Observations Associated With Long-term Treatment ... but discontinuation of treatment in only one. .... weakness, myopathy, hair loss, abortions, anemia,leu-.
The Western
Journal of Medicine
Coichicine Use for Familial Mediterranean Fever Observations Associated With Long-term Treatment ROBERT S. PETERS, MD, Fresno, California; THOMAS J. A. LEHMAN, MD, Bethesda, Maryland, and ARTHUR D. SCHWABE, MD, Los Angeles
Of 85 patients with familial Mediterranean fever receiving continuous prophylactic colchicine therapy, 62 (73 percent) have had a significant reduction in the severity and frequency of their attacks. All 62 have been observed for three years or more, for a total of 4,680 patient-months and a mean duration of 75.5 months. Of the 85 patients, 23 (27 percent) did not complete three years of treatment for a variety of reasons. Diarrhea was the most common side effect, necessitating reduction of colchicine dosage in 12 patients, but discontinuation of treatment in only one. No other significant side effects were observed. Continuous, prophylactic colchicine therapy is effective in preventing the recurrent febrile paroxysms of familial Mediterranean fever and is indicated in those patients who are incapacitated by frequent attacks or who are at risk for amyloidosis developing. The efficacy of prophylactic, continuous colchicine therapy in preventing the recurrence of febrile attacks of familial Mediterranean fever was established by three controlled studies in 19741-3 and later confirmed by reports from several centers.4-6 Between the years 1967 and 1978 a total of 99 patients with familial Mediterranean fever from the clinics of two California hospitals were selected to receive continuous colchicine therapy. The subsequent course of these patients, including adherence to the recommended regimen, dosage and side effects, and the long-term efficacy of the treatment in preventing attacks, constitutes the basis of this report.
Methods The diagnosis of familial Mediterranean fever in all patients in this study was based on established criteria.4'7 The 99 patients included 62 Armenians, 30 Jews and 7 of other ethnic origin. There were 56 male
and 43 female patients, ranging in age from 4 to 64 years, Indications for administering continuous colchicine therapy were one or more of the following: frequent, severe attacks significantly interfering with a normal pattern of life; failure of alternative therapy, and a family history of familial Mediterranean fever amyloidosis. The patients were informed of the indications for colchicine therapy, possible side effects and potential benefits. Patients with a reproductive potential were also advised to interrupt the colchicine therapy before a planned conception. Initially, a dosage of 0.5 or 0.6 mg of colchicine twice a day was recommended, but the dosage was increased to 0.6 mg three times a day for all patients older than 16 years of age in 1974. Patients were observed at regular intervals and questioned about adherence to the regimen, symptoms, frequency of attacks and side effects. A physical examination and a qualitative test for urine protein were carried out at each visit. Routine blood counts were done before
Refer to: Peters RS, Lehman TJA, Schwabe AD: Colchicine use for familial Mediterranean fever-Observations associated with long-term treatment. West J Med 1983 Jan; 138:43-46. From the Departments of Medicine, UCLA School of Medicine, Los Angeles, and Valley Medical Center of Fresno; and the Department of Pediatrics, University of California, San Diego. Dr Lehman, formerly with the Department of Pediatrics, University of California, San Diego, is now affiliated with the National Institute of Arthritis, Digestive and Kidney Diseases, Bethesda, Maryland.
Submitted April 29, 1982.
Reprint requests to Arthur D. Schwabe, MD, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90024.
JANUARY 1983 * 138 * 1
43
PROPHYLACTIC COLCHICINE USE
Current Dosage
and at the time of two or more subsequent monthly clinic visits.
Results Duration of Treatment The course of the 99 patients originally entered in the study is outlined in Table 1. Two patients died of causes unrelated to familial Mediterranean fever or treatment and 12 were lost to follow-up. Of the remaining 85 patients available for analysis, 62 (73 percent) have continued to take colchicine for three or more years. The mean duration of treatment as of April 1981 was 75.5 months, with a range of 36 to 169 months (Figure 1). A total of 42 patients have completed five or more years of continuous colchicine therapy. Of the 85 patients 23 (27 percent) interrupted, discontinued or were withdrawn from therapy for. reasons shown in Table 1 and detailed later in this report. Eight patients-who were apprehensive about the possible side effects of colchicine-used the drug sporadically or discontinued using it entirely and were therefore classified as noncompliant. One patient was withdrawn from colchicine therapy due to chronic diarrhea that became intractable when quinidine had to be added to his regimen because of a coexistent arrhythmia. In a second patient, a 44-year-old man who had been successfully treated for three years, a progressive decrease in libido developed. He attributed this to the colchicine therapy and discontinued taking the drug. A third patient, a 22-year-old man who had been successfully TABLE 1.-A Long-term Study of Coichicine Therapy for Familial Mediterranean Fever Showing Degree of Compliance to Recommended Regimen Description of Patients
No.
Entered in study ...................... Removed from study ................... Died (unrelated to FMF) ..... ....... Lost to follow-up .......... ........... Followed regularly ..................... Did not complete full course of therapy ... Did not comply with regimen ..... ..... Therapy withdrawn because of side effects Failed to respond to colchicine ..... .... .......... Completed >3 years of therapy
z
'LI lLi a. U-
0
d z
99 14 2 12 85 (100) 23 ( 27) 8 3 12
62 ( 73)
Duration of Therapy
30[ cn
No. (percent)
25
20F 15 10 5
LM 3647
L7
607296844859 71 107 83 95 MONTHS OF CONTINUOUS THERAPY
>107
Figure 1.-Duration of continuous, daily colchicine treatment in 62 patients with familial Mediterranean fever. 44
(I, z LiJ ,.,
0
ci z
D. L
D.O
(mg.
DAILY DOSE (mg)
Figure 2.-Current daily coichicine dosage in 62 patients with familial Mediterranean fever on long-term treatment.
treated for more than five years, was advised to interrupt therapy when he decided to start a family. These three patients did not complete the prescribed course of therapy because of actual, presumed or potential side effects. Eight patients with coexistent functional or psychological disorders continued to have a variety of symptoms, such as chronic abdominal pain, weakness and headaches, which were unaffected by taking colchicine. In three patients who were found to be addicted to narcotics and who continued to complain of symptoms, neither the efficacy nor the adherence to the prescribed regimen could be verified. An additional patient reported no change in the frequency and severity of his attacks while taking colchicine. These 12 patients were classified as treatment failures (Table 1). Dosage of Colichicine From 1967 to 1974 patients were maintained on a regimen of 1.0 to 1.2 mg of colchicine per day. Subsequently, however, a dosage of 1.8 mg (0.6 mg three times a day) was prescribed for all adults entering the study for optimal suppression of attacks. The effects of familial Mediterranean fever were controlled in six children with the administration of 1.2 mg a day. The dosage was reduced to 1.2 mg a day in 22 adult patients. Reduction was necessitated in 12 patients due to side effects, which will be detailed later in this report. The other ten patients voluntarily reduced their dosage on advice from other family members or friends who were doing well on a lower dosage, or because they forgot to take the midday dose and seemed to notice no ill effect. No patients were maintained on less than 1.2 mg a day. The colchicine dosage was increased to 2.4 mg a day in two patients whose attacks were partially, but not completely, suppressed on the lower dosage. The THE WESTERN JOURNAL OF MEDICINE
PROPHYLACTIC COLCHICINE USE
Effec:t on Frequency of Attacks 7 Before ,8 During
the addition of a psyllium seed preparation and a third to the administration of diphenoxylate hydrochloride
with atropine. Three patients continued to have increased frequency of bowel movements, but prefer this side effect to recurrent attacks of familial Mediterraz LLJ nean fever. The 13th previously cited patient with intractable diarrhea after the addition of quinidine had to be withdrawn from colchicine therapy. 0 In four patients transient, self-limited anorexia and z r | nausea developed, but no vomiting. No weight loss, H ,weakness, 1 1-4 -myopathy, hair loss, abortions, anemia, leuF 4 5-8 9- 12 >" , kopenia or steatorrhea was observed in any of the patients. Small intestinal biopsies are being carried out in NO. OF ATTACKS PER YEAR a number of the patients; preliminary results do not indicate any significant histologic abnormalities. Except Figure 3.-Long-term Eeffect on the frequency of attacks of for one patient mentioned previously, no one reported familial Mediterranean fever in 62 patients taking daily, prophylactic colchicine. libidinal disturbances or infertility. None of the women or sexual 'artners of the men in this studv became amount of colchicine currently taken by the 62 papregnant during the study period. tients is shown in Figure 2. :V)
-
Effect of Colchicine Therapy on Attacks All of the 62 (73 percent) patients still receiving colchicine therapy in April 1981 had a significant reduction in the severity and frequency of their attacks, as shown in Figure 3. In all, 39 patients ceased to have attacks for the period of study-that is, more than three years-and 22 patients had only one to four attacks a year. None of the treated patients required hospital admission for familial Mediterranean fever during the period of treatment. This attack frequency is in sharp contrast to the number of attacks occurring before the institution of therapy. Of the 85, there were 23 (27 percent) who failed to complete three years of therapy or had terminated therapy before April 1981 for the reasons previously mentioned. Although several of these patients clearly benefited from taking the drug, all were considered long-term treatment failures. It should be stressed, however, that for patients with familial Mediterranean fever, treatment requires a flexible, multifaceted approach that takes into account the tendency of addiction to narcotics, the coexistence of other physical and emotional disorders and the concern about long-term side effects of colchicine use and its potential harmful effects on conception. Any of these problems may result either in noncompliance or failure of colchicine therapy. Side Effects
Virtually all patients had mild, transient diarrhea and abdominal discomfort for one to three days after the institution of treatment. However, 13 patients continued to have two to four loose or watery bowel movements a day for more than a month. In 6 of the 13 patients, reducing the colchicine dosage from 1.8 to 1.2 mg a day resulted in a return to normal bowel habits. The other seven patients did not improve with reduction in drug dosage alone. Two of them responded to JANUARY 1983 * 138 * 1
Discussion During the past seven years continuous, prophylactic colchicine therapy has significantly improved the management and prognosis of patients with familial Mediterranean fever.'- The long-term follow-up study presented here shows not only that this form of treatment continues to be effective, but also that it is relatively free of significant side effects. Administration of the drug had to be discontinued in only one patient because of intractable diarrhea. In dosages of more than 1.8 mg a day colchicine may cause malabsorption of fat, D-xylose and vitamin B,2, as well as inhibition of intestinal enzymes,8'9 complications not observed in our patients. In even larger doses, colchicine may be toxic to gastrointestinal mucosa, bone marrow, kidneys, lungs and cardiovascular system.10-'2 Such severe toxicity, however, occurs most often after accidental overdoses or suicide attempts in patients who have received 7 to 350 mg of colchicine in relatively short periods of time.'3 The relative safety of recommended daily dosages of colchicine (that is, 1 to 1.8 mg) has been emphasized in other articles.5"14 Nevertheless, we continue to be concerned about the effect of colchicine on fertilization, implantation and pregnancy and advise our patients to stop taking the drug three months before planned conception. Wright and co-workers15 found that three of five patients who had premonitory symptoms could abort an attack by taking 6 mg of colchicine in divided doses over 72 hours. This intermittent therapy is difficult for most patients. Many cannot clearly recognize the earliest signs of an attack and wait until the attack is well established and no longer amenable to colchicine suppression. Others start taking colchicine for unrelated symptoms, especially upper respiratory tract infections and functional abdominal pain, and wrongly conclude that the drug is totally ineffective. Another strong argument for continuous colchicine therapy is its possible beneficial effect on amyloidosis. Early evidence suggests 45
PROPHYLACTIC COLCHICINE USE
that colchicine therapy may prevent, reverse or impede the progression of amyloidosis.14 16 At present, therefore, there is little question that those ethnic groups at high risk for amyloidosis developing should be receiving continuous colchicine therapy. Colchicine administration has been used with variable success in several other clinical disorders such as gout, pseudogout, Behget's disease, necrotizing vasculitis, scleroderma and Paget's disease, but little is known about its mechanism of action. Although interference with microtubule formation, degranulation of neutrophils and alteration of leukocyte adenosine 3':5'-cyclic phosphate levels have been found in vitro, the relevance of these effects to colchicine prophylaxis for familial Mediterranean fever is unclear.'7"18 REFERENCES 1. Zemer D, Revach M-, Pras M, et al: Controlled trial of colchicine in preventing attacks of familial Mediterranean fever. N Engl J Med 1974; 291:932-934 2. Dinarello CA, Wolff SM, Goldfinger SE, et al: Colchicine therapy for familial Mediterranean fever-A double-blind trial. N Engl J Med 1974; 291:934-937 3. Goldstein RC, Schwabe AD: Prophylactic colchicine therapy in familial Mediterrean fever-A controlled, double-blind study. Ann Intern Med 1974; 81:792-794
4. Schwabe AD, Terasaki PI, Barnett EV, et al: Familial Mediterranean fever-Recent advances in pathogenesis and management. West J Med 1977; 127:15-23 5. Levy M, Eliakim M: Long-term colchicine prophylaxis in familial Mediterranean fever. Br Med J 1977 Sep 24; 2:808 6. Bakir F: Periodic peritonitis-Present management and future prospects. Ann Intern Med 1979; 139:781-783 7. Heller H, Sohar E, Sherf L: Familial Mediterranean fever. Arch Intern Med 1958; 102:50-71 8. Race TF, Paes LC, Faloon WW: Intestinal malabsorption induced by oral colchicine-Comparison with neomycin and cathartic agents. Am J Med Sci 1970; 259:32-41 9. Webb DI, Chodos RB, Mahar CQ, et al: Mechanism of vitamin B,2 malabsorption in patients receiving colchicine. N Engl J Med 1968; 279: 845-850 10. Carr AA: Colchicine toxicity. Arch Intern Med 1965; 115:29-33 11. Stemmermann GN, Hayashi T: Colchicine intoxication-A reappraisal of its pathology based on a study of three fatal cases. Hum Pathol 1971; 2:321-332 12. Liu YK, Hymowitz R, Carroll MG: Marrow aplasia induced by colchicine-A case report. Arthr Rheum 1978; 21:731-735 13. Stapczynski JS, Rothstein RJ, Gaye WA, et al: Colchicine overdose: Report of two cases and review of the literature. Ann Emerg Med 1981 Jul; 10:364-369 14. Zemer D, Pras M, Sohar E, et al: Colchicine in familial Mediterranean fever (Letter). N Engl J Med 1976; 294:170-171 15. Wright DG, Wolff SM, Fauci AS, et al: Efficacy of intermittent colchicine therapy in familial Mediterranean fever. Ann Intern Med 1977;
86:162-165 16. Ravid M, Robson M, Kedar I: Prolonged colchicine treatment in four patients with amyloidosis. Ann Intern Med 1977; 87:568-570 17. Rudolph SA, Greengard P, Malawista SE: Effects of colchicine on cyclic AMP levels in human leukocytes. Proc Natl Acad Sci 1977; 74: 3404-3408 18. Greene WC, Parker CM, Parker CW: Colchicine-sensitive structures and lymphocyte activation. J Immunol 1976; 117:1015-1022
Medical Practice Questions EDITOR'S NOTE: From time to time medical practice questions from organizations with a legitimate interest in the information are referred to the Scientific Board by the Quality Care Review Commission of the California Medical Association. The opinions offered are based on training, experience and literature reviewed by specialists. These opinions are, however, informational only and should not be interpreted as directives, instructions or policy statements.
Transcutaneous Electrical Nerve Stimulation (TENS) and Percutaneous Electrical Nerve Stimulation (PENS) and Electroacutherapy QUESTIONS:
Has the use of transcutaneous electrical nerve stimulation (TENS) or percutaneous electrical nerve stimulation (PENS) for the relief of pain become accepted medical practice, or are they investigational? Is it accepted medical practice to use electroacutherapy modalities in conjunction with either transcutaneous electrical nerve stimulation or percutaneous stimulation? OPINION: In the opinion of the Advisory Panels on Internal Medicine, Neurology, Neurosurgery and Physical Medicine and Rehabilitation, transcutaneous electrical nerve stimulation (TENS) and percutaneous electrical nerve stimulation (PENS) have been accepted as established therapeutic modalities for the relief of pain. TENS iS acceptable treatment for acute as well as chronic pain, primarily of musculoskeletal or neurological etiology. PENS is also acceptable treatment but because of associated risks it should be reserved for chronic, intractable pain conditions. Electroacutherapy modalities used in conjunction with either TENS or PENS for relief of pain are not established medical practice. Further investigation is required to determine their safety and efficacy in patients with pain syndromes or other conditions. Such research should be carried out under a strict scientific protocol.
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THE WESTERN JOURNAL OF MEDICINE
