Reserpine: A tragic victim of myths, marketing, and fashionable prescribing

Henry S. Fraser, MB,BS, PhD Briddetown, Bmbados

The drug explosion of the last 50 years has in- cluded an ever-increasing range of antihypertensive drugs. There are almost 100 antihypertensive agents in current use, and many hundreds of different brands and combination products. Ever since reser- pine replaced the first antihypertensives (the gan- glion blockers such as trimethaphan) each wave of new drugs has been hailed as a major advance. They displace the older, less costly drugs (the “old faith- ful?), which are used less and less frequently and are soon consigned by opinion leaders to obscurity. Meanwhile, the cost of treatment rises sharply with each new advance.

Today’s drug, tomorrow’s poison Fashions in prescribing can change rapidly. Sir

William Osler put it caustically: “One should treat as many patients as possible with a new drug while it still has the power to heal,” whereas William Heb- erden said: “. . . new medicines always work miracles for a while.” Although the cycle of popularity, den- igration, and return to accepted use of digoxin is an instructive example, the Fifth Report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure (JNC V) recom- mendation of thiazides for first line use in hyperten- sion has major implications for millions of patients and enormous benefits for drug budgets.

In the case of both digoxin and the thiazides, the reassessments and the verdicts of “not guilty” have been associated with a better understanding of the optimal therapeutic dose ranges. The 10 mg dose of bendroflumethiazide used in the Medical Research Council trial of mild hypertension’ was a clear case

From the Faculty of Medical Sciences, University of the West Indies, Queen Elizabeth Hospital.

Received for publication March 181996; accepted May 20, 1996. Reprint requests: Hemy S. Fraser, MB, BS, PhD, Faculty of

Medical Sciences, University of the West Indies, Queen Eliz- abeth Hospital, Bridgetwon, Barbados.

Clin Pharmacol Ther 1996;60:368-73. Copyright 0 1996 by Mosby-Year Book, Inc. 0009-9236/961$5.00 + 0 13/l/75210

368

of “overkill” with a potentially toxic dose. The cur- rent recommended dose of 2.5 mg is one-quarter of the original.3 In fact, recent work has shown that 1.25 mg is efficacious, with virtual elimination of metabolic side effects.4

Careful review of the evidence suggests that the potent antihypertensive reserpine, an adrenergic an- tagonist with some central action, has been the vic- tim both of massive overdosage and of faulty sci- ence. Early doses were very high (i.e., 0.75 to 10 mg/day), and medical texts of the 1960s uniformly recommended a dose regimen of 0.25 mg three times daily (i.e., 0.75 mg daily) or higher. It is now known that the half-life is several days, duration of effects may be several weeks, and that 0.1 to 0.25 mg is an effective dose-one-seventh to one-third of the most widely used early dose.5 It is not surprising that those toxic doses produced a poor side-effect profile, including gastric intolerance, peptic ulceration, diz- ziness, and depression.

Scientific errors, but a bad name sticks However, what really ruined the reputation of

reserpine was the erroneous link with breast cancer reported in the Boston Collaborative Drug Surveil- lance Program.6 Several million dollars, thousands of patients’ files, and 2 years later the claim was refuted (see below for references), but the label had stuck. A bright new contender for the role of cen- trally acting antiadrenergic was “in the wings.” That was clonidine, a potent drug effective at doses of 0.1 mg for 8 to 12 hours. Although this drug was being intensively studied and promoted, reserpine was not merely abandoned but in the United Kingdom it was withdrawn from use and dropped from the British National Formulary, largely because of the impact of an adverse effect of which it was shown to be innocent! Ironically, clonidine has not established a major role or special place in hypertension treat- ment partly because of severe rebound hypertension on withdrawal.

Reserpine has continued to be used extensively in the United States, where B-blockers were slow to

CLINICAL PHARMACOLOGY &THERAPEUTICS VOLUME 60, NUMBER4 Fraser 369

gain approval. A large body of very positive data has accumulated, but only occasional pleas have been made for its rehabilitation. Widmer7 has called it “ . . . the maligned antihypertensive drug.” Magar- ian* has reviewed an impressive body of evidence to support a valuable role for reserpine calling it “. . . a neglected drug for achieving cost containment in treating hypertension.” What are the facts?

Depression The reputation of reserpine for serious side ef-

fects was based largely on three perceived problems: depression, peptic ulceration, and breast cancer. It began with early case reports of depression in pa- tients treated with large doses.‘,” These included cases of suicide after administration of doses up to 10 mg per day. In the largest series” the mean dose was 1.36 mg daily, or 6 to 14 times the currently recommended doses. In 1958 Ayd12 showed that patients with mild or “pseudo-depression” re- sponded to a decrease in dose, and some patients’ relatives reported that patients had mild depression before treatment.

In a questionnaire evaluation of side effects of hypertensive drugs, Bulpitt and Dollery13 found no statistically significant difference in the incidence of depression between patients taking reserpine (0.25 to 0.5 mg daily) methyldopa, guanethidine, bethani- dine, thiazide, or P-blocker. They concluded that reserpine could not be a cause of depression. Similar conclusions have been reached by other research- ers, 14,15 and in the Veterans Affairs Cooperative Study, low-dose reserpine had no adverse effect on Zung Depression Scale scores.16

Peptic ulcer disease In 1956 Hussar and Bruno17 reported duodenal

ulceration associated with reserpine therapy. Other reports followed, all with high reserpine doses of several milligrams daily. Reserpine was shown to stimulate the secretion of gastric acid, but there is little or no effect at doses of 0.25 mg daily or less.18 More recent studies have shown no difference in dyspepsia between reserpine and other antihyper- tensive drug treatments, whereas the most recent major study with reserpine showed dyspepsia in only 1.5% of reserpine patients, compared with 7.7% of patients receiving metoprolol.19

Shorr et a1.20 carried out a nested case-control study of the association between reserpine use and hospitalization for peptic ulcer disease in elderly Medicaid enrollees. The relative risk of hospitaliza-

tion for peptic ulcer disease among current reser- pine users compared with that of nonusers was 0.8 (95% confidence interval, 0.6 to 1.0). After a review of the literature and their own findings, they con- cluded that reserpine is not associated with ulcer disease in the elderly and that a history of ulcer disease need not be a contraindication to its use.

Breast cancer Perhaps the allegation that ruined the reputation

in Britain and Europe, in particular, was that of an association with breast cancer. In 1974 three case- comparison studies were published,6,21,22 all in the same issue of the Lance& suggesting an association between reserpine use and breast cancer. Both the reputable sources of these data and their simulta- neous publication undoubtedly added to their im- pact. Over the next 4 years, 10 similar large studies refuted these findings, including studies from the United States, the United Kingdom, Germany, and Finland.23M26 The myth of this association has been described as a classic error of study design.27

However, the damage had been done, and an equally potent centrally acting drug-clonidine- was waiting in the wings; it was under intensive and sophisticated clinical investigation at that time and was strongly promoted as the safe alternative to reserpine, although its major side effects of sedation and rebound hypertension have ultimately shown that it has considerable risks of its own. The more acceptable choices in Britain and Europe over the next decade were the newly released P-blockers. However, in the United States, propranolol was the only P-blocker available in the 197Os, because of the scare related to the toxicity of practolol. As a result, reserpine remained the adrenergic blocker of choice in the United States; it was regarded as well toler- ated with few central side effects when used in lower doses of 0.25 to 0.5 mg, and it was included, with or without thiazide, in several major antihypertensive trials. Through these trials considerable data were acquired on its efficacy and tolerability at low doses, as well as data concerning reduction in vascular morbidity and mortality.

Efficacy at low doses The Veterans Administration Cooperative Study,

which first showed the benefits of treatment in se- vere hypertension2* and mild to moderate hyperten- sion,29 used reserpine at a dose of 0.2 mg, with 100 mg hydrochlorothiazide and 150 mg hydralazine daily, versus placebo. It has since been used in nu-

370 l+m?v CLINICAL PHARMACOLOGY&THERAPEUTICS

OCTOBER 1996

merous large and small trials, including the Hyper- tension Detection and Follow-up Program,30 the Multiple Risk Factor Intervention Trial (MRFIT),31 and other Veterans AfEairs trials, including the re- cent study of hypertension in the elderly (SHEP).32 With or without a diuretic, reserpine has been compared favorably in many studies with methyl- dopa, with or without a diuretic, and has been better tolerated.32‘35 Similarly, a reserpine- hydrochlorothiazide combination has proved to be more effective than a combination of propranolol (from 40 to 160 mg three times daily) alone or in combination with hydralazine (25 mg three times daily) or in combination with hydrochlorothiazide (100 mg daily).36 Other studies have shown equal or greater efficacy compared with several p-blocker combinations with thiazide in black, Indian, and Chinese patients with hypertension.37,38 Finally, in a double-blind study that compared 0.1 or 0.3 mg reserpine daily (without a thiazide) with the calcium channel blocker diltiazem (30 to 60 mg daily) in 107 patients with blood pressures greater than 160/90 mm Hg, blood pressure reduction was almost iden- tica1.39

In all of these studies the reserpine dose was between 0.1 and 0.3 mg daily. A dose of 0.125 mg daily has been shown to be as effective as 0.25 mg daily, and a dose as low as 0.05 mg achieved goal blood pressure 89% as often as the 0.25 mg dose.40 It is therefore clear that the effective dose range is between 0.05 and 0.25 mg, many times lower than the doses of the 1960s that led to an undeserved poor side-effect profile.

Minor adverse effects In the large trials, reserpine has been consistently

shown to be equal or superior to widely accepted drugs in both efficacy and tolerance. But several other adverse effects deserve mention. The most common is nasal congestion, which is variously re- ported at from 6% to 15%-20%.35,40 Unlike other side effects, it does not appear to decrease with lower doses. Other possible concerns have been im- potence and lipid changes. Numerous studies have shown impotence to be infrequent; lower than with methyldopa, other centrally acting drugs, or p-blockers; and frequently lower than in subjects receiving placebo. ’ Finally, other central nervous system effects, such as extrapyramidal effects and sedation, are not a problem with current doses.35,36

On its own, reserpine has no effect on serum lipids.41 With thiazides, which produce transient el-

evation of lipid levels, it may contribute to the re- duction of cholesterol levels to the pre-thiazide baseline.32740 This merits further study.

Tolerance and compliance Inasmuch as the major reputed adverse effects of

reserpine-depression, impotence, dyspepsia, and peptic ulceration-are less common than for most drugs, it is not surprising that it is as well tolerated as other frequently used regimens and that compli- ance may be better. 32,35,36 The most common side effect-nasal congestion-is no more common than cough in angiotensin converting enzyme (ACE) in- hibitors and does not appear to be a major deter- minant of compliance. The advantage of a single daily dose is a consistent factor in the improvement of compliance.42,43 Unlike other centrally acting drugs (clonidine and methyldopa), poor compliance does not cause rebound hypertension because of the prolonged therapeutic effect of reserpine. This has a distinct added benefit of maintaining blood pressure control even if compliance is erratic.

Recent perspectives Left ventricular hypertrophy (LVH) is now known

to be an independent predictor of cardiac morbidity and mortality in patients with hypertension.44 It therefore seems likely that drugs that cause regres- sion of LVH may be more effective in preventing long-term cardiovascular complications. This ap- plies to most drugs that have been studied, except for vasodilators and a-blockers. The issue of LVH regression has been better and more thoroughly studied by echocardiography, with the newer drugs-the ACE inhibitors and calcium channel blockers-receiving more attention. However, both thiazides45 and reserpine28’45’46 also appear to cause regression of LVH. Although variable responses have been shown with thiazides, chiefly in smaller, short-term, and unblinded studies,45 more consis- tent reduction of LVH has occurred in blinded larger studies.47-50

The other characteristic of reserpine that is now of increasing importance, not only in poor develop- ing countries but in developed countries, is cost. In the United States, medications account for nearly 60% of the cost of hypertension treatment. Reser- pine is by far the cheapest of all drugs, and a reserpine-thiazide combination is universally the cheapest two-drug combination. Thiazide and reser- pine thus provide hypertension control “. . . in as high as 80% of patients with mild to moderately

CLINICAL P HARMACOLOGY &THERAPEUTICS VOLUME 60, NUMBER4

severe hypertension”51 at a small fraction (15- to 50- fold differences) of the cost of proprietary ACE inhib- itors and calcium channel blockers; that is, wholesale costs of 2~ or 3~ compared with $1 to $2 per day.52 Clearly, reserpine and thiazide use permits “. , . phe- nomenal savings in health care costs”53 and may mean the difference between life and death for many pa- tients without health insurance in the United States and for millions of patients in the developing world.

The market place Tragically, the advantage of very low cost now ap-

pears to operate against professional acceptance and wide use of many valuable drugs, of which reserpine is perhaps the most dramatic example. There are many reasons for this, including aggressive new drug mar- keting, active discouragement of older drugs (as with thiazides), lack of marketing and promotion of generic drugs (for which profits are minimal and there is no industry sponsor), lack of research funding, lack of discussion in continuing education forums or research meetings, changes in emphasis in medical training, lack of response or enthusiasm for responding to neg- ative reports and, partly as a consequence of all of these trends, “fashion” in prescribing.54”6 With wide- spread information sharing and media interest in health matters, patient pressures may also have a sig- nificant impact on prescribing practices. Reserpine has the added disadvantage of having been removed from some national formularies (e.g., the British National Formulary), at the height of the unfortunate hype over the medical “misinformation” about breast cancer. This appears to have placed an official stamp of ap- proval on the “medical myths.”

Nevertheless, there has been a steadily increasing number of voices championing the use of reserpine, beginning with Widmer’s7 “Reserpine the Maligned Antihypertensive Drug” in 1985 and followed by editorials by Moser57 in 1988, by Moser et a1.55 in 1991, and by Lederle et a1?6 in 1993. “Reserpine reconsidered” in 1993 reviewed the absence of as- sociation with peptic ulcer disease,20 whereas in 1991 Magarian’ reviewed the reserpine literature in depth, with 143 references, and concluded that 0.1 to 0.25 mg reserpine daily in combination with low dose thiazide “. . . should once again be given seri- ous consideration for use in many patients with mild to moderate hypertension.”

Conclusions In several large trials, regimens with reserpine

and thiazide have been shown beyond doubt to be

Fraser 371

effective both in lowering blood pressure and in reducing morbidity and mortality. Furthermore, they may cost as little as one-fiftieth of the cost of most ACE inhibitor- calcium channel blocker com- binations. This translates into treatment of 50 pa- tients for the price of one. In spite of the strength of these data and economic facts, reserpine has fallen “out of fashion.”

The reserpine story can be described as a classic example of the impact of false information, exces- sive early dose recommendations, and marketing strategies on prescribing fashions. The result can be a misled profession and the loss to society of a safe, effective, and highly economical drug. Efforts must be made to prevent such mistakes in the future.

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