Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00051
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Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: April 2007
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Bibliographic ID: UF00087345
Volume ID: VID00051
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Jay Becker, Pharm.D. Candidate

During the peak of cough and cold season
millions, of Americans find themselves searching
through the cold medicine section of the neighbor-
hood store in an attempt to relieve nasal stuffiness
and sinus pressure. Until recently, the choice in-
cluded with the ingredient pseudoephedrine found in
over 700 cough and cold remedies. Pseudoephedrine
(Sudafed), phenylpropanolamine, and
phenylephrine were three of the oral decongestants
deemed safe and effective by the US Food and Drug
Administration in 1976 for the relief of nasal conges-
tion caused by the common cold, allergic rhinitis,
and sinusitis.1 After a large, multi-centered trial in
2000 confirming the link between phenylpropanola-
mine use and hemorrhagic stroke in women, all phar-
maceutical manufacturers voluntarily removed it
from their products.2 The FDA estimates that phenyl-
propanolamine caused between 200 and 500 strokes
a year among 18 to 49 year-old users.2
More recently, after passing the USA Patriot
Act (HR 3889, Title VII) in September of 2006, all
stores are required to keep pseudoephedrine contain-
ing products behind the counter requiring purchasers
to show photo identification and sign a log book
prior to purchase. These changes are part of a na-
tion-wide effort to reduce home-based "meth labs"
that create methamphetamine, a highly addictive
street drug derived from pseudoephedrine. Fearing

customers would shy away from pharmacists to ask
for these products, Pfizer introduced a replacement
product containing 10 mg phenylephrine (Sudafed-
PE) that cannot be converted to methamphetamine
and has no restrictions. This conversion has left the
consumer with a package that looks indistinguishable
from the previous product, but with unproven effi-

Pharmacology and Pharmacokinetics
Phenylephrine is a potent vasoconstrictor that
stimulates a-receptors with minimal effect on 3-
receptors of the heart. It is chemically related to epi-
nephrine. Phenylephrine increases both systolic and
diastolic blood pressure in a dose-dependent manor,
but because it has little affinity for P-receptors, heart
rate and contractility are generally unaffected.3'4
However, reflex bradycardia is sometimes seen fol-
lowing the use of phenylephrine.6 Pseudoephedrine
is a stereoisomer of ephedrine and exerts its effects
both directly through a-receptor agonism and indi-
rectly via release of norepinephrine from storage
Sympathomimetics, such as pseudoephedrine
and phenylephrine, carry a risk of cardiovascular
side effects. However, nasal blood vessels are ap-
proximately 5 times more sensitive than the heart to




* l *




Volume 22, Issue 7 April 2007


circulating catecholamines.8 This explains why pseu-
doephedrine in OTC products in a low dose causes
effective nasal congestion relief with minimal car-
diac effects.
Despite the fact that both pseudoephedrine
and phenylephrine cause vasoconstriction of the na-
sal mucosa, little evidence substantiates the effective-
ness of oral phenylephrine in its 10 mg dosage form.
This difference in efficacy is most likely due to the
metabolism of each compound. Both phenylephrine
and pseudoephedrine are well absorbed in the gut.
Phenylephrine, however, undergoes extensive pre-
synaptic metabolism by monoamine oxidase in the
gut wall.9'10 As a result, less than 40% of
phenylephrine actually reaches systemic circulation.
Pseudoephedrine is resistant to the actions of mono-
amine oxidase resulting in over 90% of the drug re-
maining unchanged in the body. Pseudoephedrine
also lacks the hydroxyl group on the benzene ring
increasing its lipid solubility; thus, increasing CNS
stimulant effects. The tolerability of phenylephrine
as an oral nasal decongestant is likely to be due to its
poor access to the systemic circulation rather than to
its pharmacological profile.11

The efficacy of pseudoephedrine as a nasal
decongestant has been documented in several trials.
Pseudoephedrine reduces airway resistance in pa-
tients suffering from nasal congestion.12-15 Pseu-
doephedrine is also an effective treatment for nasal
congestion associated with the common cold when
administered in multiple doses over several days.12,16
Phenylephrine on the other hand, has conflicting data
supporting its efficacy as an oral dosage form for the
relief of nasal decongestion. The limited evidence
the FDA used to accept phenylephrine as an effective
oral decongestant is derived from five in-house stud-
ies provided by the pharmaceutical companies.17
These unpublished studies demonstrated either a mi-
nor improvement or no difference in airway resis-
tance as compared to placebo. Despite the concern
expressed about the efficacy of phenylephrine as an
oral decongestant, the FDA maintained its approval
for phenylephrine as an effective nasal decongestant
and phenylephrine was accepted as an effective oral
nasal decongestant in the FDA's final conclusions on
nasal decongestants published in 1994.18
A summary of studies comparing the efficacy
of phenylephrine and pseudoephedrine in patients

PharmaNote 4

suffering from nasal congestion is located in Table
1. This is not meant to be an exhaustive list of all
pseudoephedrine and phenylephrine trials, but rather
a summary of a few of the better designed random-
ized, double-blinded, placebo-controlled clinical tri-

When oral pseudoephedrine and
phenylephrine are used as indicated (including the
dosing, length of time used, and medications to
avoid), they are safe for use without medical supervi-
sion. Because most formulations of these OTC prod-
ucts contain analgesics or antihistamines, it is diffi-
cult to ascertain whether or not adverse events are
associated with the drug or its combination ingredi-
ents. Nevertheless, millions of people have used
pseudoephedrine and phenylephrine containing prod-
ucts for years without trends pointing to adverse
As with all sympathomimetics, pseudoephed-
rine and phenylephrine should be avoided in patients
with hypertension, hyperthyroidism or heart disease
as their vasoconstrictive properties could exacerbate
these conditions.2325 Also, patients suffering from
Raynaud's syndrome or taking medicines that inhibit
monoamine oxidase should consult their doctor be-
fore taking phenylepherine.
Phenylephrine and pseudoephedrine may
cause urinary retention in patients with prostatic hy-
pertrophy. Pseudoephedrine is associated with an
increased incidence of CNS adverse events com-
pared with phenylephrine, but when taken in OTC
doses, the most commonly reported side effect of
pseudoephedrine is insomnia.16

Federal impact of pseudoephedrine regulations
Because of the recent restrictions surrounding
the sale of pseudoephedrine containing OTC prod-
ucts, it is expected that fewer methamphetamine ar-
rests and hospital admissions will occur. Numerous
governments have regulated methamphetamine pre-
cursor chemicals to help limit the production and
availability of methamphetamine.26 In 2005, Cun-
ningham et a127 concluded that methamphetamine
arrests declined 31% to 45% when large scale manu-
factures were regulated. Regulation targeting
smaller-scale products had very little effect on the
number of arrests.
Similar results were found among hospital

Volume 22, Issue 7 April 2007

Table 1. Clinical trial summaries on the efficacy of pseudoephedrine and phenylephrine
Source Demographics Design Oral Dose N Results

Taverner et al.13

Eccles et al.12

Roth et al.14

Benson et al.1

Mclaurin et al.19

Bickerman et al.20

Huntingdon et al.21

Elizabeth et al.22

Previously healthy patients
who had the common cold
for 5 days or less with
moderate to severe nasal

Patients suffering from
nasal congestion associated
with common cold

Patients suffering from
acute or chronic nonsuppu-
rative rhinitis
Patients suffering from
nasal congestion associated
with a common cold

Patients with nasal conges-
tion from a variety of

Symptoms of congestion improved at
times 60, 90,120, and 150 minutes
DB, PC, R PDE 60 mg 54 after dose of PDE. NAR decreased
significantly (p= 0.018, p=0.003 re-




DB, PC, R,

Patients with chronic nasal R D
stuffineDB, CO

Patients with elevated
flow/resistance (F/R) meas-
urements from colds

Patients with "head colds"

R, DB, PC,

PDE had significantly lower area un-
der the NAR curve than placebo
PDE 60mg 238
(p=0.006) and on day 3 after multiple
doses (p= 0.001)

Reduction in NAR occurred within 30
PDE 60 mg 64 min and was maintained for at least 4
hours (p=0.04)

PDE showed a decrease in NAR
PDE 60mg 112n c d t p .
(p=0.001) when compared to placebo.

PE 10mg

PDE 60mg,
PP 41 1im PE

PE 10, PE

R, DB, PC, PE 5mg,PE
C 15mg, PE

10 mg of phenylephrine was no more
effective than placebo in decreasing
either NAR or subjective symptom

Nasal stuffiness declined significantly
within 30 minutes and was maintained
for 4 hours with PDE (p=0.01), but not
with PP or PE (p > 0.05)

NAR was not reduced in either 10mg
or 25mg

No significant reduction in airway
33e for all three doses of
resistance for all three doses of PE

N= number of patients, NAR= nasal airway resistance, DB= double-blind, R= randomized, PC= placebo-controlled,
doephedrine, PP= phenylpropanolamine

admissions in California, Arizona and Nevada when
pseudoephedrine regulations were established.28 Re-
ductions in methamphetamine-related hospital ad-
missions dropped 35% to 71% during the study pe-
riod. However, these reductions only occurred when
large-scale bulk powder regulations were enacted.
Restrictions of small-scale ephedrine and pseu-
doephedrine combination products had little to no
impact on hospital admissions.28

Alternative Therapies
Patients suffering from nasal congestion

CO= cross-over, PE= phenylephrine, PDE= pseu-

caused by the flu or the common cold are encouraged
to ask the pharmacist for the pseudoephedrine-
containing products located behind the pharmacy
counter. Another alternative for patients suffering
from congestion are topical nasal decongestants,
such as oxymetazoline hydrochloride (Afrin),
phenylephrine ( Neo-Synephrine), and xylometa-
zoline (Otrivin), which are available over-the-
counter in the United States. These agents work very
quickly to open nasal passages by constricting blood
vessels in the lining of the nose.29'30 With prolonged
use, these types of sprays can damage the delicate

PharmaNote Volume 22, Issue 7 April 2007

Volume 22, Issue 7 April 2007


mucous membranes in the nose, ironically causing an
increased inflammatory effect known as rhinitis
medicamentosa, or the "rebound effect".31 As a re-
sult, decongestant nasal sprays are advised for short-
term use only. Short-term use (3-4 days) can be ad-
vantageous for nasal congestion relief as most cold
symptoms usually last fewer than three days
Saline sprays are a common and safe alterna-
tive to decongestants. A mist of saline solution helps
to moisturize dry or irritated nostrils, but will have
little effect on decreasing nasal resistance.
A future approach to treating nasal conges-
tion may involve targeting G2-receptors. Alpha2-
receptor agonists (yohimbine and BHT-920) have
been shown to contract the nasal mucosa of several
different species (dog, pig, monkey) and elicit decon-
gestion without the side effects seen with other sym-
pathomimetic agents (hypertension, increased heart
rate, insomnia, nervousness).32 These studies have
not been performed in humans and currently there is
no FDA approved a2-adrenoceptor agonist available
for treatment of nasal congestion.

Pseudoephedrine has been used safely and
effectively for many years to relieve nasal congestion
associated with the common cold. The effectiveness
of pseudoephedrine (60 mg orally) has been well
documented in several trials.12-16 However, there is
little evidence supporting the use of oral
phenylephrine as a decongestant.19-22 There has been
a reduction in the number of methamphetamine-
related hospital admissions and arrests when strict
regulations are applied to bulk manufactures of pseu-
doephedrine, but no evidence showing a decline
when small-scale, combination products are re-
In an attempt to reduce the number of clan-
destine "meth" labs by restricting all pseudoephed-
rine containing OTC products, the FDA has pulled
the only effective oral decongestant from the shelves.
Its replacement, phenylephrine, has similar packag-
ing with dissimilar, unproven efficacy. Lack of sales
of the "hidden" or behind-the-counter products may
force pharmacies to reduce inventory of these pseu-
doephedrine-containing cold medicines depriving the
public of a safe and effective nasal decongestant.

1. FDA. Establishment of a monograph for OTC cold,
cough, allergy, bronchodilator and antiasthmatic prod-

ucts. Federal Register 1976; 41: 38399-400.
2. W.N. Keman, C.M. Viscoli, L.M. Brass, J.P. Broder-
ick, T. Brott and E. Feldmann. Phenylpropanolamine
and the risk of hemorrhagic stroke. N Engl J Med
2000; 343: 1826-32.
3. Oliver AL, Anderson BN, Roddick FA. Factors affect-
ing the production of L-phenylacetylcarbinol by yeast:
a case study. Advances in Microbial Physiology 1999;
41: 1-45.
4. Neo-Synephrine phenylephrinee hydrochloride 1% in-
jection) [package insert]. North Chicago, Ill: Abbott
Laboratories; October 1998.
5. Hoffman BB. Catecholamines, sympathomimetic
drugs, and adrenergic receptor antagonists. In: Good-
man LS, Gilman A, Hardman JG, et al, eds. 10th ed.
Goodman & Gilman's The Pharmacological Basis of
Therapeutics. New York, NY: McGraw-Hill; 2001:
6. Lee TJ, Stitzel RE. Adrenomimetic drugs. In: Craig
CR, Stitzel RE, eds. 5th ed. Modem Pharmacology
with Clinical Applications. Boston, Mass: Little,
Brown and Company; 1997: 109-121.
7. Hieble JP, Nichols AJ, Langer SZ, et al. Pharmacology
of the sympathetic nervous system. In: Munson PL,
Mueller RA, Breese GR, eds. Principles of Pharmacol-
ogy: Basic Concepts & Clinical Applications. New
York, NY: Chapman & Hall; 1995:121-144.
8. Malcolmson KG. The vasomotor activities of the nasal
mucous membrane. J Laryngol Otol 1959; 37: 73-98.
9. Kanfer I, Dowse R, Vuma V. Pharmacokinetics of oral
decongestants. Pharmacotherapy 1993; 6: 116S-128S.
10. Hengstmann JH, Goronzy J. Pharmacokinetics of 3H-
phenylephrine in man. Eur J Clin Pharmacol 1982; 21:
11. Eccles R. Substitution of phenylephrine for pseu-
doephedrine as a nasal decongeststant. An illogical way
to control methamphetamine abuse. Br J Clin Pharma-
col 2007; 63: 10-4.
12. Eccles R, Jawad MS, Jawad SS, Angello JT, Druce
HM. Efficacy and safety of single and multiple doses
of pseudoephedrine in the treatment of nasal conges-
tion associated with common cold. Am J Rhinol 2005;
13. Taverner D, Danz C, Economos D. The effects of oral
pseudoephedrine on nasal patency in the common cold:
a double-blind single-dose placebo-controlled trial.
Clin Otolaryngol 1999; 24: 47-51.
14. Roth R, Canterkin E, Bluestone C, Welch R, Cho Y.
Nasal decongestant activity of pseudoephedrine. Ann
Otol 1977; 86: 235-42.
15. Benson MK. Maximal nasal inspiratory flow rate. Its
use in assessing the effect of pseudoephedrine in vaso-
motor rhinitis. Eur J Clin Pharmacol 1971; 3: 182-4.
16. Bye CE, Cooper J, Empey DW, Fowle AS, Hughes
DT, Letley E, O'Grady J. Effects of pseudoephedrine
and triprolidine, alone and in combination, on symp-
toms of the common cold. BMJ 1980; 281:189-90.

PharmaNote Volume 22, Issue 7 April 2007

Volume 22, Issue 7 April 2007


17. FDA. Establishment of a monograph for OTC cold,
cough, allergy, bronchodilator and antiasthmatic prod-
ucts. Federal Register 1976; 41: 38399-400.
18. FDA. Cold, cough, allergy, bronchodilator and an-
tiasthmatic drug products for over-the-counter human
use; final monograph for over-the counter nasal drug
decongestant products. Federal Register 1994; 59:
19. McLaurin JW, Shipman WF, Rosedale R. Oral decon-
gestants: a double blind comparison study of the effec-
tiveness of four sympathomimetic drugs: objective and
subjective. Laryngoscope 1961; 71: 54-67.
20. Bickerman HA. Physiologic and pharmacologic studies
on nasal airway resistance (RN). Presented at a confer-
ence sponsored by the Scientific Development Com-
mittee of the Proprietary Association. Washington, DC.
December 8, 1971. (Available in the Online Repository
at www.jacionline.org).
21. Memo to Blackmore from NA Hulme. Oral Neo-
Synephrine Clintest Study No 3. In: FDA OTC 1970;
Volume 040298.
22. Memo to Suter from NA Hulme. Nasal Decongestant
study by Elizabeth Biochemical No 1. In: FDA OTC
1967; Volume 040298.
23. Radack K, Deck CC. Are oral decongestants safe in
hypertension? An evaluation of the evidence and a
framework for assessing clinical trials. Ann Allergy
1986; 56: 396-401.
24. Chua SS, Benrimoj SI. Non-prescription sympathomi-
metic agents and hypertension. Med Toxicol Adverse
Drug Exp 1988; 3: 387-417.
25. Thomas SHL, Clark KL, Allen R, Smith SE. A com-
parison of the cardiovascular effects of phenylpropa-
nolamine and phenylephrine containing proprietary
cold remedies. Br J Clin Pharmacol 1991; 32: 705-11.
26. Sevick JR (1993) Precursor and Essential Chemicals in
Illicit Drug Production: Approaches to Enforcement. :
National Institute of Justice.
27. Cunningham JK, Liu LM. Impacts of federal precursor
chemical regulations on methamphetamine arrests. Ad-
diction 2005;100: 479-88.
28. Cunningham JK, Liu LM. Impacts of federal ephedrine
and pseudoephedrine regulations on methampheta-
mine-related hospital admissions. Addiction 2003; 98:
29. Black MJ, Remsen KA. Rhinitis medicamentosa,
CMAJ 1980; 122: 881-4.
30. Connell JT. Effectiveness of topical nasal deconges-
tants. Ann Allergy 1969; 27: 541-6.
31. Cohen BM. Clinical and physiologic "significance" in
drug-induced changes in nasal flow/resistance, Eur J
Clin Pharmacol 1972; 5: 81-6.
32. Corboz MR, Mutter JC, Rivelli MA, Mingo GG, et al.
Alpha2-adrenoceptor agonists as nasal decongestants.
Pulm Pharmacol Ther 2007; 20: 149-56.


Amanda Oni, Pharm.D. Candidate

Migraine headache is a debilitating chronic
condition affecting approximately 18% of women
and 7% of men. At this prevalence, migraine affects
30 million people in the US.1 The prevalence of mi-
graine varies by geographic location, age, gender,
race, and socioeconomic status. Currently, the ra-
tionale behind relief of acute migraine is rooted in
vasoconstriction versus a vasodilatory approach de-
sired in prophylaxis treatment. Triptans were devel-
oped to mimic serotonin's ability to cause vasocon-
striction, which diminishes migraine attacks. Trip-
tans were also designed to be more selective at re-
ceptor subtypes in order to decrease unwanted side
effects and increase tolerability.3 The triptans, as a
class of drugs, have a FDA indication for acute treat-
ment of migraine with or without aura. The original
triptan, sumatriptan, also has an indication for cluster
In clinical guidelines, the triptans are gener-
ally held as migraine-specific medications reserved
for those who have failed NSAID therapy. The U.S.
Headache Consortium Recommendations place the
triptans as first line therapy for patients with severe
migraine and as second-line therapy for those who
respond poorly to analgesics.5 The American Col-
lege of Physicians-American Society of Internal
Medicine recommend using triptans in those patients

who fail to respond to NSAIDS.6 This paper will
review the pharmacodynamics, pharmacokinetics,
clinical trials, adverse effects, and cost of triptans in
the treatment of acute migraine.

The mechanism of action of triptans is spe-
cific for the treatment of migraine pain; the patho-
physiology of which is believed to involve both neu-
ral and vascular mechanisms. The triptans are sero-
tonin (5-HT)lB/1Dreceptor agonists with three mecha-
nisms contributing to their antimigraine activity.
The first targets the vascular pathophysiology of mi-
graine. Activation of the sensory trigeminovascular

PharmaNote Volume 22, Issue 7 April 2007

Volume 22, Issue 7 April 2007


system leads to vasoactive substance release from
trigeminal nerve terminals. This in turn causes an
inflammatory reaction, including vasodilation,
plasma protein extravasation, and platelet activation.7
The dilation of these intracranial extracerebral ves-
sels generates the pain of migraine headaches. Sero-
toninlB receptors are expressed on neuronal tissue
and vascular smooth muscle cells and evidence sug-
gests that these receptors are responsible for vascular
smooth muscle contraction. When triptans bind
these receptors, they cause vasoconstriction of the
vasculature, resulting in reduction of painfully vaso-
dilated vessels.8
A secondary mechanism of action includes
stimulation of the 5-HT1D receptors. Peripherally,
this causes inhibition of trigeminal nerves and pre-
vents release of vasoactive neuropeptides, which dur-
ing migraine contribute to the manifestation of head
pain. Centrally, stimulation of 5-HT1D receptors
works to decrease pain signal transmission by inhib-
iting the release of neurotransmitters.8
The first triptan developed, sumatriptan,
proved to be a useful tool in treating patients with
migraine. However, it possessed some limiting phar-
macokinetic parameters such as low bioavailability,
short plasma half-life, and low lipidsolubility. These
limitations provided other companies an opportunity
to improve on the pharmacokinetics of newer triptan
formulations.8 A concise summary of the available
triptans and their specific pharmacokinetics is pre-
sented in Table 1.

Clinical Trials
There is an abundance of primary literature
on the use of triptans in the treatment of acute mi-
graine. Although there are many trials, meta-
analyses, and guidelines to evaluate the benefit of
triptans vs. placebo and other anti-migraine medica-
tions, this article will focus on comparison trials with
other triptans.9 Some acute migraine treatment out-
comes include therapeutic gain (defined as reduction
of moderate-severe pain to mild-moderate pain at 2
hours post-dose), percent of patients pain free at 2
hours post-dose, percent of patients requiring rescue
medication 2 hours post-dose, and percent of patients
with headache recurrence 24 hours post-dose.2
Some differences among products have been
elucidated, and even though they seem to be small,
clinical response and tolerability to these products
vary.10 This is best demonstrated by a meta-analysis
of 53 trials conducted by Ferrari et al. in 2001.11 For
this meta-analysis, they collected raw data of double-
blind (DB), randomized (R), controlled clinical trials
involving triptans. This included trials of triptan vs.
placebo and triptan comparison trials. There were 22
eligible comparison trials of triptan vs. triptan similar
to those outlined in Table 2.
In trials comparing sumatriptan (SU) 100 mg
against other triptans for efficacy endpoints and ad-
verse reactions: zolmitriptan (ZO) 5 mg showed no
difference (p=0.7); naratriptan (NA) 2.5 mg showed
lower efficacy at 4 hours (p<.001, p=.03) and lower
adverse effects (AE) overall (p<.05) in two trials;

Table 1. Pharmacokinetics of triptans12

PaSumatriptan Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Zolmitriptan
100mg 12.5mg 80mg 2.5mg 2.5mg 10mg 2.5mg

Cm, (ng/ml) 54.0-78.4 49.5 107-190 4.2-7.0 7.8-14.4 20mg 1.3-4.7
tmx (h) 1.5-2.3 1.4-3.8 1.0-1.5 2-4 0.8-4.1 1-3 0.5-6.0
t (h) 2.0 3.0-3.7 3.6-6.9 25 4.5-6.6 1.8-3 1.5-3.6
Bioavailability 14 70-80 50 24-30 63-74 40-45 40-49
Protein binding 14-21 NR NR NR 28-31 14 25
Major metabolic CYP3A P P CYP 1A2
enzyme MAO-A MAO-A
Volume of Dis-
olumeofDis- 2.4-3.3 2.5 2.4 3-4 2.4-2.9 1.3-2.5 7.0-2.3
tribution (L/kg)
Cle anc 3.5-3.9 8.6 6.6 1.9-3.1 2.7-3.8 3.2-5.3 2.0-3.1
Lipid solubility Low NR High Low High High High

PharmaNote Volume 22, Issue 7 April 2007

Table 2. Clinical trials comparing triptans
Trial Design Drug/Dose Results Conclusion
Response at 1 h Response at 2 h

Eletriptan vs.


EL 40mg

EL 80mg

SU 50mg

SU 100mg

Rizatriptan vs.

R, DB, PC,
N= 1447

RI 5mg

RI 10mg

Naratriptan vs.

N= 253

NA 2.5mg

SU 100mg

30%; p<.005 vs.

37%; p<.05 vs. SU

24%; p<.05 vs. pla-

27%; p=.053 vs. EL

36.4%; p=0.1 vs.
SU 25mg

40.5%; p=.04 vs.
SU 50mg

Second dose re-
quired for same

40%; p <.001 vs

Relief at 2 hours

Almotriptan vs.

Zolmitriptan vs.

N= 1255

N = 1445

AL 12.5mg

SU 50mg

ZO 2.5mg

ZO 5mg

58%; NS


Relief at 2 hours
67.1%; p<.05 vs.
SU 50mg

64.8%; p=.064 vs.
SU 50mg

64%; p<.05 vs.

67%; %; p<.05 vs.
SU 100mg

50%; p<.01 vs.

53%; p<.01 vs.

65.7%; p=.004 vs.
SU 25mg

68%; p=.29 vs.
SU 50mg

Headache recur-
rence 4-24 hours
after initial dosing

45%; NS vs SU


Headache free-
dom at 2 hours
17.9%; p = .005 vs

Both doses of EL showed
significantly higher rates of
sustained response than SU

Both SU and EL are well
tolerated and efficacious for
the treatment of acute mi-

Response at 1 hour was supe-
rior in RI 10mg vs. SU 50mg

Response at 2 hours was su-
perior in RI 5mg vs. SU

NA showed a difference in
the ability to use only one
dose for one single acute

NA was not different from
SU in reducing headache

AL and SU are similarly ef-
fective at treating migraine


Relief at 4 hours
p<.05 vs. SU 25mg

p=.01 vs. SU 50mg

Both doses of ZO were as
effective as both doses of SU

ZO 2.5mg was superior to
SU 50mg at both 2 and 4

N = number of patients EL eletriptan, SU sumatriptan, RI=rizatriptan, NA naratriptan, AL almotriptan, DB=double-blind, PC-placebo-controlled, R randomized,
XO crossover study, NS = not statistically significant

Phara~ot Volme 2, Isue 7Apri 200

Volume 22, Issue 7 April 2007


Table 3. Efficacy and tolerability in direct comparison trials 12

,b c Sustained Any- CNS- Chest- Primary
Comparison Response Pain free ad a,e a,f AE a,g endpoint
pain free d AE 'e AE AE endpoint

NA 2.5 mg vs. 1% 1% -23% -10% -9% N/A h
ZO 2.5mg (-15, 17) (-12, 15) (-37, -8) (-20, 1) (-16,-2)

RI 10 mg vs. 4% 8% 9% -8% -6% -1%
ZO 2.5mg (-4, 11) (-0, 15) (1, 16) (-15, 0) (12,-0) (-4, 1)

RI 10 mg vs. 20% 24% 12% 10% 11% 1%<
NA 2.5mg (11, 30) (15, 33) (4, 20) (1, 19) (4, 18) (-2, 4)

a Direct difference (95% CI); b patients with headache response at 2 h; c patients with pain free at 2 h; d patients with sustained freedom from pain; e patients with at
least one adverse event (AE); patients with at least one CNS AE; g patient with at least one chest AE; h comparison not done

rizatriptan (RI) 10 mg was superior in one of 2 stud-
ies (p=.03); eletriptan (EL) 40 mg showed superior-
ity in all parameters (p<.05) when two studies were
combined; EL 80 mg was superior in two trials on all
parameters (p<.01) and when combined (p<.05), but
showed more AE when two studies were combined
(p<.05); and finally almotriptan (AL) 12.5 mg
showed no difference in efficacy.11-13 Comparing SU
50 mg against other triptans: ZO 2.5 mg is superior
in the primary endpoint in one of two trials (p=.02);
ZO 5 mg showed no difference in two trials (p=0.8,
p=0.6); RI 5 mg showed no difference in three stud-

ies except for slightly more AEs; RI 10 mg was sig-
nificant for the primary endpoint alone (p=.046) in
one of two trials; EL 40 mg was superior when two
trials were combined (p<.05), but caused more AEs
in the combination of trials (p<.05); EL 80 mg was
superior in the combination of two trials for all pa-
rameters (p<.05), but showed more AEs (p<.05).
The meta-analysis evaluated placebo-controlled trials
of each triptan product. When the placebo effect was
subtracted, the effect of each triptan was remarkably
similar to the direct comparison trial results.11-13
There are a few trials in the literature which

Table 4. Currently available FDA approved triptans
Generic Manufacturer Brand Formulations Standard dosing
Tablets 25-100 mg (Max dose 200 mg daily)
GlaxoSmith- mi Nasal spray 5-20 mg (Max dose 40 mg daily)
Sumatriptan Imitrex
Kline Subcutaneous injec-
ton 6 mg (Max dose two 6 mg injection in 24-48 hours)
Zomig Tablets Up to 2.5 mg per dose (Max dose 10 mg daily)

Zolmitriptan AstraZeneca Zomig-ZMT Orally disintegrating Up to 2.5 mg per dose (Max dose 10 mg daily)
Zomig Nasal spray 5 mg daily (Max dose 10 mg daily)
Maxalt Tablets 5-10 mg per dose (Max dose 30 mg daily)
Rizatriptan Merck Orally disintegrating
Maxalt-MLT all tat 5-10 mg per dose (Max dose 30 mg daily)
Naratriptan l i Amerge Tablets 1 or 2.5 mg per dose (Max dose 5 mg daily)
Almotriptan o Axert Tablets 6.25-12.5 mg daily (Max dose 25 mg daily)
Roerig Division
Eletriptan Rof Pfier R cIpa \ Tablets 20 or 40 mg per dose (Max dose 80 mg daily)
of Pfizer
Endo Pharma-
Frovatriptan Eno P FrovaM Tablets 2.5 mg per dose (Max dose 7.5 mg daily)

PharmaNote %I Volume 22, Issue 7 April 2007

Table 5. Cost of triptans per dose

S 50mg 100mg 2.5mg 5mg 5mg 10mg 2.5mg 12.5mg 40 mg 2.5mg

Chain $23.50 $24.30 $15.70 $16.60 $23.10 $23.10 $24.50 $21.30 $25.10 $24.30

Discount $23.45 $23.45 $21.03 $22.94 $22.44 $22.44 $26.67 $21.73 $22.14 $22.54

Independent $22.62 $22.62 $25.81 $25.89 $29.97 $29.97 $27.50 $28.40 $25.54 $23.72

Average $23.19 $23.46 $20.85 $21.81 $25.17 $25.17 $26.22 $23.81 $24.26 $23.52

compare triptans, where the comparator is not suma-
triptan. ZO 2.5 mg was compared to NA 2.5mg and
found to be comparable in relief at 4 hours. RI 10
mg did not reach statistical significance in response
against ZO 2.5 mg. However, RI 10 mg was superior
to NA 2.5 mg in all parameters, but caused more
AEs (Table 3).12
Based on triptan comparison trials, recur-
rence rates, adverse effect profiles, or quicker time to
relief may differ between agents. However, this usu-
ally comes at a cost.2 For instance, eletriptan has one
of the highest rates of efficacy, but it also has a
slightly higher rate of treatment-related adverse
events. 14

Adverse Reactions
Overall, the triptans as a class are well toler-
ated. Most patients who discontinue triptans do not
do so due to adverse reactions. The more common
adverse reactions include fatigue, dizziness, pares-
thesias, warm sensations, and chest, neck, and throat
tightness.8 However, there is a safety concern with
triptans in heart disease. Triptans may cause signifi-
cant coronary vasoconstriction in patients with coro-
nary artery disease, uncontrolled hypertension, or
those with other cardiac risk factors. Triptans have
been used extensively in the last decade, and history
has shown that this risk is minimal. The 5-HT1B re-
ceptors are present at a higher density in the men-
ingeal arteries than the coronary arteries, which pro-
duces the differential vasoconstrictive selectivity of
the triptans. There is no safe triptan in the presence
of significant vascular disease; however, in the ab-

PharmaNote "W

sence of vascular disease, the
relatively safe.15,20

triptans appear to be


Standard dosing for each product is listed in Table 4.

All triptans, which are migraine-specific
agents, are effective treatment options in acute mi-
graine. However, since some differences amongst
agents have been noted, price should also be in-
cluded in this analysis. Price was solicited from
three different types of pharmacies: chain retail, dis-
count, and independent. The price at each location
for a dose and the average of all three locations for
each triptan is listed in Table 5.

Triptans have been used for nearly a decade,
and have proven to be a valuable asset in treating
patients with acute migraine. This class of drugs is
typically used to treat migraine in patients who have
not responded to traditional analgesics. They work
to combat the pathogenesis of acute migraine by
stimulating 5-HT1B/1D receptors to produce vasocon-
striction of severely dilated cranial blood vessels,
decrease release of vasoactive neuropeptides, and
inhibit pain transmission centrally. Clinical trials
comparing triptans show some statistically signifi-
cant results for one product over another for certain
endpoints; however, there is not enough consistent
evidence to suggest that any one triptan is superior.

Volume 22, Issue 7 April 2007

As noted earlier, each product has its own clinical
strengths and weaknesses, and selecting a triptan
should be patient specific and tailored to optimize
these differences.

1. Lipton RB, Stewart WF, Diamond S, Diamond
ML, et al. Prevalence and burden of migraine in the
United States: data from the American Migraine
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2. Deleu D, Hanssens Y. Current and emerging sec-
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A comparative review. Journal of Clinical Pharma-
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3. Unger J. Migraine headaches: A historical pro-
spective, a glimpse into the future, migraine epide-
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4. Gold Standard Inc. Clinical Pharmacology 2007.
http://cpip.gsm.com/ Accessed March 27, 2007.
5. Matchar DB, Young WB, Rosenberg JH, Pietrzak
MP, et al. Evidence-based guidelines for migraine
headache in the primary care setting: pharmacol-
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cessed at www.aan.com/professionals/practice/
6. Snow V, Weiss K, Wall EM, Mottur-Pilson C.
Pharmacologic management of acute attacks of mi-
graine and prevention of migraine headache. An-
nals of Internal Medicine 2002; 137: 840-849.
7. Silberstein SD. Preventive treatment of migraine.
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(8): 410-5.
8. Tepper SJ, Rapoport AM, Sheftell FD. Mecha-
nisms of action of the 5-HTB/1D receptor agonists.
Archives of Neurology 2002; 50:1084-8.
9. Schuurmans A, van Weel C. Pharmacologic treat-
ment of migraine. Comparison of guidelines. Ca-
nadian Family Physician 2005; 51: 838-43.
10. Elrington G. Migraine: diagnosis and management.
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11. Ferrari MD, Roon CI, Lipton RB, Goadsby PJ. Oral
triptans (serotonin, 5-HT1B/1D agonists) in acute mi-
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12. Ferrari MD, Roon CI, Lipton RB, Goadsby PJ.
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17. Gallagher RM, Dennish G, Spierings EL, Chitra R.
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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor

IPam ot Volume 22, Isse 7 April 200

Volume 22, Issue 7 April 2007


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