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Placebo responses in patients complaining of chronic fatigue
PLACEBORESPONSESIN PATIENTS COMPLAININGOF CHRONIC FATIGUE Ta the Editor:
Patients whose chief complaint is chronic fatigue show a high rate of response to therapy whether it be the study drug or its placebo [l]. In the investigation reported by Lloyd and co-workers [2], the infusion of gamma globulin produced significantly more adverse effects than the infusion of maltose (p
768
June
1991
The American
Journal
cannot be distinguished by either the patients, their physicians, or both. Yet, this unblinding may not invalidate the study if response can be measured easily through objective findings. But, when the complaints are subjective, the laboratory abnormalities subtle, and the patients suggestible, the design of the placebo treatment is crucial. Since some caregivers are far better mesmerizers than others, all treatments should be administered with a stern but professional indifference such as might be encountered in a drug evaluation unit. When studying patients complaining of chronic fatigue, we must all be convinced that the investigation was, in fact, doubleblind and placebo-controlled. Trumpeting these terms in the title will not suffice. EDWARDB. ROTHERAM,J~.,M.D. Allegheny General Hospital Medical College of Pennsylvania Pittsburgh, Pennsylvania 1. Straus SE, Dale JK. Tobi M, et a/. Acyclovir treatment of the chronic fatigue syndrome: lack of efficacy in a placebo-controlled trial. N Engl J Med 1988; 319: 1692-8. 2. Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J. Adouble-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med 1990; 89: 561-8. 3. Peterson PK, Shepard J, Macres M. et al. A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Am J Med 1990; 89: 554-60. Submitted
November
29,1990,
and accepted January 12, 1991
A PROPOSEDMECHANISM FORCARDBOARD-INDUCED IRON-DEFICIENCYANEMIA To the Editor:
The report by Callinan and O’Hare [l] of a cardboard-chewing patient adds an interesting new substance to the spectrum of materials ingested by patients with pica. The authors suggest that the pica for cardboard was not only a symptom of the .ane-
of Medicine
Volume
90
mia, but may have caused the iron deficiency by inducing satiety, thereby limiting the patient’s oral intake of iron. We would agree that the cardboard may have contributed to the patient’s anemia, but would like to suggest an alternate mechanism by which this may have occurred, For many forms of pica, such as pica for laundry starch, olives, raw potatoes, or ice, it is believed that the iron deficiency is primary and the pica merely a symptom. There is, however, one notable exception: the ingestion of clay, which has been causally linked to iron deficiency [2], and to zinc deficiency [3] and hypokalemia [4]. The physicochemical properties of clay impart to it excellent adsorptive properties for free mineral ions; ingestion of clay may thus prevent the absorption of minerals from the gastrointestinal tract [5]. Ancient physicians recognized this property of clay empirically, and incorporated terra sigillata and terra silesiaca into their pharmacopoeias as antidotes for poisoning [6]. The efficacy of clay in this regard is illustrated by the report of a condemned prisoner who volunteered to consume a lethal dose of mercury if he were allowed to ingest clay prior to the poison. The authorities watched with interest as he survived three times the normal lethal dose, and in recognition of his contribution to medical knowledge and to their entertainment, they thereafter granted him a full pardon [6,7]. Modern laboratory techniques have confirmed that 16thcentury terra sigillata possessed sufficient cation-exchange potential to neutralize ingested mercuric chloride [8]. Recent studies have documented the efficacy of conventional clay in preventing the absorption of iron from the gastrointestinal tract [2]; 5 g of clay decreased ra-
Patients whose chief complaint is chronic fatigue show a high rate of response to therapy whether it be the study drug or its placebo [l]. In the investigation reported by Lloyd and co-workers [2], the infusion of gamma globulin produced significantly more adverse effects than the infusion of maltose (p
768
June
1991
The American
Journal
cannot be distinguished by either the patients, their physicians, or both. Yet, this unblinding may not invalidate the study if response can be measured easily through objective findings. But, when the complaints are subjective, the laboratory abnormalities subtle, and the patients suggestible, the design of the placebo treatment is crucial. Since some caregivers are far better mesmerizers than others, all treatments should be administered with a stern but professional indifference such as might be encountered in a drug evaluation unit. When studying patients complaining of chronic fatigue, we must all be convinced that the investigation was, in fact, doubleblind and placebo-controlled. Trumpeting these terms in the title will not suffice. EDWARDB. ROTHERAM,J~.,M.D. Allegheny General Hospital Medical College of Pennsylvania Pittsburgh, Pennsylvania 1. Straus SE, Dale JK. Tobi M, et a/. Acyclovir treatment of the chronic fatigue syndrome: lack of efficacy in a placebo-controlled trial. N Engl J Med 1988; 319: 1692-8. 2. Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J. Adouble-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med 1990; 89: 561-8. 3. Peterson PK, Shepard J, Macres M. et al. A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Am J Med 1990; 89: 554-60. Submitted
November
29,1990,
and accepted January 12, 1991
A PROPOSEDMECHANISM FORCARDBOARD-INDUCED IRON-DEFICIENCYANEMIA To the Editor:
The report by Callinan and O’Hare [l] of a cardboard-chewing patient adds an interesting new substance to the spectrum of materials ingested by patients with pica. The authors suggest that the pica for cardboard was not only a symptom of the .ane-
of Medicine
Volume
90
mia, but may have caused the iron deficiency by inducing satiety, thereby limiting the patient’s oral intake of iron. We would agree that the cardboard may have contributed to the patient’s anemia, but would like to suggest an alternate mechanism by which this may have occurred, For many forms of pica, such as pica for laundry starch, olives, raw potatoes, or ice, it is believed that the iron deficiency is primary and the pica merely a symptom. There is, however, one notable exception: the ingestion of clay, which has been causally linked to iron deficiency [2], and to zinc deficiency [3] and hypokalemia [4]. The physicochemical properties of clay impart to it excellent adsorptive properties for free mineral ions; ingestion of clay may thus prevent the absorption of minerals from the gastrointestinal tract [5]. Ancient physicians recognized this property of clay empirically, and incorporated terra sigillata and terra silesiaca into their pharmacopoeias as antidotes for poisoning [6]. The efficacy of clay in this regard is illustrated by the report of a condemned prisoner who volunteered to consume a lethal dose of mercury if he were allowed to ingest clay prior to the poison. The authorities watched with interest as he survived three times the normal lethal dose, and in recognition of his contribution to medical knowledge and to their entertainment, they thereafter granted him a full pardon [6,7]. Modern laboratory techniques have confirmed that 16thcentury terra sigillata possessed sufficient cation-exchange potential to neutralize ingested mercuric chloride [8]. Recent studies have documented the efficacy of conventional clay in preventing the absorption of iron from the gastrointestinal tract [2]; 5 g of clay decreased ra-