The increase in over-the-counter (OTC) sales comes as no surprise. Buying an analgesic off the shelf is considerably easier and more convenient – and far less expensive – than seeing a doctor and going through the process of getting a prescribed drug. OTC medications are widely promoted and readily available. Unfortunately, the average American does not realize that a drug purchased OTC may be associated with the same adverse effects as the same drug purchased by prescription. In the case of OTC NSAIDs, adverse reactions may include kidney damage, hypertension, and gastrointestinal (GI) symptoms ranging from mild dyspepsia to serious or even fatal GI bleeding.

NSAID-induced GI Disease

GI disease associated with NSAIDs has been reported as the most common serious adverse drug effect in the United States. Nonsteroidal antiinflammatory drugs (NSAIDs) can exacerbate underlying disease or cause new lesions. From 38% to 50% of patients taking NSAIDs report dyspepsia, and gastric ulcers may develop in up to 28% of patients taking NSAIDs regularly. Studies have shown that a person exposed to NSAIDs has three to four times the risk of non-users for upper GI bleeding, perforation, or both. Increased risk of a serious adverse reaction has been associated with age, female sex, and rheumatoid arthritis, while independent risk factors associated with upper GI bleeding include male sex, history of peptic ulcer (with or without complications), and the use of alcohol, cigarettes, anticoagulants, and corticosteroids.

Lands et al. found that 80% of patients with either upper or lower GI bleeding, and 78% of patients with upper GI bleeding only, had recently consumed NSAIDs (verified by measuring platelet cyclooxygenase activity and serum salicylate levels, as well as taking patient history). Klein et al. also found a higher frequency of GI bleeding in NSAID users. They examined discharge data from hospitalized patients who had suffered GI hemorrhage (both NSAID users and nonusers). Patients using nonsteroidal antiinflammatory drugs (NSAIDs) spent more time in intensive care than nonusers (median 1 day versus 0 days), and daily users had a higher transfusion requirement than nonusers (4 units versus 1 unit), both of which suggest that NSAID use has a substantial impact on health-care resource allocation.

OTC NSAIDs and GI Hemorrhage

A two-year study of hospitalized patients admitted with upper GI bleeding has demonstrated that the self-administration of OTC NSAIDs can substantially increase the risk of bleeding. Wilcox et al. evaluated consecutive patients admitted with upper GI hemorrhage to a large inner-city hospital in Atlanta, Georgia. The use of any OTC or prescription nonsteroidal antiinflammatory drug (NSAID) during the week before admission was assessed prospectively (from patient and family interview and pharmacy records). Inclusion criteria included age more than 18 years; presence of hematemesis and a subnormal hematocrit (or a decrease in hematocrit of more than 5 points from baseline); and documented lesion (disclosed by endoscopy, barium upper GI series, or at autopsy). Patients were excluded if the GI bleeding first occurred during hospitalization.

During the 2-year period, 421 patients were evaluated. Mean age was 50 (range 18-89); 352 patients were black, 63 white, 4 Hispanic, and 2 Asian; 276 patients were male, and 145 were female. Peptic ulcer was the most common cause of bleeding, identified in more than half the patients. Acute gastric mucosal lesions – including nonspecific gastritis, portal hypertension, and gastropathy (alcohol- or aspirin- induced) – were relatively infrequent. More women than men and more subjects over age 60 than under 60 were taking prescription NSAIDs; those younger than 60 were more likely to use OTCs, and those over 60 were more likely to use prescription NSAIDs. Drug use was not related to race.

Aspirin was taken during the week before admission by 41% of patients (and OTC aspirin by a total of 35%). OTC nonaspirin-NSAIDs were taken by 9% of patients and prescription NSAIDs by 14%. The investigators described the use of OTC aspirin and nonaspirin NSAIDs as “striking” in patients with upper GI bleeding (all causes). These products were used most frequently by patients with ulcer-related bleeding (66%), esophagitis (62%), and Mallory-Weiss tears (laceration of the gastric cardia) (56%) but were also used commonly by patients with bleeding unrelated to ulcers. The investigators concluded, “We believe, as do others, that short-term NSAID use (less than 1 week) may be one of the most important precipitating factors for ulcer related hemorrhage.”

Epidemiology of NSAID-GI Bleeding

A large retrospective study of NSAID use and upper GI (gastrointestinal) bleeding has illuminated the use and misuse of nonsteroidal antiinflammatory drugs (NSAIDs). Rodriguez et al. used a database of 4 million patients (the UK General Practitioners’ Computerized Records) to identify 1467 patients with upper GI bleeding over a 3-year period, and 10,000 matched controls. The site of bleeding was gastric in 483 patients and duodenal in 787; 40 patients had multiple sites of bleeding, 147 had peptic ulcer only, and 261 had perforation; 64 patients died. One major indication for NSAID therapy was ill-defined back pain (13% for cases and 10% for controls). Although patients used any of 17 different NSAIDs, sufficient data for individual analyses were obtained for ibu- profen, naproxen, diclofenac, ketoprofen, indomethacin, piroxicam and azapropanone (the latter not available in the United States). Aspirin use was not specifically addressed, because use was seen as too widespread and underreported.

The investigators found that the mean relative risk for upper GI bleeding associated with current NSAID use was 4.7 (7.0 with high doses and 2.6 with low doses). Current users were patients who most likely used nonsteroidal antiinflammatory drugs (NSAIDs) within the previous month (last NSAID prescription ordered during the month before the index date, or duration of therapy including the index date). NSAIDs associated with highest risk of GI bleeding were azapropanone (relative risk 23.4) and piroxicam (relative risk 18). Ibuprofen at low doses had the smallest risk (2.1), although risk was substantially increased with higher doses (6.5 for 1500 mg/day or more). Both short- and long-duration exposure increased the risk of upper GI bleeding, long duration only slightly more than short duration. Patients who recently switched from one NSAID to another or used more than one NSAID simultaneously had more than twice the risk of patients exposed to only one NSAID. In cases where current aspirin use was recorded on the computer, adjustment did not greatly alter risks, which differs from the other studies.

The biggest risk factor for GI bleeding in NSAID users was a history of peptic ulceration (relative risk 17.2). Age also played a role: people under 60 exposed to NSAIDs had a relative risk of 2.8; people over 60 had a relative risk of 13.2. NSAID use was slightly greater in women than in men, yet male sex was associated with a greater risk. The investigators described the patient at greatest risk of presenting with an episode of upper GI (gastrointestinal) bleeding as “a male smoker of advanced age who has a history of peptic ulcer, and is a user of oral corticosteroids, anticoagulants, and NSAIDs.”

Managing NSAID-induced Dyspepsia

How should patients with NSAID-induced dyspepsia be managed? A prospective study by questionnaire (sent to 300 general practitioners, 261 of whom responded) found that management strategies include NSAID discontinuation (87%), switching to another NSAID (12%), and referral for endosco-py (14%) or barium meal (2%). The drugs preferred for management of dyspepsia included histamine2-receptor blockers (41%), antacids (about 25%), and misoprostol (25%).

The authors of the report offered the following guidelines for patients with persistent NSAID- related dyspepsia when simple analgesics are inadequate: Endoscopy is advisable when symptoms persist for more than 3 weeks in patients who need long-term NSAID therapy; when dyspeptic symptoms or signs suggest organic disease; and when the patient is receiving both steroids and NSAIDs. Misoprostol prophylaxis for NSAID-related dyspepsia is recommended at the onset of NSAID therapy for patients with a history of peptic ulcer disease and may also be justified if NSAID therapy is short term, or if endoscopy is intolerable, impractical, or unavailable.

NSAIDs and hypertension in the elderly.

Do NSAIDs alter blood pressure? In elderly patients, the answer to this question is a qualified “maybe.” Johnson et al. found NSAID use an independent risk factor for hypertension in nearly 3000 Australian subjects aged 60 years or more who answered a questionnaire and underwent blood pressure mea- surements. Frequency of NSAID usage was determined for all study participants – 1237 men and 1568 women stratified by age, sex, blood pressure group, and history of arthritis.

Nonsteroidal antiinflammatory drug (NSAID) usage was 26% overall (females 28% and males 23%). Usage increased with age and was higher in females than males in every group studied. Among patients with a history of “arthritis,” 45% were using NSAIDS; 12% were taking both NSAIDS and antihypertensive agents. NSAID usage significantly predicted the presence of hypertension, with an attributable risk of 29%. It is difficult to tell whether NSAIDs raise blood pressure or antagonize the effects of antihypertensive agents, said the investigators, however, “In this elderly population… 29% of the hypertension occurring amongst those taking NSAIDs could be attributed to the NSAID, underscoring the potential contribution of NSAID usage to the prevalence of hypertension in the elderly.”

How It Works

Bromfenac is a peripherally acting analgesic that belongs to the nonsteroidal anti-inflammatory drug (NSAID) class. Although the exact mechanism of action of this class of drugs is not known, there are many theories. Duract (bromfenac) seems to have anti- inflammatory, antinociceptive, and antipyretic effects. These activities of the drug are thought to be the result of its inhibition of the arachidonic acid cascade at the cyclooxygenase level.

Following bromfenac administration, the onset of analgesia occurs within about 30 minutes. The peak effect is seen within 2 to 3 hours and lasts about 6 to 7 hours. Bromfenac is more than 99% protein bound and has an elimination half-life of about 1.3 hours. The half-life, however, does not correlate with the duration of action of this drug. Bromfenac is metabolized by the liver into a cyclic amide metabolite and four glucuronide conjugates of aglycone metabolites and is excreted via the urine.

Duract (Bromfenac): Clinical Tips

Currently, the recommended dose for bromfenac is 25 mg every 6 to 8 hours for short-term pain management. If bromfenac is to be taken with a high-fat meal, the dose should be increased to 50 mg every 6 to 8 hours. However, the total daily dose of bromfenac should not exceed 150 mg. If a physician wishes to prescribe this medication for longer than 4 weeks, it would be advisable to monitor the liver enzymes, which can become elevated. Other possible adverse events include abdominal pain, headache, nausea, and vomiting.

Although opioids have proved to be excellent agents in the management of moderate to severe pain, their adverse event profile leaves much to be desired. These agents are known to make people drowsy, tired, and “spaced out,” often leading to noncompliance with the drug regimen. The efficacy of Duract (bromfenac) in relieving pain has already been demonstrated, and, unlike opioids, it does not interfere with people’s lifestyles. As experience with this agent grows, people may elect to use it instead of the opioid analgesic because of its favorable adverse event profile.

It is available in two strengths. One formulation (Arthrotec 50) contains 50 mg of diclofenac and 200 mcg of misoprostol while the other (Arthrotec 75) contains 75 mg of diclofenac and 200 mcg of misoprostol. The usual dose of Arthrotec in the management of osteoarthritis is 50 TID and for rheumatoid arthritis is 50 TID or QID; BID dosing can be used.

How it works:

Diclofenac sodium:

Diclofenac sodium is an NSAID that exhibits classical anti-inflammatory, antipyretic, as well as analgesic properties. As with other NSAIDs, its exact mechanism is not completely understood but it is believed that diclofenac, like other NSAIDs, works in part by inhibiting prostaglandin synthetase.

Misoprostol:

Misoprostol is a synthetic prostaglandin E1 analog. In animals, misoprostol inhibits gastric acid secretion and promotes mucosal protective properties. Misoprostol can increase bicarbonate and mucus production and decrease the secretion of gastric acid. The exact reason for protection against ulcers has not be determined.

Clinical Tips

Diclofenac:

Diclofenac is completely absorbed through the gastrointestinal tract following oral administration. The diclofenac portion of Arthrotec is stable in the acidic environment of the stomach. However, it is rapidly released from the formulation once it enters the more basic environment of the duodenum. Peak plasma levels of this portion are reached in about 2 hours. Because of the extensive first pass effect, only 50% of the dose is available for absorption. The diclofenac portion of Arthrotec is metabolized by the liver and cleared by the urine (65%) and the biliary route (35%).

Misoprostol:

Misoprostol is rapidly absorbed following oral administration, but must undergo metabolic activation into misoprostol acid before it can exerts it pharmacologic actions. The misoprostol acid that is present in Arthrotec reaches peak plasma levels in about 20 minutes and is rapidly eliminated with an approximate half-life of 30 minutes.

Arthrotec follows similar pharmacokinetic parameters as the individual components. The amount of absorption of the two components from the preparation of Arthrotec is comparable to the amount of absorption of the two individual components separately. Importantly, food tends to decrease the bioavailability of the two components of Arthrotec. The pharmacokinetic profile of the diclofenac component in Arthrotec is unchanged in elderly patients and in patients who are renally and hepatically challenged. The pharmacokinetics of misoprostol is influenced by age as well as renal and hepatic impairment; the levels of misoprostol in these individual may double. Hence, it is necessary to adjust the dose in elderly patients and in patients who have renal and hepatic problems.

Clinical studies have shown that diclofenac alone, or in combination with misoprostol, is effective in the treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis. When given alone, misoprostol has been shown to reduce the occurrence of gastric and duodenal ulcers in patients who were receiving a variety of NSAIDs for the management of arthritic conditions. When Arthrotec was compared to diclofenac alone in patients who had osteoarthritis, the incidence of drug-induced ulcers was lower in patients who were receiving Arthrotec than those who were receiving diclofenac. Even though the incidence of gastric and duodenal ulcers was lower with Arthrotec, only the incidence of gastric ulcers was significantly lower in patients who were receiving Arthrotec than those who were receiving diclofenac.

Abdominal pain, diarrhea, upset stomach, and nausea are among the most common side effects with Arthrotec. Diarrhea may be reduced if this medication is taken with meals. Most adverse effects that occur with misoprostol are mild to moderate and generally resolve following a few days of treatment.

Instructions for the Patient

Arthrotec should not be given to patients who are allergic to aspirin, who have pre-existing asthma, and who have severe renal failure. It should not be given to patients who are pregnant or who are planning to become pregnant because it is believed the misoprostol component can cause fetal death.

Patients should also be advised to swallow Arthrotec whole; they should not chew, crush or dissolve this medication. In addition, patients should be advised to report any signs and symptoms of liver failure (jaundice, itching, nausea) to their physician.

• researchers at the Merck Research Laboratories compared the effects of rofecoxib to those of both the non-steroidal anti-inflammatory drug (NSAID) naproxen sodium and placebo in 127 women, aged 18 and older, who had histories of moderate to severe menstrual pain.
• found that menstrual pain at eight and 12 hours after medication was relieved similarly in both rofecoxib and naproxen sodium recipients.
• side-effects were similar among all three groups in the study.
• authors note that menstrual pain is thought to be caused, at least in part, by substances called prostaglandins, and that rofecoxib works to reduce the production of prostaglandins by inhibiting the COX-2 enzyme.

Dr Barry Stimmel, The Haworth Medical Press, 10 Alice St, Binghamton, NT 13904-1580, USA, 1993, 366pp

Family physicians often see patients who misuse drugs. This widespread problem is the source of much hidden morbidity and mortality for patients and much frustration for doctors.

Family doctors are likely to have had little formal training in identifying and intervening in this area. Their attitudes toward problem drug use probably differ little from those held by the public.

This book was written “to enable those with little or no background in science or health care to understand the often complex issues of drug use” and “is presented clearly, concisely, and without jargon.” It presents the facts about drug use with authority.

The book is divided into three parts: basic concepts, mood-altering drugs, and areas of special concern. Information is based on statistics from the United States. The regulations and laws quoted are American. Treatments discussed are based on the American system of privately funded health care.

In part 1 (basic concepts), the chapter titled “Habituation, Dependency and Addiction” is useful for defining terms and distinguishing misuse from abuse and dependency from addiction. This chapter briefly describes the neurophysiological basis for the ability of drugs to produce mood alteration, which can lead to dependency and addiction.

Part 2 discusses each different class of mood-altering drugs and provides lots of factual information. However, the chapter on opiates underemphasizes their importance as drugs of abuse in clinical practice while the chapter on heroin and on methadone maintenance is too long. In the chapter on nicotine, the nicotine patch is referred to only briefly.

In part 3 (areas of special concern), well written, factual chapters cover such topics as drugs and AIDS, drugs and pregnancy, and drugs and sports. The final chapter is one with a decidedly American slant entitled “Why has the War Against Drugs Failed?”

Three appendices covering sources for reporting drug use (American), drug testing technology, and common street names for drugs are followed by almost 400 references. This book is not written for family physicians. It does not develop skills for identifying problems or intervening in this area or even challenge attitudes. However, it would be useful for family doctors interested in the facts on drug use and as an addition to a hospital, school, or public library.

Gordon E. Johnson, PHD W.B. Sounders Company, 55 Homer Ave, Toronto, ON M8Z 4X6, 1991, 425 pp

Essentials of Drug Therapy is a clearly written book, summarizing information on drugs that are commonly used. It is not a reference text in pharmacology or an exhaustive detailed volume, such as the Compendium of Pharmaceuticals and Specialties, but is a practical source of information for the medical student and practitioner.

The chapters are organized according to therapeutic categories and are introduced by a brief overview of the therapeutic rationale for use of pharmacologie agents. Most drug groups are included, even those used for symptomatic relief, such as antitussives and analgesics. It is somewhat surprising that laxatives are not included, but these have never been an attractive group of drugs for pharmacologists.

The text is clear and succinct. Paragraph headings facilitate rapid access to information, with paragraphs on mechanism of action and pharmacological effects, therapeutic uses, adverse effects, drug interactions, and doses.

The book should be a useful volume for the busy practitioner and the medical student.

Ed by RG Cameron, G Feuer, FA de la Iglesia, 681 pp, ISBN 3 540 60201 1, Berlin: Springer Verlag 1996

The editors of this splendid volume have invited an international array of contributors to cover its 26 chapters on all aspects of hepatotoxicity due to drugs — adverse effects that mimic acute fulminant hepatitis, chronic active hepatitis, cirrhosis and even malignancy. Turn to one of these chapters for an update on molecular aspects of hepatic drug reactions, in vitro models, cytochrome P450, drug-induced cholestasis, choline deficiency, the fatty liver, immune mechanisms, encephalopathy, pregnancy, Reye syndrome, or hepatotoxicity in infants and the elderly; and, of course, for separate information on each individual drug, including one of the most important, alcohol.

This new Canadian text naturally invites comparison with an Australian text, Drug-induced Liver Disease, edited by GC Farrell (Churchill Livingstone), published in 1994. They are both very good and equally helpful when asked to solve a laboratory or clinical problem. Australian Ian Mackay contributes the immune mechanisms of drug hepatotoxicity in both books. To his credit they are in many respects different. In the earlier book he mentions the Th1 and Th2 subclasses of CD4 helper T cells. In the new Canadian book he advances his thoughts and forecasts that tipping towards Th1 or Th2 subsets influences the mode of expression of allergies and autoimmune diseases.

Both books will undoubtedly achieve new editions, so that each will leapfrog the other effectively in different segments of the Commonwealth in the long-term future. It is true to say that clinicians and pathologists have combined admirably to cover the whole gamut of adverse reactions in a single volume which is authoritative, academic and readable.

Complete Guide To Women's Health

Author: American Medical Association
Random House of Canada, Ltd, 1265 Aerowood Dr, Mississauga, ON L4W1B9
1996/759 pp

Good starter guide to women’s health

Strengths

Well formatted, easy to read, practical approaches to common problems, focus on wellness and preventive health

Audience

General public

This comprehensive reference volume for women contains common-sense approaches to a number of important health issues. Its target audience is middle-class American women with a moderately high level of literacy. The book aims to provide women with up-to-date medical information to guide decision making and to facilitate communication with their physicians.

Its four main sections cover health maintenance, sexual and reproductive health, pregnancy, and the common health concerns of women. It is well laid out with useful summaries, flow charts, sidebars containing helpful hints, questions women often ask, and narrative vignettes that lend a dynamic and personal tone to the main text.

I found the chapters on nutrition, fitness, avoiding risky behaviour, and stress management refreshingly frank and practical. The sections on pregnancy and childbirth are well illustrated and cover many of the issues women enquire about in my own practice. Although there are excellent chapters on family violence, sexual assault, and bereavement, the social context of women’s health is not explored in sufficient depth. The short section on sexual abuse, for example, makes only passing mention of the health consequences that an adult survivor of abuse might experience. In contrast, the 19 pages on elective cosmetic surgery seemed excessive.

The book is written with a specialty focus, emphasizing early referral. Very little is said about family physicians and their potential for providing comprehensive care and building health partnerships with women over time. There are no references or suggestions for further reading for women who wish to pursue controversial or rapidly changing issues, such as prevention guidelines. It is also unclear how consultants evaluated the evidence behind their recommendations. I found it surprising, for example, to see episiotomy presented as a procedure to prevent excessive tears during childbirth when there is evidence in the literature to the contrary.

The overall strength of this publication is its range, its detail, and its attention to the prevention of illness, making it a good starting place for many women to access health information and to consider dialogue with their physicians. In this regard, it fulfils the authors’ objectives. Because of its expense and likelihood of dating quickly, I would recommend it as a resource volume for a public library or community health clinic.

Atlas Of Clinical Diagnosis

M. Afzal Mir
W.B. Saunders Company, 55 Horner Ave, Toronto, ON M8Z 4X6
1995/266 pp

Strengths

Practical, excellent illustrations

Audience

Medical students and practitioners

This book aims to provide medical students and practitioners with a comprehensive survey of clinical signs organized by external body parts. The underlying assumption is that most diagnoses from clinical signs are based on pattern recognition, so the book is a rich collection of colour illustrations of common, rare, and esoteric conditions. Using arrows to highlight the more subtle signs would help readers, like me, who need more guidance.

The organization of the book is excellent with a logical approach to each external body part; for example, the chapter on the external eye deals with eyelids and orbit and the conjunctiva. Some interesting clinical tips include listening to a patient’s breathing by putting the stethoscope bell in front of the patient’s mouth.

The focus at times is esoteric with eight pages on various porphyrias, something I was taught in great detail in medical school and have yet to see in practice. Useful diagrams for such conditions as acromegaly or Cushing’s disease illustrate that clinical signs from each anatomical area are only part of the overall picture. Suggestions for further investigation of these major conditions are given but are brief and superficial. Common conditions seen in family practice, such as viral exanthemas, otitis media, and pharyngitis, are given less coverage, and there is a paucity of penile or vulval lesions.

The book is a good reference for unusual conditions and has excellent chapters on fundi, nail disorders, and hands. But the high price of the book could limit how widely it is used.

Antioxidants in Nutrition, Health, and Disease

John M.C. Gutteridge, Barry Halliwell
Oxford University Press, 70 Wynford Dr, Don Mills, ON M3C 1J9
1994/143 pp

Strengths

Summarizes current thought on free radicals and antioxidants. A clear, pithy, scientific, informative text

Audience

Physicians, medical students, nurses, biologists, nutritionists, and chemists

The authors have written a short textbook introducing antioxidants to clinical practice. They also refresh readers with a review of the basic clinical sciences.

A short, informative preface asks succinct questions on using antioxidants for treating heart disease, cancer, and degenerative illnesses. The authors answer their questions with sufficient information on free radicals, cholesterol, and oxidative stress for readers to use in laboratories and practices.

A historical discussion of oxygen, oxidation-reduction definitions, and electron transport is followed by scientific information on the Krebs cycle, vitamins, and nutrients and a timely presentation of free radicals as contributing to cardiovascular and degenerative disease.

Later, epidemiologic and pathologic evidence on nutrient use is presented. This evidence allows us to understand information applicable to a scientific study of tissue damage and regeneration. Clearly, interest in the effects of nutrition and vitamins on health has increased. This short text will help practitioners upgrade current knowledge and share the information with patients.

The authors acknowledge the brevity of their text. They have challenged readers to examine modern concepts that might be discussed with our patients in the office. They also give us sufficient information to provide our patients and colleagues with current thinking on the activity of essential vitamins A, E, and C.

The style of this book flows well with diagrams, bold headings, illustrations, and informative tables. I enjoyed the quotations from The Beatles and Butch Cassidy and the Sundance Kid mixed with Paracelsus and Francis Bacon, which set the tone for the discussion in each of the seven chapters.

Appendices supplementing chapters 1, 4, and 5 provide further information on cholesterol, saturated and unsaturated fats, and their effect on the cardiovascular system. The authors raise questions not only for academics, but also for the less scientific. Skillfully, they then lead us through a historical discussion of the building blocks of life: carbon, hydrogen, oxygen, and nitrogen. Are antioxidants elixirs or media hype? Are human phagocytes useful? Does oxidative stress help or hinder our health? Should vitamins and minerals be used as supplements? What is the window of optimum activity of antioxidants?

Although the jury is still out on the results of antioxidant research, the authors present much food for thought. This book is valuable, and a few nights’ perusal should give readers sufficient vital information on antioxidant therapy to guide application.