"An additional reported adverse effect may be of more concern. Several case reports of anosmia, or a loss of sense of smell, believed to be due to zinc product administration have been published. A case series of 17 adult patients with anosmia or hyposomia from zinc product use was recently published (Alexander, 2006). These patients had all used zinc nasal sprays, by sniffing deeply with product administration. This use differs from some product instructions, as deep sniffing is discouraged. Some patients in this case series continued to have olfactory deficiency for several months after product use. As zinc toxicity to the olfactory system has been documented in animal studies, a mechanistic framework for this adverse effect is plausible. A recent Consumer Reports edition briefly commented on this concern. "
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Jury still out on zinc for the common cold
The potential for anosmia deserves some consideration.
by Edward A. Bell, PharmD, BCPS
Special to Infectious Diseases in Children
January 2008
Edward A. Bell
Numerous drug products are available over-the-counter and by prescription to treat symptoms of the common cold.
Recommendations from the FDA on the use of pediatric OTC cough/cold products are pending after an FDA advisory panel agreed these products should not be used in children younger than age 6. Thus, the popular use of these products in infants and young children may change.
As viral upper respiratory tract infections become more common at this time of year, it is understandable that caregivers and parents seek relief for their children from OTC products. A chemical agent not specified in the recent FDA advisory panel review of pediatric OTC drug products, but commonly advertised for the common cold, is zinc (eg, Zicam, Nasal-Ease).
Zinc has been evaluated in numerous studies for its potential antiviral and anti-inflammatory effects. Most of these studies have evaluated adults, although one well-done, controlled pediatric trial has been published. The exact mechanism of action of zinc has not been fully elucidated, although it has been proposed that zinc inhibits the binding of rhinovirus to intercellular adhesion molecule-1, found in nasal mucosa. Zinc may also inhibit viral replication and may have immunomodulatory effects.
Conflicting clinical trials
Many clinical trials evaluating zinc in the treatment of the common cold, mostly enrolling adult patients, have been published. Many of these trials have been criticized for methodological discrepancies, including the potential for un-blinding, as oral zinc commonly leaves a bad, metallic taste.
Various zinc products have been used, including oral lozenges and nasal sprays or gels. Dosage form development can be problematic, as zinc ions are believed to be the most effective chemical form, and yet zinc ions are unpalatable. Additionally, zinc may be most effective when delivered to the nasal mucosa, where virus particles are likely to initiate infection and symptom development. Pharmaceutical dosage forms to mask bad taste may reduce ion availability and potential efficacy.
Results of these clinical trials have conflicted, with some trials reporting positive effects, while others have reported no beneficial effect. Researchers of two published meta-analyses have concluded that combined data from clinical trials do not support a role for zinc in the treatment of the common cold. Most recently, Caruso and colleagues reviewed randomized, placebo-controlled trials of zinc in oral lozenge, nasal gel or spray forms, in the treatment of the common cold. Fourteen trials were evaluated according to 11 criteria assessing experimental design. Of these 14 trials, seven trials found a benefit to zinc and seven trials reported no beneficial effect. Of the positive trials, two trials used nasal gel products and five trials employed oral lozenge products. Of the four trials that met all 11 methodological criteria, three trials reported no beneficial effect, and one trial found a benefit from the use of zinc. Caruso and colleagues concluded that a benefit for the use of zinc in the treatment of the common cold has not yet been established.
Two trials included in Caruso’s analysis deserve review, both of which met all 11 of the stated experimental design criteria.
Mossad evaluated zinc nasal gel spray (zinc gluconium four times daily) in 78 adult patients with the common cold in Los Angeles. Twenty-seven patients had rhinovirus. Symptoms were reduced by two to three days in treatment patients compared with patients receiving placebo (P<.05). Adverse events, most commonly nasal stinging, were similar among the treatment and placebo groups.
Macknin and colleagues evaluated zinc oral lozenges and placebo (10 mg five to six times daily) in 249 school children in Cleveland, Ohio. In this study, there was no difference in the time to resolution of symptoms among the treatment and placebo groups. Adverse events such as bad taste or nausea were significantly more common among children receiving zinc lozenges.
As the above review of clinical trials indicates, discrepancies exist in the results and conclusions of published trials. Some researchers have interpreted these results in a positive light, concluding that enough data exist to support the use of zinc, while others have concluded that there is insufficient evidence to recommend zinc for common cold treatment.
Several factors may have contributed to the discrepancy in the results of these trials. It is believed that zinc ions are most likely to be the chemical state responsible for zinc’s potential effectiveness. Ionized zinc is unpalatable, with a metallic taste, and pharmaceutical efforts to disguise this offensive taste may reduce zinc ion availability, and thus potential efficacy. Some have criticized negative trials because of this. Effective doses and local concentrations are not known, and it has been suggested that negative trials may result from the use of subtherapeutic dosing. Dosage form may also be important, as nasal sprays may be more likely to achieve effective zinc ion concentrations, compared with oral products. Zinc’s potency toward specific viruses may differ. It is also possible that zinc may be most effective when used early in the onset of symptoms, when viral replication is likely to be more active. Thus, the timing of zinc administration may be an additional study characteristic potentially affecting study results.
Adverse effects
The most commonly reported adverse effects in published trials relate to the metallic unpleasant taste of zinc, which may be of significant practical importance, especially in children.
An additional reported adverse effect may be of more concern. Several case reports of anosmia, or a loss of sense of smell, believed to be due to zinc product administration have been published. A case series of 17 adult patients with anosmia or hyposomia from zinc product use was recently published (Alexander, 2006). These patients had all used zinc nasal sprays, by sniffing deeply with product administration. This use differs from some product instructions, as deep sniffing is discouraged. Some patients in this case series continued to have olfactory deficiency for several months after product use. As zinc toxicity to the olfactory system has been documented in animal studies, a mechanistic framework for this adverse effect is plausible. A recent Consumer Reports edition briefly commented on this concern.
Conclusions
Although zinc has been evaluated in many clinical trials, the inconsistency of the study results lends hesitancy to a recommendation for the use of commercially-available zinc products. This hesitancy does not imply that zinc may not be an effective symptomatic treatment for the common cold. More data are necessary, with attention given to dosage form, dose, acceptable palatability, and virus type.
From a practical consideration, products are dosed frequently, which may cause adherence to be difficult. When considering a benefit to risk ratio, evidence to date is concerning. The potential for anosmia deserves consideration, although this adverse effect has been reported primarily in adults, and may be most likely to occur with use outside of product instructions.
Perhaps clinicians and parents should re-consider Grandma’s old recommendations for a cold – lots of rest, humidified air, and chicken soup.
For more information:
Caruso TJ, et al. Treatment of naturally acquired common colds with zinc: a structured review. CID. 2007;45:569-74
Jackson JL, et al. Zinc and the common cold: a meta-analysis revisited. J Nutritr. 2000;130:1512S-1515S
Mossad SB. Effect of zincum gluconicum nasal gel on the duration and symptom severity of the common cold in otherwise healthy adults. QJ Med. 2003;96:35-43
Macknin ML, et al. Zinc gluconate lozenges for treating the common cold in children. JAMA. 1998;279:1962-7
Hulisz D. Efficacy of zinc against common cold viruses: an overview. J Amer Pharm Assoc. 2004;44:594-603
Alexander TH, Davidson TM. Intranasal zinc and anosmia: the zinc-induced anosmia syndrome. Laryngoscope. 2006;116:217-20
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