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Allergy Season and Restless Leg Syndrome

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By Henry Ehrlich
leg-pain-symptoms

We pay a good deal of attention to the intersection of allergies and sleep disturbance around here, and it has popped up again.

Years ago I co-wrote a book called Sleep to Save Your Life with sleep specialist Dr. Gerard T. Lombardo that had a chapter called “Restless Legs—Pain in Motion.” I had never heard of it till I worked with Dr. Lombardo, but I can’t forget it. The chapter began with an account of a patient who disobeyed the instructions to bring all his accustomed props to the sleep lab for an overnight study because he was embarrassed to bring a piece of wood the size of a baseball bat and use it to pound his legs while hooked up to electronic monitors under the gaze of a video camera. Restless leg patients frequently resort to inflicting pain on themselves to relieve the pain from within—described variously as aching, burning, cramping, and “creepy crawly” sensations as from bugs or worms. Clearly, this is not Steve Martin’s “happy feet.”

By coincidence, just about the same time we worked on the book, commercials started popping up on TV for a drug to treat it. Since most of my friends had never heard of the ailment restless leg syndrome, or RLS, they tended to dismiss it as one more contrivance by the pharmaceutical industry to monetize an annoying but not serious problem. That drug no longer seems to pop up on TV.

However, RLS has not gone away. The American Sleep Association estimates that it afflicts 12 million Americans. An article that popped up in my news feed the other day mentioned that William Ondo, M.D., a Houston Methodist neurologist, thinks it’s a bigger problem for those with seasonal allergies. Double jeopardy may be impermissible as a matter of law, but for those with RLS, symptoms get worse during allergy symptoms if patients take diphenhydramine—Benadryl–and other first-generation antihistamines at night, drugs that are normally sedating (do not drive or operate heavy machinery).

The reason that Benadryl is sedating for most of us is precisely because it passes the brain-blood barrier where it suppresses brain histamine, a neurotransmitter that is at high levels during the day and crucial for keeping us alert. It down regulates at night, allowing us to sleep. But with RLS it seems to have a paradoxical effect.

Apparently RLS is fairly common among kids with atopic dermatitis: “Awakenings as a result of scratching can be brief or long, and many children with AD have a comorbid diagnosis of restless leg syndrome apparently secondary to itch-induced movements. Restless leg syndrome is diagnosed clinically as an unrelenting urge at night and before sleep onset to move the legs. Children with AD are also often given a diagnosis of periodic leg movement disorder, which is defined by the presence of repetitive limb movements that, in contrast to restless leg syndrome, only occur during sleep and not before sleep onset.”

What a drag. Parents resort to Benadryl to relieve their children’s maddening itching at night when cortisol levels are low, and get blindsided by RLS.

For these children, newer, non-sedating antihistamines such as loratadine [Claritin] and cetirizine [Zyrtec] are preferable to Benadryl. According Ondo, “We don’t yet understand why sedating antihistamines worsen restless legs syndrome, but we do know that non-sedating antihistamines do not affect the symptoms as much because they do not enter the brain as easily.”

I posed this problem to our contributor, Jessica Dabler Martin, PhD neuroscientist who found a 2009 article that elucidates some of the research on histamine and RLS, which is inconclusive on the specific pathways involved. She observes, “I’m just amazed at how little this has been looked at even though the association has been there for some time! The study referenced from Hopkins was a poster abstract at a neuroscience meeting from 2008, but it appears they never went on to fully publish the results.

“Once again, all of this shows that the same molecule – histamine in this case – can have many different functions throughout the body. The nervous and immune systems overlap yet again.”

Thanks, Jessica.

So, once again sleep disturbance and allergies collide. Poor sleep takes the fun out of waking life, not to mention overall good health. There’s a good reason that sleep deprivation is a form of torture.

Photograph: sandhillneurologists.com

Things That Go Itch in the Night

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By Dr. Paul Ehrlich

Why do allergies light up when sun goes down?
Why do allergies light up when sun goes down?

On a recent Doctor Radio program, a caller asked why her child’s eczema seemed so much worse at night than when she woke up in the morning.  I told this mother that the secretion of cortisol, the precursor of cortisone, our own natural anti-inflammatory hormone, is at its highest point in the morning and lowest at night.  Parents tell me that they go to wake up their children in the morning and find them lying asleep still scratching, before their adrenal cortex starts to kick into gear.  The perennial recommendations that children be wrapped in wet pajamas, rubbed with topical steroids and have their nails trimmed can help compensate for the down cycle.  Parents also tell me that their kids’ itching improves dramatically when they are distracted from their health issues by active play, but since playtime is associated with daytime, there may be more to it than just taking their minds off the eczema.

Hormones play a role not only in suppressing atopic dermatitis but also in the very fact of being awake and active.  For example, adrenalin, which is the body’s own epinephrine, follows the same circadian rhythm.  This may account for the reports I hear about evening doses of food allergens for oral immunotherapy, an experimental therapy not approved for private practice, producing more severe responses than morning doses.  The body’s defenses are weaker at the later hours.

Another naturally occurring substance that operates according the clock is histamine, which is familiar to anyone who has ever sneezed during pollen season.  It is released by mast cells and basophils when they encounter an allergen.  But histamine has another function.  It is a neurotransmitter that plays a vital role in governing our cycles of sleeping and waking.  Like cortisone and adrenalin, brain histamine is lowest at night and highest in the morning.  As we explain in our book, the first-generation Benadryl can pass through the brain-blood barrier with ease, neutralizing not only the histamine released during an allergic reaction but the histamine that is keeping us awake as well, which is why we are warned not to drive or operate heavy machinery.  Newer antihistamines do this to a lesser extent, although some of us are still very sensitive.  (When Zyrtec—cetirizine–was brand new and available by prescription only, a rep from the company that made it gave me one in the morning to show how non-sedating it was, and my staff had to cancel all my patients for the day.)

Even for non-allergic people, managing the cycles of these substances is an important part of health.  Our circadian rhythms are attuned to the days when there were no electric lights, TVs, iPads, and other things that occupy many of us long into the night.  As far as your adrenal cortex is concerned, we’re still living in caves, dozing as the fire dwindles, and hoping that its fading light will keep saber-tooth tigers away.  But if either a tiger or an allergen does attack, we will be jolted by the release of adrenalin and possibly other chemicals that will make it hard to go back to sleep, which will, in turn, make us sleepy the next day.  The combination of airway allergies and overweight can make matters worse, as Larry has written, because the body’s defense against breathing stoppages during sleep—aka sleep apnea—is a spontaneous jolt of adrenalin.

We should all be managing our days and nights with respect to that inner cave man, not just allergy sufferers, but those with allergies have to show these powerful chemicals an extra measure of respect.  Control inflammation, avoid your triggers, use dust-mite resistant bedding, control weight, keep skin hydrated.  AND turn off the TV and computer an hour before bedtime.

Photo by NewYorkBestDeals.com

Why Use an Environmental Exposure Unit to Study Allergic Rhinitis?

By

Anne K. Ellis, MD MSc FRCPC FAAAAI

Kingston General Hospital

Testing a new treatment for allergic rhinitis can be an “iffy” process. The “Gold Standard” by which the US Food and Drug Administration (FDA) and other regulators look to determine proof of efficacy has traditionally been the in-season, outpatient clinical trial. These typically multi-center studies aim to capture the usual conditions under which the treatment is given. Allergic participants are exposed to sensitizing allergen(s) in their natural environment as part of their normal daily routine—pollens and so on—that are already giving them symptoms. As with any study or treatment, for that matter, studying people at home and work usually has its limitations. That is, people don’t take their medication as promised, weather is variable and affects things like pollen counts (even in peak pollen season!), and participants don’t do their “homework”, dutifully recording symptoms on schedule. [1]. Then there’s geography. Pollen levels can often be highly variable between sites and/or over the course of consecutive seasons, presenting logistical problems, and can significantly impact the evaluation of treatment[2]. Furthermore, each participant’s exposure level is not only influenced by local variables such as weather patterns, but also by lifestyle, including time spent out doors[3]. It’s no use testing for outdoor allergens when someone spends all his or her time indoors. What we really need is a way of controlling these environmental exposures.

Big-Name Antihistamines Stop Here On Way to Pharmacy
That’s where the Environmental Exposure Unit can help. Cetirizine (Zyrtec), loratadine (Claritin), fexofenadine (Allegra), budesonide (RhinocortAqua), mometasone (Nasonex)—these are just a few of the household names that have been tested in the EEU. Of course, there are many that have never become well known because they failed to show efficacy—not so long ago an oral-encapsulated immunotherapy compound bit the research dust. In the long run, I’m happy to say, EEU results are borne out by what I eventually see in clinical practice.

The EEU was developed to address the variables inherent in traditional studies, while still reproducing many of the conditions present outdoors[1;4;5]. The concept of the EEU is, in effect, ‘to bring the outdoors indoors’, under strictly controlled conditions to ensure equal allergen delivery to all participants. The EEU also provides 100 percent compliance with study medication and symptom-diary-card completion. Moreover, since all participants perform the same level of activity we don’t have to correct between those who spend their springtime on the softball field or gardening or those who lie on the couch reading or watching TV [4].

Drs. James Day and Reginald Clark (Departments of Medicine and Chemical Engineering, respectively, Queen’s University) developed the EEU (the first of this kind of facility in North America) in Kingston, Ontario, Canada. Initially, the facility was designed to investigate the respiratory effects of particulates and off-gasses from urea formaldehyde foam insulation (UFFI)[6;7]. These are considered to be culprits for that nasty modern problem multi-chemical sensitivity. In 1987, utilizing particulate technology that has been significantly refined over the ensuing years, the EEU was modified to focus on allergy research.

Fine-Tuning the Climate
The EEU is a unique, internationally recognized research facility that allows for as few as 5 to as many as 150 volunteers to be simultaneously exposed to ambient levels of airborne allergens such as ragweed pollen. Located within Kingston General Hospital, the EEU allows for the tight regulation of environmental variables such as air quality, temperature, humidity, CO and CO2 levels as well as the precise maintenance of allergen concentration[4]. The EEU uses 100-percent fresh air that passes through high efficiency filters, enters the EEU, and is then exhausted outdoors at a ventilation rate of 2500 cfm. Therefore, essentially, the volume of the room is replaced every 12 min. The temperature and humidity are maintained at 23°C ± 1°C and 40% relative humidity, respectively. Room conditions can be reproduced on different days and at any time of the year, something that cannot be achieved when you have to wait for spring, or any other season.

Air samplers signal for release of additional allergens

The pollen level within the EEU is highly regulated. Every 30 minutes seven Rotorod® samplers within the participant seating area are activated to ultimately provide information to the pollen dispersal equipment and ensure equal pollen distribution throughout the room. EEU allergen concentrations of 3500 +/- 500 grains/m3 have historically proven to produce allergic symptoms in the confines of the clinical trial timeframe; however, any target pollen concentration can be achieved.

Additional air samples are taken during each study to ensure that potential fungi or bacteria from the outdoors are not present and the HVAC filtration system is properly sealed. Each pollen batch is independently lab tested for fungi and bacterial contamination prior to dispersal within the EEU. To add to the stringent air quality standards in the EEU, even the cleaning products are specifically selected for low VOC release. The CO2 target is <850 ppm with ventilation rates that exceed the ASHRAE (American Society of Heating, Refrigerating and Air conditioning Engineers) standard for hospital treatment rooms.  Any other particles in the room air are monitored using sticky surface sampling, and an accredited 3rd party laboratory conducts all outside testing.

The Participant Experience
The length of time people spend in the EEU depends on the study. Almost all studies begin with a “priming phase” where participants attend a minimum of 1 to 4 three-hour pollen exposure sessions to “re-awaken” their allergic reactivity. Once they reach the pre-determined qualifying symptom score (protocol dependent) they are sent home, then return on the study day. Depending on what we are testing, the study day can be anywhere from five hours to 14 hours long. For a typical antihistamine evaluation, they would return in the morning for two hours of pollen exposure. Those meeting the qualifying symptom score by 90 minutes are randomized and dosed at the two-hour mark, and then they record their symptoms every 20 to 30 min (protocol dependent) for the ensuing four hours of their visit. Often people return the next day to evaluate the duration of effect of the medication as well, and then a second dose is given. Evaluation of a nasal corticosteroid requires a longer exposure.

Fans mounted in room keep air and pollen circulating for as many as 150 allergic people

But enough about the science – what is it actually like for the participants in these types of studies? We try to make the experience of being in a room full of pollen as pleasant as it can be while still ensuring participants maintain their focus on why they are there – to carefully evaluate the anti-allergic medicine under investigation. Meanwhile, there’s food, wireless internet access, and participants often enjoy their usual seated activities such as reading, TV and knitting, and one fellow whose hobby is carving wax made us candles.

Safety is a high priority. Physicians stay in the room with participants and monitor them carefully. As we are located within the hospital itself, emergency care is literally steps away, if needed, but the EEU is fully stocked with all medications and equipment necessary to treat any unexpectedly severe allergic reactions.

In the FDA’s “Draft Guidance for Industry: Allergic Rhinitis: Clinical Development Programs for Drug Products” environmental exposure unit studies have been acknowledged as systems for evaluation of onset of action of anti-allergic medications for seasonal allergic rhinitis (SAR) as well as for the prophylactic treatment of SAR [9]. Both industry and regulatory agencies alike have expressed a desire to consider the EEU model as proof of clinical efficacy for IND submissions. To ensure this outcome is achieved, the author remains in discussions with the National Institute of Health, the FDA, and the Investigators from other EEU-similar facilities. For more information on the Environmental Exposure Unit, visit www.eeu.on.ca

References

1. Day JH, Ellis AK, Rafeiro E, Ratz JD, Briscoe MP. Experimental models for the evaluation of treatment of allergic rhinitis. Ann Allergy Asthma Immunol 2006; 96: 263-77.
2. Chervinsky P, Philip G, Malice MP et al. Montelukast for treating fall allergic rhinitis: effect of pollen exposure in 3 studies. Ann Allergy Asthma Immunol 2004; 92: 367-73.
3. Akerlund A, Andersson M, Leflein J, Lildholdt T, Mygind N. Clinical trial design, nasal allergen challenge models, and considerations of relevance to pediatrics, nasal polyposis, and different classes of medication. J Allergy Clin Immunol 2005; 115: S460-S482.
4. Day JH, Briscoe MP. Environmental Exposure Unit: A system to test anti-allergic treatment. Ann Allergy Asthma Immunol 1999; 83: 83-9.
5. Day JH, Horak F, Briscoe MP et al. The role of allergen challenge chambers in the evaluation of anti-allergic medication: an international consensus paper. Clin Exp Allergy 2006; 6: 31-59.
6. Pross HF, Day JH, Clark RH, Lees RE. Immunologic studies of subjects with asthma exposed to formaldehyde and urea-formaldehyde foam insulation (UFFI) off products. J Allergy Clin Immunol 1987; 79: 797-810.
7. Day JH, Lees RE, Clark RH, Pattee PL. Respiratory response to formaldehyde and off-gas of urea formaldehyde foam insulation. Can.Med.Assoc.J 1984; 131: 1061-5.
8. Heffer MJ, Ratz JD, Miller JD, Day JH. Comparison of the Rotorod to other air samplers for the determination of Ambrosia artemisiifolia pollen concentrations conducted in the Environmental Exposure Unit. Aerobiologia 2005; 21: 233-9.
9. Guidance for Industry (Draft) – Allergic Rhinitis: Clinical Development Programs for Drug Products. April 2000. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER).
Ref Type: Generic

Anne K. Ellis, MD MSc FRCPC FAAAAI. Assistant Professor and Chair, Division of Allergy & Immunology, Department of Medicine, Queen’s University. Email: ellisa@kgh.kari.net. Twitter: @DrAnneEllis 

The War on (Allergy) Drugs

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By Dr. Paul Ehrlich
I recently realized that I had reached a milestone in my 30 years plus of practice. I went more than a month without prescribing an oral antihistamine. This has implications for the way health care is bought and paid for in the United States.

Let’s review for a moment the old way of doing things. The first antihistamines, including diphenhydramine (Benadryl) and chlorpheniramine (Chlor-Trimeton) started out as prescription drugs. They had a side effect: they made you sleepy, so you couldn’t drive or operate heavy machinery after using them, as the labels still warn.

Drug companies had a medical incentive as well as a financial one to develop the next generation of antihistamines, which didn’t knock you out. And so we got the wave of drugs that included loratadine (Claritin) and cetirizine (Zyrtec), which stopped the sneezing and itching without making you long for the couch. As they approached the end of their patent protection, the drug companies that made them started to add a few bells and whistles at the molecular level so they could get premium prices again.

But things have changed. Insurance companies don’t want to pay for new drugs that don’t make a big difference from the old ones and have stopped paying for them. The OTC drugs cost about the same at retail as a standard co-payment. In the meantime, members’ health dollars go for urgent things, including asthma treatment, or cost-efficient measures like immunotherapy and asthma control medications, or so we hope. Regardless, those with chronic allergies should use the OTC drugs as part of a medication strategy, not as a substitute for monitoring and treatment. It’s not that I won’t prescribe the newer medications at all, but I will do so when indicated.

I must also point out that the OTC, self-medicating approach doesn’t work for every allergy or allergy-related condition. For example, as Dr. Chiaramonte describes so movingly in his postscript to our book, many inner-city kids rely dangerously on Primatene, the OTC inhaler, to keep their asthma in check. It gives them a dangerous jolt that’s even worse than the one they would get from prescription albuterol. Both are worse for them in the long run than inhaled therapies like Advair, which with regular conscientious use keeps them from having attacks, arrests inflammation, and halts the dangerous process of airway remodeling.

Those who rely on OTC Neo-Synephrine to keep their sinuses clear would be better off with the prescription drugs like Nasonex or Omnaris (both of which I prescribe regularly) if they have allergic rhinitis. Regular use of Neo-Synephrine can make the sinuses look like hamburger. But they would also be better off with a high-concentration 2-3% saline solution sinus rinse, such as those marketed as SaltAire and Ocean, which come in convenient plastic squeeze bottles. The bargain-minded parent can make this at home: 2 or 3 heaping teaspoons of Kosher or sea salt (no additives) and one level tablespoon of baking soda, mixed in a quart of tap water. You can buy a plastic squeeze bottle or a 30-cc bulb syringe for easy administration.

In the end, the answer to your allergic symptoms will probably lie in a combination of judicious use of drugs, both high-tech and low-tech, changing your behavior, keeping an eye on the weather, perhaps watching what you eat, and generally living right. The most important body part an allergist treats is the brain.

(To read about The Hows and Whys of Allergy Medication, turn to chapter 8, Asthma Allergies Children: a parent’s guide.)

(Note: Dr. Ehrlich has worked for the Claritin Council, sponsored by Claritin. His participation is for information purposes only and he does not, nor does this website, endorse one OTC drug over another. All have characteristics that make them more or less useful than others for certain individuals at different times.)

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