Zinc and the Common Cold: What Pharmacists Need to Know

Zinc and the Common Cold: What Pharmacists Need to Know

Darrell T. Hulisz, Pharm.D.
Assistant Professor of Family Medicine, Case Western Reserve University School of Medicine, Cleveland, OH

The common cold is one of the oldest and most bothersome conditions affecting the population. On average, adults endure three to five episodes of the common cold per year.1 In an attempt to alleviate their cold symptoms, Americans spend over $2 billion annually on over-the-counter products.2 The illness causes an estimated 23 million days of work absence—an average of almost seven days per person each year in the United States.3 The common cold results in approximately 27 million physician visits annually in the U.S., and drugs are prescribed or recommended in 94% of these cases.4 Currently available prescription and over-the-counter medications provide only limited symptomatic relief, and carry the potential to produce significant adverse effects. Furthermore, these regimens may become complicated and costly. It is not surprising then that the general public, physicians, and pharmacists are intrigued by the prospect of discovering therapies that are both beneficial and safe. The ideal treatment for the common cold would be a natural product that provides symptomatic relief or shortens the duration of symptoms, and is nontoxic. To date, however, no such therapy has conclusively been shown to fit this profile.

Despite limited evidence of efficacy from well-designed clinical trials, complementary and alternative natural products such as echinacea, feverfew leaf, ascorbic acid, garlic, and zinc salts continue to gain popularity in the self-care approach to treating colds. One of the most controversial and popular natural remedies for the common cold is the zinc salts. Zinc lozenges (e.g., Cold-Eeze) and lollipops (CoughPops) are widely available in drug stores and supermarkets and are heavily promoted to the public. Since pharmacists are frequently consulted for advice about the use of zinc to treat cold symptoms, the purpose of this article is to examine what is known about using zinc for the common cold so they could respond to these inquiries.

Why not just recommend conventional OTC cough and cold products?
Antihistamines are commonly used for relief of rhinorrhea (runny nose) and sneezing; however, their use is not without controversy since controlled studies do not clearly support their use in colds.5 Antihistamines produce an atropine-like drying effect on mucous membranes and may actually impair flow of mucus.6 Furthermore, antihistamines can cause drowsiness, dry mouth, blurred vision, urinary retention, and hypotension. Studies have shown that symptoms associated with the common cold such as sneezing, runny nose, and stuffiness are not caused by histamine release, but by virally induced release of kinins.7 Critical analyses of well-designed studies using antihistamines demonstrate little or no benefit in symptomatic relief of the common cold.5,8-10 Despite this, many nonprescription products containing antihistamines are heavily marketed and used for this indication. An expert panel has published a consensus paper stating that antihistamines have no role in the management of colds, though they are useful in obtaining relief from allergy symptoms.11

Decongestants may produce some short-term relief of cold symptoms, such as nasal congestion. Decongestants are sympathomimetic agents that, because of their alpha-agonist effect, produce vasoconstriction of the nasal mucosa. Oral decongestants are associated with systemic side effects such as cardiac and central nervous system stimulation and elevation of blood pressure. Local (topical) administration is associated with rapid development of tachyphylaxis and rebound congestion (rhinitis medicamentosa). Many pharmacists have encountered patients with this problem, which results from overuse of decongestant nasal spray. Other pharmacotherapeutic agents used in the common cold include analgesics (e.g., aspirin, acetaminophen, ibuprofen and other NSAIDs), and nasal inhalation of the anticholinergic drug ipratropium for rhinorrhea. All of these therapies carry potential risks of serious adverse reactions, especially in the elderly and in patients with comorbid conditions.

When suggesting products for self-treatment, pharmacists also should keep their patients’ preferences in mind; many people today who specifically ask for alternative products will not take conventional medicines.

Is zinc truly effective in treating cold symptoms?
Results of nine randomized controlled studies of zinc lozenges for the common cold were positive in four studies12-15 and no better than placebo in five.16-20 With one exception,18 all studies have employed zinc in the form of the gluconate salt lozenge; however, the exact formulation and dosage has differed. All studies except one16
Generally, it is believed that for zinc to work, it must be taken at the first sign of cold symptoms, and for optimal benefit, should be continued the entire duration of the cold.
have been conducted in adults. It is beyond the scope of this article to present the details of these studies; nevertheless, because the studies showed conflicting results using similar methodologies, one can conclude the evidence is contradictory.

This presents pharmacists with a unique dilemma, since we are trained to be objective and decisive in providing recommendations to patients and healthcare providers. In light of the evidence, it is quite accurate for pharmacists to tell patients that in some studies zinc is effective, and in others it is not. Many researchers believe that because the zinc story is inconclusive, further studies should be conducted.

Pharmacists may also wish to factor in anecdotal evidence and testimonials from patients when recommending zinc products. Unfortunately, we have very little to offer patients with regard to natural products or nutritional supplements that alter the usual course of the common cold.

Generally, it is believed that for zinc to work, it must be taken at the first sign of cold symptoms. Therefore, pharmacists should advise patients to begin treatment within 24 hours of onset of cold symptoms.

Why the discrepancy in study results?
Even a cursory review of clinical trials using zinc for cold symptoms reveals the fact that all studies have some methodological flaws. Criticisms include small sample size in some trials, use of too low a zinc dosage, inadequate blinding of subjects, and the use of chiefly subjective self-reported data. Some trials have been criticized for using formulations with excipients or flavoring agents which theoretically could inactivate zinc salts. Most studies do not detail how patient compliance was guaranteed. Most studies do not confirm the diagnosis of common cold by using virologic testing. Furthermore, most studies have not specifically excluded allergy sufferers; allergy symptoms (e.g., hay fever) often mimic the common cold.

An ongoing debate centers around the notion that chemically different lozenge formulations have caused the different results in the clinical trials to date. This hypothesis is supported by the fact that different lozenge formulations do in fact produce markedly different zinc ion availability in saliva.21 However, the optimum degree of ionization for a therapeutic benefit is unknown. Greater degrees of ionization may produce unpleasant taste and other side effects. The rationale behind using zinc as a lozenge and not systemically is partly because lozenges are less likely to result in higher serum concentrations with resulting adverse effects. It is generally thought that for zinc to be effective, the product should deposit in the oral, pharyngeal, and nasal mucosa. However, a potential concern with using zinc lozenges in young children (e.g., less than 4 years of age) is the possibility of a child choking on the lozenge. Zinc lollipops are a suitable and safer alternative in this case.

How does zinc exert its therapeutic effect?
At concentrations of 0.1 mmol/L, zinc is able to inhibit in vitro replication of several viruses known to cause the common cold.22,23 However, zinc’s exact mode of action in vivo is unknown. Several mechanisms have been postulated and are reviewed elsewhere.24 Proposed mechanisms by which zinc may exert its therapeutic effect include inhibiting viral capsid protein production, inducing the production of gamma interferon, and stabilizing and protecting plasma membranes against lysis by cytotoxic agents. Another suggested mechanism involves zinc inhibiting rhinoviral interaction with intercellular adhesion molecules, the site where the virus initially binds to epithelial cells. Some have also proposed that zinc may interfere with the release of histamine and other inflammatory mediators from mast cell granules. Still others have noted that zinc does have some immune-enhancing properties, at least at the deficiency end of the nutritional spectrum.25 Individuals who are zinc-deficient, such as children from economically disadvantaged populations, adolescents with low dietary intake of zinc, and adults with subclinical zinc deficiency, may benefit from zinc supplementation through an enhancement of cellular immunity. While this hypothesis seems plausible, serum zinc levels were not measured in previous studies examining the role of zinc in the common cold. One expert in this field recently advocated that future studies measure serum zinc levels before and after treatment.26

While not addressed in the literature concerning zinc lozenges, there is another explanation for symptomatic improvement; namely, the demulcent effect of lozenges. Any preparation that is dissolved slowly in the oral cavity will stimulate the flow of saliva and can, to some degree, quiet a cough and soothe an irritated pharynx. Theoretically, the greater the volume of human saliva stimulated by a product, the more soothing to the oropharynx the product would be.

What side effects does zinc cause?
Zinc lozenges can produce a bad taste that patients may describe as bitter or metallic. Some patients report nausea and mild stomachache. These effects appear to be dose-related and do not occur in everyone. In some studies, patients have also reported mouth irritation or tingling. One manufacturer has developed a lollipop formulation which, to some degree, masks the bitter taste of zinc by using an amino acid chelate of zinc acetate.27 Brief courses of zinc therapy appear to be safe. However, excessive intake of zinc has been associated with neutropenia, impaired lymphocyte activity, and copper deficiency.26
Counseling points concerning zinc
Pharmacists can respond to patients’ questions concerning the use of zinc for treating the common cold by remembering the following points:
1. Only about half the studies of zinc show it is effective for treating cold symptoms. Studies showing both positive and negative results have methodological flaws.
2. Patients should begin zinc treatment within 24 hours of onset of cold symptoms.
3. Zinc lollipops are safe alternatives to zinc lozenges for younger children where a choking risk may exist; however, controlled studies have not yet been conducted.
4. The exact mode of zinc action is unknown, but several different mechanisms seem plausible.
5. Zinc lozenges and lollipops should be dissolved slowly in the oral cavity without being bitten or chewed. This will allow for a greater demulcent effect and permit the zinc to deposit in the oral, pharyngeal, and nasal mucosa.
6. Pharmacists should discourage pregnant and lactating women from using zinc cold remedies unless future studies confirm their safety.
7. Pharmacists can tell patients that short courses of zinc appear to safe, but some mild side effects may occur. These effects are limited to the gastrointestinal tract and include bad taste, nausea, and stomachache.
The safety of zinc products has not been confirmed in pregnant and lactating women. Although no serious adverse effects have been associated with zinc-containing cold remedies, consumers as well as pharmacists should remember that these products are classified as nutritional supplements and have not been scrutinized regarding their safety and efficacy by the Food and Drug Administration.

The evidence to support efficacy of zinc products in the common cold is conflicting. Most of the studies of zinc therapy have methodological shortcomings. A fair amount of evidence exists to suggest that zinc does have a therapeutic effect if started very early in the course of a cold, ideally in the prodromal period. This is probably because most viral replication occurs before or within 24 hours of onset of cold symptoms. To obtain the maximum effectiveness of zinc, patients should suck the lozenges or lollipops every 2–3 hours while awake for the entire duration of the cold. They should not bite or chew these products, but should allow them to dissolve slowly. Patients should be discouraged from using zinc as cold treatment for conditions that might mimic cold symptoms, such as influenza, streptococcal pharyngitis (“strep throat”) and allergic rhinitis (e.g., hay fever).

The minimum effective dose of zinc has not been established, but studies indicate that approximately 13.3 mg of elemental zinc appears to be effective. The optimal zinc salt form and product formulation have not yet been determined. Since side effects of zinc products are mostly limited to the gastrointestinal tract, including nausea and bad taste, pharmacists should discourage their patients from consuming zinc on an empty stomach. Further investigations of zinc, utilizing improved study design, should assist in defining the role of zinc in the common cold. Pharmacists should await confirmatory studies before universally recommending zinc for the common cold.
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