Allergy Medications Are Nothing to Sneeze At

If you were a kid or a parent in the last 4 decades, you may remember the likes of Mr. Tickle, Mr. Greedy, or Little Miss Bossy. These stumpy characters, created by Roger Hargreaves, were intended to teach children lessons by acting according to their namesakes throughout various challenging situations.

So when Mr. Sneeze, with the help of Little Miss Sunshine, discovered that he had allergies, it appeared that educating children about hay fever was the primary goal of this 2003 children’s book. But it didn’t stop there. British pharmaceutical company GlaxoSmithKline, who commissioned the book, took it one step too far and slipped in a couple pages promoting their allergy medications, Piriton and Piriteze.

In the story told by GSK, Mr. Sneeze may be better known as Mr. Sneak.

 Although never available in stores, the book was sold at GSK roadshows and to Tesco (similar to Costco) Clubcard holders and was available through Allergy UK, a charity that collaborated on the book. How it was approved in the first place remains a mystery, as it violated a law prohibiting the direct advertising of any drug to children. Not surprisingly, GSK came under fire as the British government initiated an investigation and GSK eventually withdrew the book. The story made a splash, with many scientific journals and leading news sources, including Nature, the British Medical Journal, BBC news, and the Guardian covering it.

The BMJ article commented that adding to the controversy, the drugs GSK promoted were no longer the first choice of pediatric antihistamines. As if the real travesty was marketing an outdated product to unsuspecting children and their parents. Nevertheless, the comment highlights a key point:  allergy medications have improved drastically over the years, primarily increasing in safety, efficacy, and ease of use.

The active ingredient in GSK’s Piriton is chlorphenamine, a first generation antihistamine (also found in Advil Allergy and Congestion, for example). Another first-generation antihistamine is the ever-popular diphenhydramine, known by most as Benadryl. These antihistamines are inverse agonists, meaning they work by keeping the H₁ receptor in its inactivated form, precluding the binding of histamine. Although highly effective, first generation antihistamines are plagued with strong sedative effects. This happens because they cross the blood brain barrier (BBB), where they bind 50-90% of H₁ receptors in the central nervous system (CNS) and cause drowsiness. Diphenydramine is such a strong sedative that it is FDA-approved for over-the-counter treatment of insomnia.

Although the drowsiness side effect is undesirable and may impair daily performance, first generation antihistamines are still widely used today, popular because they are fast-acting and relatively safe if used properly. Or, perhaps some people would rather just sleep through allergy season.

The other drug advertised by Mr. Sneeze was Piriteze, which contains cetirizine, a less-drowsy second-generation antihistamine. Second-generation antihistamines, including cetirizine (Zyrtec), fexofenadine (Allegra), and loratidine (Claritin) penetrate the CNS poorly because they are pumped out by P glycoproteins, gatekeepers of the BBB. This greatly reduces the number of CNS H₁ receptors that are occupied, with fexofenadine and loratidine binding negligibly and cetirizine binding up to 30% of the receptors. So, cetirizine may still cause drowsiness at recommended doses, whereas fexofenadine and loratidine should not. Second-generation antihistamines are generally preferred over first-generation for their enhanced safety profile.

P-glycoprotein’s command only works on better-behaved second generation antihistamines; the gatekeeper blind to first-generation antihistamines, which pass through the blood brain barrier.

Antihistamines can also be administered intranasally (azelastine and olopatadine); these medications are as effective as or superior to the second-generation oral antihistamines. However, the most effective treatment for seasonal allergies is actually intranasal corticosteroids. Whereas antihistamines block the early phase allergic response, corticosteroids primarily act during the late phase. These work by inhibiting the recruitment of inflammatory cells, such as eosinophils and basophils, and blocking the secretion of pro-inflammatory mediators such as interleukins, causing a decrease in the levels of circulating leukotriene, histamine, and mast cells. The most potent and effective intranasal corticosteroids are mometasone furoate (Nasonex or Nasacort) and fluticasone propionate (Flonase). The furoate and propionate modifications on the drugs are thought to facilitate their absorption in the nasal mucosa and also reduce their systemic absorption, which means less chance of dangerous side effects.

Glucocorticoids are an anti-inflammatory subclass of corticosteroids that include the natural steroid cortisol. Cortisol, and its synthetic analogues, mometasone and fluticasone, work by activating the glucocorticoid receptor, which down-regulates the production of pro-inflammatory molecules. The furoate and propionate side chains are shown in red and blue, respectively.

Yet another treatment, allergen immunotherapy (allergy shots), may be appropriate for allergy patients who have detectable specific IgE antibodies to relevant trigger allergens. Specific immunotherapy (SIT) involves exposure to increasing doses of specific allergen(s). The dose-increase phase usually lasts 14-28 weeks during which desensitization occurs, meaning cells become less reactive or non-reactive to IgE-mediated immune responses. As discussed previously, Type I hypersensitivity reactions are mediated by T-helper 2 cells and allergy-prone infants have diminished T-helper 1 reactions. Perhaps not surprisingly, successful immunotherapy is associated with a shift towards a Th1-type reaction.

So, whereas antihistamines and glucocorticoids treat allergy symptoms, SIT can actually modify the disease and provide lasting protection against allergies. Furthermore, it has been shown to prevent subsequent sensitization to new allergens. In one study, 3 years of immunotherapy provided protection in some patients for up to 12 years and reduced the occurrence of additional allergies in almost half the patients.

Traditionally, SIT is administered subcutaneously (under the skin) by injection. However, last year three sublingual (under the tongue) allergen immunotherapy drugs were approved by the FDA in rapid succession. Oralair, which contains 5 grass pollen extracts (timothy, Kentucky blue, perennial rye, orchard and sweet vernal), became the first FDA-approved sublingual allergen extract. Eight days later, the FDA announced approval of Grastek, which contains only timothy grass extracts. Another 6 days later, Ragwitek was approved for the treatment of short ragweed pollen allergies. Whereas Oralair and Grastek are approved for pediatric use (10+ and 5+ years, respectively), Ragwitek is for adults (18+) only. All drugs showed moderate efficacy in clinical trials, with approximately 20-25% reduction in symptoms and need for symptom-management medication during one allergy season, compared to patients in the placebo group.

If needles aren’t your cup of tea, sublingual immunotherapy may provide a more palatable option.

Interestingly, the allergen extracts given by injection are not tested in clinical trials, but are FDA-approved based on purity, safety, and potency. Nonetheless, subcutaneous immunotherapy (SCIT) has been used safely and successfully worldwide for decades. And although it is new in the US, sublingual immunotherapy (SLIT) has been used successfully in Europe for years. From a cost perspective, immunotherapies compare favorably to pharmacotherapies (drugs like antihistamines and glucocorticoids).

Some people want a spoonful of sugar to help the medicine go down…or perhaps a spoonful of honey in place of medication entirely. Anecdotal evidence suggests that eating local, unfiltered raw honey can have similar effects to SIT by desensitizing the immune system. The idea is logical:  bees incorporate pollen into honey; therefore, eating local, unprocessed honey will expose you to the pollen prevalent in your area. Only a few studies have addressed the efficacy of honey for allergy treatments; one lasted only 10 days (no reduction in allergies observed) or used birch pollen-spiked honey for 5 months (effective at reducing allergies). Unfortunately, neither of these studies properly evaluated honey as an allergy treatment. The first had the right idea, but desensitization requires months (not days) to be effective, and while the second study demonstrates the feasibility of the idea, artificially-spiked honey does not address the real question.

Despite the shortcomings of these studies, the reason honey will never be recommended for allergy treatment is also logical:  the types of pollen bees primarily use are from fragrant flowers, not the wind-carried pollen from grasses like timothy and ragweed or trees like birch, which are responsible for the majority of allergies. Furthermore, the dose of any allergenic pollen in honey is very low and not controlled, making it virtually impossible to achieve desensitization analogous to that observed with SIT.

Searching for an allergy cure in a “hunny” jar will only get you sticky…you’d be better off sticking your head in it to reduce your exposure to wind-carried pollen.

While honey may help clear the bitter aftertaste from intranasal or sublingual medications, it will do little to alleviate your allergies. Better to stick to the tried-and-true methods for real allergy relief - while we may not yet know how best to prevent allergies, certainly many effective options exist to treat them.

Contributed by: Julia van Rensburg, PhD

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