Download Inhaler Sequence

Sequencing of Short-acting Versus Long-acting Inhaled
Bronchodilator Medications: An Explanation
Mark W. Mangus, Sr., BSRC, RRT, RPFT, FAARC
When long-acting versions of beta agonist and anticholinergic medications were
introduced, they were touted by the manufacturers as intended "replacements" for their
earlier short-acting counterparts. FDA efficacy, safety and dosage studies are the basis
upon which usage recommendations were established. Those medications were tested
as "stand-alone" drugs for FDA approval purposes. Note that the first of the long-acting
beta-agonist medications was Salmeterol with Formoterol and others coming to market
later on the time-line.
Once the long-acting medications were introduced on the market, physicians were
initially skeptical of the potential for the long-acting medications to actually perform as
their efficacy data established, at least not for the broader population. That skepticism
was in part due to FDA-required cautions about the slower onset of action of the longacting medications that were initially introduced and the additional caution that they
shouldn't be used as "rescue" or quick-acting medications when such medications were
needed for emergent onset of breathing difficulties.
Without giving the medications significant trial as stand-alone treatment, as they were
intended to be, physicians began prescribing short-acting versions of those medications
as a "preparation" to subsequent administration of the long-acting versions. The fear
was that if the long-acting medications were taken first AND the patient was in distress,
that additional dosing with short-acting medications in a rescue mode would be
ineffective or insufficient to get the patient out of trouble or could also represent
potential "over-dose" of those medications. Hence the short-acting dosing practice
became established as the "standard" practice. No studies have been done to support
or refute that standard practice. It has been strictly a 'physician-generated' and
perpetuated practice without empiric evidence to support it.
After a period of time - perhaps a year or two - I noticed through communications with
patients on EFFORTS, your USA-counterpart to COPD-Canada, in a manner of
speaking, AND from the patients I was seeing in my pulmonary rehabilitation practice
that what seemed the vast majority - all following the short-acting dosing as a
preparatory to subsequent dosing with long-acting versions - complained that they felt
they didn't get significant effect/receive significant or meaningful benefit from use of the
long-acting medications as evidenced by their need to use just as much short-acting
medications as before they started using the long-acting medications. Indeed, much
angst was expressed regarding the high cost of the long-acting medications and the fact
that, in the USA, insurance companies don't cover the cost of inhalers, like they do for
liquid versions taken by aerosol devices (a.k.a. - nebulized). Many complained to their
physicians who over time came to opine that long-acting medications, while a nice idea,
simply didn't live up to the evidence upon which they were based, or the effectiveness
they claimed. So, the practice of using short-acting medications as a "preparation" to
THEN using the long-acting medications gained stronger support and prevalence.
Theories emerged that the short-acting medications "opened up the airways for deeper
and better penetration, deposition and distribution of the long-acting medications", this
theory based upon the notion that the likely reason the long-acting medications failed to
be effective for so many was because the patients weren't "getting them down deep
enough to reach the sites of action."
When Spiriva (Tiotropium Bromide) was brought to market, it came with cautions that
Atrovent (Ipratropium Bromide) should NOT be taken with Spiriva, as it would interfere
with the uptake and action of Spiriva, reducing effectiveness and benefit. The official
position of Boehringer Ingelheim was that taking Ipratropium Bromide and Tiotropium
Bromide together/at the same time/proximate to each other "had not been studied". So
the company could not surmise safety and efficacy of the two taken in tandem, in any
way. With anticholinergics, two points make the recommendation salient. First, there are
far fewer muscarinic receptors in the airways than there are beta receptors. So, taking
Atrovent too soon before taking Spiriva could conceivably tie up most of the muscarinic
receptors, leaving too few or none to which the Spiriva could bind. As well, muscarinic
receptors are located primarily in the large airways, so any notion that deeper
penetration would be advantageous to better deposition or effectiveness would be
misplaced and incorrect. Still, many physicians continued to prescribe Combivent
(Albuterol and Ipratropium Bromide in combination) as the preparatory inhalation to
open up the airways for long-acting beta-agonists. The thinking was, at least in part, that
a little bit of short-acting anticholinergic wouldn't hurt.
As time passed and the complaints about wasted money and ineffectiveness of longacting beta-agonists and anticholinergics continued to mount, I had an epiphany to the
effect that perhaps what was causing the lack of effectiveness and benefit from the
long-acting beta-agonists was that the preparatory inhalations of short-acting betaagonist was tying up too many beta receptors such that there were too few to which the
long-acting beta-agonist could subsequently bind, and therefore, by design it
represented an ineffective dosing pattern.
I did a literature search looking for studies comparing the combination usage of betaagonists in the manner that had become "the standard" and found absolutely no studies
had been done. I then contacted the manufacturers of Salmeterol and Formoterol and
was routed to their research pharmacologists to whom I asked several questions
regarding the pattern that was in use and widely practiced. I asked if the companies
recommended the use of short-acting before/as preparation for ling-acting beta-agonists
and was told that they "do not" make such recommendations. I asked if they
recommended "against" such a usage pattern. They responded that they had no 'official'
recommendation for or against such a usage pattern. I then asked "again" if they had
any 'official policy' recommending the usage pattern commonly advocated, to which
they responded that they could make no such recommendation. I asked why they held
the stance that they could not 'recommend' the use of a short-acting beta-agonist,
followed almost immediately by a long-acting beta-agonist, yet they would not
recommend against such a usage pattern and was given the following reasons: (1) the
use of short-acting, followed by long-acting beta agonists had not been studied.
Therefore, (2) they could not recommend following such a pattern of use. I asked why
they acknowledged that the "standard" had become to use a short-acting beta-agonist
as a preparatory to use of a long-acting beta-agonist, but they had not intervened to
correct this practice? Their response was simply that while they study the medications
they manufacture to satisfy their safety and efficacy questions/issues and to present
that data to the FDA as required for the drug's approval for marketing, physicians have
the inherent right by nature and their license to use the drug in any way they see fit and
can justify using any medications as long as they can reasonably satisfy safety
requirements germane to their practice of medicine (a fancy way of saying "off-label"
usage and/or application).
Next, I asked if they were aware of the now "standard" pattern in use across the US and
elsewhere in the world. They acknowledged that they were well aware of it. I asked if
they thought that - as I suspected - use of a short-acting beta-agonist (like usage of a
short-acting anticholinergic) immediately before using a long-acting beta-agonist could
result in reduced and/or insufficient efficacy of the long-acting beta agonist. Unofficially,
they acknowledged that the possibility, even likelihood existed, but they could not
"officially" take that position "because the comparison studies have not been done”.
So, I asked why such studies have not been done. They responded that no interest had
been shown in doing such studies. They further responded that no requests for such
studies had been forthcoming. And they concluded with the response that no
investigational groups outside their company had undertaken such studies. I asked if
they would be inclined to do such studies in view of the questionable practice as I was
observing/opining it to be. They responded that they had no incentive to undertake such
studies and likely wouldn't be required to do such studies as the practice did not result
in observable injury or danger to patients to that point. Therefore, since studies involve
significant costs and they weren't expecting any directive from the FDA to do such
studies, they would not be inclined to spend the resources to do them. An implied
conclusion can be drawn that since the pattern is to use two medications where only
one was the original intention, manufacturers now make increased returns/profits from
selling more product than they would if they were to study and report the negative
benefit of using both kinds of medications in the manner that they are commonly used.
So, the "lack of incentive" is easy to understand!
By this point, I had begun to recommend that my patients NOT use the short-acting
forms of their medications before, or as a preparatory to using their long-acting
medications. Instead, I asked them to hold off using any short-acting medications for at
least two hours, figuring that the "dissociation half-life" (how long it takes for 50 % of the
drug to 'detach' from the receptor site - not to be confused with length of efficacy) of the
short-acting drugs was likely past that time period, rendering at least half the remaining
receptor sites able to bind with more drug (of any form, short or long-acting). I also
asked EFFORTS members to try not using their short-acting medications too soon
before using their long-acting medications.
Slowly, but surely, the results started coming in from those who tried my
recommendations. As well, I was seeing my own results in my patient population. As
time went by and word got out, I received additional feedback from physician practices
who switched their patients’ usage pattern to long-acting dosage first and short-acting
reserved for rescue, as needed. With few exceptions, nearly all of those who tried my
recommended pattern found the following to be true: (1) Their long-acting medications
became far more effective than they had been when taking the short-acting forms first.
(2) Patients who had felt no increased or different effect from the use of long-acting
forms of the medication began experiencing significant benefit. (3) All patients reduced
their need for short-acting beta agonists, some ceasing to use them altogether. (4) One
pulmonary medicine practice wrote to me telling me of their experience splitting 100
patients into two groups. All patients had been managed using short-acting betaagonists in preparation to subsequent dosing with long-acting beta-agonists. Group one
used only long-acting medications for maintenance dosing and held their short-acting
medications to "prn" (as needed, only) usage. Group two acted as a control. All patients
kept track of their usage pattern for both short-and long-acting beta-agonists. Group one
reported significantly reduced need for short-acting beta-agonists, some ceasing to
require their usage, altogether. Group two reported no change from pre-observation
usage of each form of medication. Group two was then changed to use of long-acting
beta agonists alone, reserving use of short-acting beta-agonists to prn only usage. They
subsequently reported the same results as did group one. They (the physicians of that
ractice) expressed their astonishment at the change and lauded my recommendations.
They did not study their patients in a 'formal' enough manner to report their findings in
the form of a paper. But, they were convinced that my theory was correct, as evidenced
by their anecdotal observations.
The requests for more information and repeated inquiries about "order of medications"
from members of EFFORTS became so frequent, that Frank Barrett offered to help me
develop the chart to which you refer. We completed it and posted it to the EFFORTS
site as you now see it.
Sometime after its posting to the website, I was contacted by a nationally prominent
pulmonary physician at one of our top-rated lung disease facilities, here in the USA. He
wrote of great concern about my chart and wanted to know how it came about. He was
concerned that it contradicted what is considered "standard of practice" and wanted to
see supporting evidence, literature/studies that give it credibility. I wrote the explanation
you now read (in spirit, if not in direct quote) to which he responded that, while my
theory and observations were intriguing, I was still going against the grain insofar as
standard of practice was concerned. And he expressed skepticism that significant
numbers of beta-receptors were indeed taken out of play for the long-acting beta
agonists, since there are so many beta receptors. I then asked him if he could produce
studies or literature or recommendations from the drug manufacturers to support what
he called the "standard of practice". I explained that I had done a literature search and
was able to find no such studies having been done. He ultimately responded that he
also could find no such studies or empiric evidence. He subsequently conceded that I
had a point to my argument and perhaps as much or more anecdotal evidence to
validate it as does the standard of practice. I asked him if his institution, with its vast
research facilities and resources could conduct a comparative study to gain empiric
insight into which practice is the better. He responded that regretfully, their resources
weren't so vast that such a study would hold significant enough priority as to merit use
of those resources. BUT, he also conceded that what I had arrived at was remarkable
and certainly plausible, given the observations of so many patients, to that point. He
also expressed one concern with which I had to agree. That is that patients who wake in
the morning and are having significant trouble breathing should be aware that they
might do better to take their short-acting beta-agonist to 'get over the hump' and then
take their long-acting beta-agonist after sufficient interval has passed. This is where the
“wait time” intervals before and after taking the different medications came into play.
I continued my effort to learn more about the discrepancies in common practice and in
seeking an answer to the speculation of the doctor from our top-rated lung disease
institute that there were far too many beta-receptors to be overwhelmingly occupied by
the short-acting beta-agonist dosing administered in preparation for the long-acting
form, by contacting colleagues who are expert in pharmacokinetics off bronchodilator
medications. I put my suspicions and theory and the doctor's contention that he felt that
there were plenty of beta receptors such that he didn’t feel that too many would be
occupied by short-acting beta-agonists such that their occupation would significantly
interfere with sufficient uptake of an effective dose of long-acting beta-agonist
medication if taken immediately following/ soon after use of a short-acting beta-agonist.
I asked for their expert opinions on his and my points and contentions. In each instance,
they agreed with me that the problem was that the short-acting beta-agonists were
indeed occupying the vast majority of the beta receptors leaving far too few for the longacting medications to bind with. Therefore sufficient benefit, let alone maximum benefit
could not be achieved. I went on to fill them in on my experience, observations and to
share with them the inhaler sequence chart I had devised with Frank Barrett. In each
case, they endorsed my conclusions and chart based upon their expert understanding
of pharmacokinetic theory and the evidence I shared with them of the 'then' several
years’ experience and many hundreds of patients by that time.
Today, the trend continues that patients who change their inhaler usage pattern to
comply with the recommendations of my sequence chart continue to achieve similar
results. They continue to consistently achieve more benefit from use of their long-acting
beta-agonist and anticholinergic medications while realizing reduced need for shortacting forms of these medications.
Reference Inhaler Sequence Chart: http://www.emphysema.net/inhaler_sequence.htm