Frovatriptan for The Prevention of Postdural Puncture Headache

ArticleinCephalalgia 27(7):809-13 · August 2007with48 Reads
Impact Factor: 4.89 · DOI: 10.1111/j.1468-2982.2007.01327.x · Source: PubMed
Abstract

Bussone G, Tullo V, d'Onofrio F, Petretta V, Curone M, Frediani F, Tonini C & Omboni S. Frovatriptan for the prevention of postdural puncture headache. Cephalalgia 2007; 27:809–813. London. ISSN 0333-1024 Efficacy of 5-day treatment with oral frovatriptan 2.5 mg/die for the prophylaxis of post-dural puncture headache (PDPH) was tested in 50 in-patients. A mild headache occurred in 7 (14%) patients for a total of 9 days (p < 0.01 vs. no-PDPH). Most episodes of PDPH occurred in the first days of treatment (only 1 patient had headache at dismissal): 5 patients had only 1 episode, while 2 had headache for 2 consecutive days. No other symptoms were recorded. Occurrence of PDPH in a subgroup of 6 (12%) patients previously submitted to a diagnostic lumbar puncture was also examined: 4 of them reported a PDPH on the previous lumbar puncture in absence of triptans. In only 1 of these 4 patients PDPH recurred under treatment with frovatriptan. In conclusion, our non-randomized open-label study suggests efficacy of oral frovatriptan for PDPH prevention. These results need to be confirmed in a randomized, controlled, double-blind study.

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Frovatriptan for the prevention of postdural puncture headache
G Bussone
1
, V Tullo
1
, F d’Onofrio
2
, V Petretta
2
, M Curone
1
, F Frediani
3
, C Tonini
4
& S Omboni
5
1
Department of Clinical Neurology, Istituto Nazionale Neurologico C. Besta, Milano,
2
Neurology Unit, Ospedale ‘Moscati’, Avellino,
3
Neurology Unit, Ospedale ‘San Pietro’, Ponte San Pietro,
4
Neurology Unit, Ospedale ‘G. Salvini’ Garbagnate Milanese and
5
Data
Management Unit, Docleader, Somma Lombardo, Varese, Italy
Bussone G, Tullo V, d’Onofrio F, Petretta V, Curone M, Frediani F, Tonini C &
Omboni S. Frovatriptan for the prevention of postdural puncture headache.
Cephalalgia 2007; 27:809–813. London. ISSN 0333-1024
Efficacy of 5-day treatment with oral frovatriptan 2.5 mg/die for the prophylaxis
of post-dural puncture headache (PDPH) was tested in 50 in-patients. A mild
headache occurred in 7 (14%) patients for a total of 9 days (p < 0.01 vs.
no-PDPH). Most episodes of PDPH occurred in the first days of treatment (only
1 patient had headache at dismissal): 5 patients had only 1 episode, while 2 had
headache for 2 consecutive days. No other symptoms were recorded. Occurrence
of PDPH in a subgroup of 6 (12%) patients previously submitted to a diagnostic
lumbar puncture was also examined: 4 of them reported a PDPH on the previous
lumbar puncture in absence of triptans. In only 1 of these 4 patients PDPH
recurred under treatment with frovatriptan. In conclusion, our non-randomized
open-label study suggests efficacy of oral frovatriptan for PDPH prevention.
These results need to be confirmed in a randomized, controlled, double-blind
study. Diagnostic lumbar puncture, frovatriptan, postdural puncture headache
Prof. Gennaro Bussone, Istituto Nazionale Neurologico Carlo Besta, Dipartimento di
Neuroscienze Cliniche, U.O. di Neurologia III Cefalee e Malattie Cerebro Vascolari,
Via Celoria, 11, 20133 Milano, Italy. Tel. + 39 02 2394 2209, fax + 39 02 7063 8067,
e-mail bussone@istituto-besta.it Received 23 September 2006, accepted 13 january
2007
Introduction
Post-dural puncture headache (PDPH) occurs in up
to 40% of patients undergoing diagnostic lumbar
puncture (DLP), its incidence varying depending
upon how the procedure is performed (e.g. replace-
ment of the stylet or insertion plane of the bevel
with the Quincke needle), the needle used (atrau-
matic vs. cutting Quincke and diameter) and the
demographics of the patients (age and gender) (1,
2). Its origin has been related to the decrease in
cerebrospinal fluid volume or pressure, or both,
through the hole made by the spinal or epidural
needle. This loss leads to PDPH due to shifts of
intracranial contents and traction on pain-sensitive
structures in the upright position, activation of
adenosine receptors and consequent induction of
arterial and venous dilation in the central nervous
system (1, 3). Several measures have been proposed
for treatment of PDPH, but very few of them have
proved to be effective (e.g. epidural blood patch in
up to 98% of patients), while most have not been
shown to work with certainty (1).
Although a few case reports have suggested
that subcutaneous injections of sumatriptan, a
serotonin agonist acting on 5-HT
1B/1D
receptors
and used for treatment of migraine, may be suc-
cessfully employed for treatment of PDPH (4–6), a
small controlled trial found no evidence of benefit
from sumatriptan for the treatment of PDPH (7).
Frovatriptan is an oral 5-HT
1B/1D
receptor agonist,
used for the treatment and prophylaxis of
migraine, whose high selectivity for cerebral vas-
culature, long elimination half-life and high per-
sistence of therapeutic action make it a potential
effective preventive for PDPH (8). It acts on
extracerebral, intracranial arteries by inhibiting
excessive dilation of these vessels occurring
during migraine attacks and it is better tolerated
than other triptans (9).
doi:10.1111/j.1468-2982.2007.01327.x
809© Blackwell Publishing Ltd Cephalalgia, 2007, 27, 809–813
Page 1
The present study aimed at assessing the efficacy
of frovatriptan given orally as a prophylactic treat-
ment of PDPH.
Methods
This was a non-randomized, open-label, non-
placebo-controlled, pilot study. Eligible patients
were considered those of either gender, aged
18–65 years and needing a DLP. Exclusion criteria
included: (i) moderate or severe arterial hyperten-
sion or mild uncontrolled arterial hypertension; (ii)
positive medical history of ischaemic heart disease,
myocardial infarction, peripheral vascular disease,
severe liver failure; (iii) treatment with ergot
medications, other 5-HT agonists or monoamine
oxidase inhibitors at the time of enrolment; (iv)
known hypersensitivity to frovatriptan; and (v)
pregnant women or those with childbearing poten-
tial but not practising an effective method of birth
control. The study protocol was reviewed and
approved by the Institutional Review Board and
all patients provided written informed consent
prior to inclusion.
All patients underwent a DLP according to pro-
cedures indicated by the American Academy of
Neurology. Briefly, a 20-G Quincke needle was
inserted in the dura with the bevel parallel to the
dura fibres and stylet was replaced before needle
withdrawal (10, 11).
Following the DLP patients were treated with
frovatriptan 2.5 mg orally once daily for 5 days.
Occurrence of PDPH was recorded through a
patient’s diary. PDPH was diagnosed according to
the International Classification of Headache Dis-
orders (ICHD)-II (12) as a headache (i) worsening
within 15 min after sitting or standing and improv-
ing within 15 min after lying, with at least one
symptom among neck stiffness, tinnitus, hypacusia,
photophobia and nausea, (ii) developing within
5 days after dural puncture, and (iii) resolving
either spontaneously within 1 week or within 48 h
after effective treatment of the spinal fluid leak
(usually by epidural blood patch). In addition to
frovatriptan, patients could be treated conserva-
tively (fluid hydration and bed rest), provided that
no drugs interfering with study treatment were
administered during the study (e.g. triptans, corti-
sone, analgesics, etc.).
Study efficacy variables were the occurrence (per-
centage of patients and number of days), intensity
(mild, moderate or severe) and duration of PDPH
and related symptoms assessed during the 5-day
in-hospital treatment period following DLP.
Differences in the percentages of patients with and
without PDPH were assessed by c
2
test. Compari-
son of the number of days with and without PDPH
was made by Student’s t-test. P < 0.05 was taken as
the minimum level of statistical significance.
Results
A total of 50 patients were enrolled. Their main
demographic and clinical data are shown in
Table 1. Most of the patients had suspected multiple
sclerosis or myelitis or encephalitis at entry, these
diagnoses being confirmed at final visit after cere-
brospinal fluid examination (Table 1). No patients
reported headache prior to the procedure. Symp-
toms associated with encephalitis were fever and
ataxia, with no patient showing an altered mental
status.
Only seven (14%) of the 50 patients studied
reported PDPH. The rate of patients with PDPH
was significantly (P < 0.01) lower than that without
PDPH (Fig. 1a). In all cases PDPH was of mild
intensity.
A total of 9 days of PDPH out of 250 days of
treatment were recorded (P < 0.01 vs. number of
days without PDPH) (Fig. 1b).
Most episodes of PDPH occurred in the first
days of treatment, and only one patient still had
Table 1 Demographic and clinical data of the study
population
Age, years (mean SD) 39 13
Gender, M/F (%) 40/60
Most common final diagnosis (n,%)
Multiple sclerosis 11 (22)
Myelitis or encephalitis 6 (12)
Demyelinating disease of CNS 6 (12)
Acute infective polyneuritis 4 (8)
Migraine 3 (6)
Arteritis 3 (6)
Benign intracranial hypertension 2 (4)
Lymphocytic meningitis 2 (4)
Viral encephalitis 2 (4)
Multifocal leuco-encephalopathy 1 (2)
Degenerating disease of CNS 1 (2)
Trigeminal neuralgia 1 (2)
Cranial polyneuritis 1 (2)
Ptosis 1 (2)
Optic neuritis 1 (2)
Exophoria 1 (2)
Ophthalmoplegia 1 (2)
Cervical arthrosis 1 (2)
Cervical radiculitis 1 (2)
Headache 1 (2)
CNS, Central nervous system.
810 G Bussone et al.
© Blackwell Publishing Ltd Cephalalgia, 2007, 27, 809–813
Page 2
headache at dismissal from the hospital. Of the
seven patients reporting PDPH, five had only one
episode, whereas two had headache for two con-
secutive days (Fig. 2). No symptoms except head-
ache were reported.
Occurrence of PDPH in a subgroup of six (12%)
patients previously submitted to a DLP was also
examined. These patients served as a sort of control
group; four of them reported a PDPH on the pre-
vious lumbar puncture in absence of triptans. In
only one of these four patients did PDPH recur
under treatment with frovatriptan (P = NS).
Discusssion
Results of our study report the efficacy of oral
frovatriptan at a dose of 2.5 mg for the prevention
of PDPH. It also prevented symptoms related to
PDPH. The drug reduced the risk but also the
duration of PDPH, which occurred in only seven
out of 50 patients and lasted only 1 day in the
majority (71%) of them. Since headache usually
occurs in up to 40% of patients following lumbar
puncture (1, 2), our results demonstrate that pro-
phylactic treatment with frovatriptan of patients
undergoing DLP may reduce by more than half the
chance of having a PDPH.
Although previous case reports of patients
treated with subcutaneous sumatriptan seem to
support the use of triptans in these patients for the
treatment of the acute attack (4–6), there is no
previous evidence of such a beneficial effect for the
prevention of PDPH by oral formulations. Results
achieved in our study with frovatriptan are encour-
aging. They add to previous evidence of effective
prophylactic activity of frovatriptan observed in a
different clinical setting (546 women with menstru-
ally associated migraine) by a randomized, double-
blind, placebo-controlled study (13). We postulate
that the success of headache prevention with fro-
vatriptan may be ascribed to its high affinity for
14
86
0
20
40
60
80
100
PDPH+ (n=7) PDPH– (n=43)
Frequency of patients (%)
9
241
0
50
100
150
200
250
PDPH+ (n=7) PDPH– (n=43)
Number of days
P < 0.01
P
< 0.01
(a)
(b)
Figure 1 Frequency (%) of patients (a) and total number of
days (b) with (+) or without (–) a postdural puncture
headache (PDPH).
2
4
2
0
1
0
1
2
3
4
5
Day 1 Day 2 Day 3 Day 4 Day 5
Number of patients with PDPH
Figure 2 Number of patients/day with a postdural
puncture headache (PDPH) in the 5 days of study
treatment with frovatriptan.
Frovatriptan and postdural puncture headache 811
© Blackwell Publishing Ltd Cephalalgia, 2007, 27, 809–813
Page 3
cerebral artery 5-HT
1B/1D
receptors and to its long
elimination half-life (26 h), resulting in a consistent
and long duration of action (9).
Few other results need further discussion. First,
although we followed currently suggested proce-
dures for DLP (10), we used a larger needle than in
the previous randomized controlled study with
other triptans (20 G vs. 25 G), potentially increasing
the risk of PDPH and reducing the drug preven-
tive efficacy (1). However, we recorded a limited
number of cases of PDPH. Second, as expected,
PDPH occurred in the first 3 days following lumbar
puncture, which strengthens the importance of pro-
phylactic treatment being commenced as soon as
possible after the diagnostic procedure. Three, fro-
vatriptan was effective in the oral form, with no
need for subcutaneous administration as for other
triptans. Four, no adverse events or accompanying
symptoms except headache were reported by any
patient.
We acknowledge that our study has some limi-
tations, related to its non-randomized, open-label,
non-placebo-controlled design, including a rela-
tively limited number of subjects. Although a
control group was lacking, we could analyse data
from a very small subgroup of patients with a
positive history of PDPH. In these patients recur-
rence of PDPH was low (one out of four patients).
It should also be acknowledged that our sample
size was much greater than that of the only avail-
able randomized controlled study with a triptan (7)
or other treatments (14, 15). Finally, one may argue
that, even if frovatriptan seems to be an effective
preventive treatment for PDPH, we could have
reduced the risk of PDPH simply by using an
atraumatic lumbar puncture needle such as the
Sprotte, which has been proven in randomized
trials to reduce the incidence of PDPH to 3–15%,
depending upon the study and the diameter of the
needle (16–18). However, use of such a needle
requires greater attention and expertise by doctors
and is thus not easy to apply in all hospitals and
situations. It is also true that, even in case of use of
a smaller needle, risk of PDPH is not completely
abolished and thus frovatriptan may be considered
as an effective prophylactic treatment.
In conclusion, our results support the hypothesis
that prophylaxis with oral frovatriptan may suc-
cessfully reduce the risk of PDPH, avoiding the use
of blood patch or other aggressive, invasive thera-
pies. Adequately powered, double-blind, random-
ized, placebo-controlled studies are needed in order
to demonstrate definitely the efficacy and safety of
oral frovatriptan for the prevention of PDPH.
Acknowledgements
The authors thank Istituto Lusofarmaco d’Italia for the
support given to this study. Results of this study have been
presented at the 12th International Congress of the Interna-
tional Headache Society held in Kyoto (Japan), 9–12 October
2005.
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Frovatriptan and postdural puncture headache 813
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  • [Show abstract] [Hide abstract] ABSTRACT: Frovatriptan belongs to the triptan compounds used for the acute treatment of migraine. Its affinity for the migraine-specific serotonin 5HT1B-receptors is highest in the class. Its long half-life in plasma (26 h) and metabolism by multiple pathways are unique characteristics among the triptans. These features can translate into long duration of action and low risk of interactions with other drugs. Frovatriptan has been effective and well tolerated over a wide range of doses in randomised, double-blind, placebo-controlled acute migraine trials and long-term, open-label trials. The 2.5-mg dose is recommended for both efficacy and a favourable side effect profile for acute migraine treatment. Frovatriptan has the lowest headache recurrence rate of all the triptans. Frovatriptan was better tolerated than sumatriptan in a head-to-head comparison study. Frovatriptan could make its mark especially in slowly progressing migraine attacks and in attacks that are highly predictable. For example, for the short-term prophylaxis of menstrual migraine, frovatriptan is the triptan of first choice.
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  • [Show abstract] [Hide abstract] ABSTRACT: Frovatriptan is a 5-HT(1B/1D) receptor agonist that belongs to the triptan therapeutic class. Relative to other triptans, frovatriptan has a long half-life (26 h) and a low incidence of migraine recurrence (17%). Frovatriptan is indicated for the acute treatment of migraine with or without aura, and has a relatively good safety and tolerability profile. Recent studies have also shown that a 6-day regimen of frovatriptan scheduled during the perimenstrual period significantly reduced the incidence and severity of menstrual migraine (MM; attacks that regularly start day -2 to +3 relative to menses). Prevention may be important because MM attacks have been characterized as being of longer duration, more severe and more refractory to treatment than non-MM attacks.
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  • [Show abstract] [Hide abstract] ABSTRACT: The treatment of postdural puncture headache remains controversial, largely because it is insufficiently evidence based. With high rates of neuraxial block in the obstetric population likely to continue, postdural puncture headache will remain a primary cause of morbidity and increased duration of hospital stay. This review describes new reports of relevance published in 2006 and until October 2007. New evidence justifies epidural blood patch as the treatment of choice for severe postdural puncture headache, but technical aspects such as optimal timing and volume are less clear. Symptomatic medical management remains diverse, with a multitude of therapies often advocated, despite a lack of scientific support. Reports of misdiagnosis and of complications associated with postdural puncture headache and its treatment emphasize the importance of multidisciplinary management and additional investigation, including radiological imaging, when the clinical picture warrants. The key reports in this epoch have shed light on the benefits of careful assessment of postpartum headache and treatment with an epidural blood patch. New management paradigms have been suggested and serious complications continue to be reported.
    No preview · Article · Jul 2008 · Current opinion in anaesthesiology
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