis would not be used more frequently by most oncologists, even if legalized. For the few patients receiving highly emetogenic chemotherapeutic drugs who are not helped by available antiemetics, case-by-case exemptions from the current restrictive marijuana laws would seem more appropriate. Richard H. Schwartz, MD Georgetown University School of Medicine Washington, D.C. 22180
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References 1. Doblin R, Kleiman MA. Medical use of marijuana. Ann Intern Med. 1991;114:809-10. 2. Doblin R. Marijuana: a question of currently accepted medical use. In: RC Randall; ed. Cancer Treatment and Marijuana Therapy. Washington, D.C.: Galen Press; 1990:341-52. 3. American Society for Clinical Oncology. Program proceedings of the American Journal of Clinical Oncology [Abstract no. 12141. Am J Clin Oncol. 1991; 10:342. 4. Doblin RE, Kleiman MA. Marijuana as antiemetic medicine: a survey of oncologists' experiences and attitudes. Am J Clin Oncol. 1991 ;9: 1314-9. To the Editors: In May 1991, Annals published a letter by Doblin and Kleiman (1) that referred to a survey they had conducted on the medical value of the smokeable form of marijuana (as opposed to dronabinol). Others are better qualified to comment on the unscientific nature of the study and its inability to support its conclusions. I want instead to point out that, although the authors stated their association with the John F. Kennedy School of Government of Harvard University, they failed to mention that Mr. Doblin is the founder and president of the Multidisciplinary Association for Psychedelic Studies (MAPS), referred to as the "People's Psychedelic Pharmaceutical Company" in their newsletter head. The organization has advocated research on humans with the street drug Ecstasy and the gradual medicalization and legalization of psychedelics. In MAPS newsletters dated Summer 1990 and August 1991, Doblin outlines a plan to use different scientific forums, including Annals and the press, to lend credibility to the campaign to legalize marijuana use and to bolster a suit against the Drug Enforcement Administration. I believe that the authors' bias and hidden agenda should be made known to your readers.
Sandra S. Bennett Oregon Federation of Parents for Drug Free Youth Milwaukie, OR 97267 Reference 1. Doblin R, Kleiman MA. Medical use of marijuana. Ann Intern Med. 1991;114:809-10. A final order was issued by the administrator of the Drug Enforcement Administration (DEA) effective 26 March 1992, ". . . concluding the plant material marijuana has no currently accepted medical use and denying the petition of NORML {National Organization for Reform of Marijuana Laws] to reschedule marijuana from schedule I to schedule II of the Controlled Substances Act" (1). The Public Health Service also recently concluded after a review of its medical usefulness that "smoked marijuana is potentially more harmful than helpful to patients with compromised immune systems" (2). Because of this and the availability of Marinol (dronabinol; Unimed, Inc., Somerville, New Jersey), which contains the major active substance, tetrahydrocannabinol, they have decided not to provide additional patients with marijuana for medicinal purposes. They will continue to supply the 13 patients already receiving it. There had been 28 other petitions, but by the time of the decision, 10 patients had been convinced to use alternatives and had withdrawn their applications.—The Editors References 1. U.S. Department of Justice, Drug Enforcement Administration. Marijuana scheduling petition: final order. Federal Register. 1992 Mar 26;57:10499-508. 2. Public Health Service denying new requests for medicinal marijuana. Internal Medicine News & Cardiology News. 1992 May 1;25:31.
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