many Migraineurs share this problem — finding treatment for intractable or
refractory Migraines. Those are the Migraines that don't seem to respond to
treatment no matter what they try, be it preventives, abortives, or pain
management. This situation often leads to feelings of desperation on the part of
the patient and extreme frustration on the part of their physicians.
The truth of the situation is that
intractable and refractory Migraines need aggressive treatment, but few doctors
are prepared to offer such treatment. That statement is not an indictment of
those doctors who are not prepared to offer treatment, simply a statement of
fact. With the exception of true headache and Migraine specialists, doctors
simply have too many conditions to treat to be expected to have the expertise to
treat such cases.
John Claude Krusz, PhD, MD; (Ask
the Clinician) and his colleagues; Virginia Scott-Krusz; Jeanne Belanger, RN;
and Jane Cagle, LVN; have been using outpatient IV treatment for refractory
Migraines in Dr. Krusz's Dallas clinic since 1994 and collecting research data.
"The future of aggressive
headache treatment is in the specialty clinic, a far more cost- and
time-effective mode of treating intractable headaches, including refractory
and chronic Migraines. Compared with the emergency department, the headache
clinic can offer a wider range of effective and definitive treatments and
offer headache patients maximum degree of success for control of Migraines.
We have used IV treatment in the clinic since 1994 and presented initial
data regarding its effectiveness in 1998. This study continues in
documenting the degree of success of outpatient IV treatment of headaches.
Our total treated patients number over 1,700. Of these, 874 were treated for
refractory Migraines or headaches; the rest were for pain flare-ups or a
mixture of both.
We utilized the following treatments: IV magnesium sulfate, dexamethasone,
valproate sodium, lidocaine, droperidol, dihydroergotamine, promethazine,
propofol, tramadol, levetiracetam and ketamine. Results are measured on the
basis of successful resolution of symptoms, defined by at least a 50%
decrease in severity of the presenting headache or Migraine, or by return to
work or regular activity. On this basis, 62 patients from the total pool,
and 22 from the headache pool (22/874) [2.5%] had unsuccessful treatment
that required re-treatment in the clinic, hospital ED or inpatient. This
represents a 97.5% rate of effective treatment in the clinic setting.
We conclude that outpatient aggressive therapy of refractory headaches and
Migraines is highly successful with a very low need for retreatment. It
contributes to productivity, most importantly in the workplace and also at
home and in personal life.*"
It has been the theory and experience of some head pain and pain management
specialists that head and other pain flare-ups could be better managed
aggressively in an outpatient setting as opposed to inpatient or emergency room
settings. Obviously, such treatment is dependent upon the outpatient clinic
being set up for the appropriate treatments. Krusz and his colleagues believe and have
demonstrated that such outpatient treatment is more effective for and preferable
to the patient, being less expensive and offering more options that can be
offered in an emergency department setting. Based on the results of their work,
they urge headache and pain practitioners to incorporate these IV treatment
techniques when they are seeing a patient with refractory headache or Migraine.
Optimal clinic set up:
This outpatient IV treatment approach requires
nursing staff trained in IV therapy to start and monitor IV lines.
Pulse oximetry monitoring is desirable in many
cases, and even necessary for some of the medications.
A comfortable room or rooms where patients can
be treated, hopefully where lights can be dimmed, would also be ideal.
Many of the IV rooms in Dr. Krusz's clinic are
multi-use so that the psychologists or other clinicians can use them as
A room for cervical
and lumbar traction, a fluoroscopy room and an EEG room that can be used for
Some of these rooms already have easy chairs
Krusz and his colleagues utilized the following
IV treatments (listed alphabetically): antinauseants, dexamethasone, lidocaine,
dihydroergotamine, droperidol, ketamine, levetiracetam, magnesium sulfate,
propofol, tramadol, steroids, and valproate sodium. (see Table 1). These
treatment protocols, and their specifics, will be described in more detail
||Available in Europe
*ACLS trained staff and crash cart is recommended on
IV antinauseants (IV droperidol,
metochlopramide, promethazine, prochlorperazine, and ondansetron) Antinauseants
have long been used along with acute opiate therapy for headaches and for pain
treatment, on the notion that use of both agents was somehow synergistic. Animal
experiments seemed to support this idea, but human studies are not at all
conclusive on this point. We’ve looked for evidence of this, but it is almost
non-existent. Nevertheless, ED treatment of headache most often uses both
opiates with antinauseants.
IV MgSO4 (Magnesium Sulfate) - In the
headache clinic, this treatment is a sort of “opening shot” for intractable
headaches and Migraines. It can be given alone, or combined with antinauseants
(IV metochlopramide, promethazine, prochlorperazine or droperidol) or with IV
steroids. There is a substantial literature on use of magnesium intravenously
for Migraines and cluster headaches.
IV Steroids - There is very little
published literature on the use of corticosteroids to treat Migraines, although
there is more data in the cluster headache field or treatment of Status
Migrainosus or analgesic rebound (medication overuse) headaches. We use
dexamethasone in the clinic fairly often for refractory Migraines, for helping
the detoxification regimens, and for pain flare-ups.
IV Dihydroergotamine (DHE) - The gold
standard for treating intractable Migraines is dihydroergotamine (DHE), a
compound similar to, but very different pharmacologically from, ergotamine. Many
people forget that the pharmacologic profile of DHE is predominantly that of a
venoconstrictor (as well as an arterial constrictor), whereas ergotamine is a
pure arterial vasoconstrictor. DHE can be given IV or IM and has a 10- to
14-hour half-life. The original IV DHE protocol to treat refractory Migraine was
introduced in 1986 by Professor Raskin, and it became the mainstay of inpatient
and in-clinic treatments. Typically, it was given every 8 hours with IV
metochlopramide, 10mg, for two to three days. In retrospect, metochlopramide
probably also has a Migraine blocking effect as discussed under the
antinauseants. Comparisons of this protocol against “typical” treatment with
meperidine and promethazine showed similar efficacy with significantly fewer
side effects in the DHE/metochlopramide group, making it very useful for
office-based treatment of Migraines. Dr. Krusz introduced the DHE45 protocol to
Dallas in 1987. In his clinic, they have switched to an outpatient protocol
where they give two or even three doses of IV or IM DHE/metochlopramide per day
for up to three days. The third dose, if needed, can be given at home by the
patient or a family member. This results in a tremendous cost and time savings
for the patient and for the clinical staff. The patient can also continue a
short protocol (three to five days) of two
IM doses at home each day to break a bad cycle of Migraines. This is especially
useful for peri-menstrual or seasonal Migraine flare-ups.
IV Valproate Sodium - Sodium valproate
(divalproex sodium/Depakote as an enteric-coated preparation) was approved in
1994 for oral use in the prophylaxis of Migraines in the United States. It was
the first anticonvulsant molecule to be found useful in treating Migraines in a
prophylaxis manner. After a time, an IV version of the valproate sodium was
developed and has been used for treatment of seizures. In the search for
additional agents to use in the clinic intravenously for intractable Migraines
and other headaches, Dr. Krusz and his colleagues turned to this compound and
presented an initial open-label study in 2001. Their IV study was a sample of 85
intractable Migraineurs and the response to IV valproate sodium was a 88 %
reduction in severity of Migraine, patient-rated on a 0-10 numeric rating scale.
IV propofol - Sometimes, interesting
results are found serendipitously, as occurred in the case of the pre-anesthetic
agent, propofol. Dr. Krusz and his staff use this agent routinely in the clinic
as a mild sedative prior to epidural steroid and other nerve blocks in a
conscious sedation manner. They noted that some patients who had Migraines at
the time of their blocks would comment on betterment of the Migraine before the
block was performed but after propofol was given in conscious sedation doses.
After researching the literature, they found no other mention of this agent in
treating Migraines and undertook a formal open-label study in the clinic to
treat refractory Migraines unresponsive to usual abortive approaches. They
treated 77 patients and the results were nothing short of spectacular. Propofol
was the most effective IV agent that they had ever employed, with a 95.4%
success rate in reducing ongoing Migraines. The total dose was only 120mg, given
slowly by IV push 20mg at a time. The most fascinating element in this study was
the specific pharmacologic effect of propofol, which has sole effects on
subtypes of the GABAA receptor. It had Dr. Krusz speculating as to the role that
this receptor system might play in the maintenance of Migraine headaches.
Indeed, topiramate has been approved for Migraine prophylaxis last year and one
of its mechanisms of action is on GABAA receptors.
IV lidocaine - Lidocaine is an
indiscriminate blocker of sodium (Na+) channels, and blockade of this system has
definite implications for reducing neuropathic pain disorders. Many of the
so-called anticonvulsants (better termed neuronal stabilizing agents) have this
mechanism of action, at least, in their pharmacology. Dr. Krusz and his staff
have used IV lidocaine, with pulse oximetry monitoring, in the clinic for years
in the treatment of headache and pain flare-ups. The paradigm is to treat very
slowly, so as to saturate the Na+ channels and obtain the best possible
blockade. Often, the response is short-lived (12-48 hours) and buys time for
other treatments to be put in place. This is not a first-line choice for
Migraines, but IV lidocaine may be part of a regimen of daily or nearly-daily IV
treatments to break a cycle of headache. IV lidocaine and Ca+ channel blockade
(via IV MgSO4) can be particularly effective, along with IV dexamethasone.
IV tramadol (Ultram) - Tramadol has been available in the US for a number
of years and has been used in Europe for over 30 years. Half a billion people
worldwide have been treated for pain with this agent, whose pharmacologic
activity includes opiate-like effects on the mu receptor, as well as weak
presynaptic reuptake inhibition of norepinephrine and serotonin (like
venlafaxine or duloxetine). IV tramadol has been available in Europe but not the
US. Dr. Krusz decided to formulate a sterile IV preparation to treat headache
and Migraine. An IV form is available in Europe and has a fairly extensive
literature in treating pain. The IV preparation of tramadol turned out to be
very efficacious, very well-tolerated and treated refractory Migraines and mixed
headaches with pain flare-ups. Krusz et al use 50mg IV every 5-15 minutes given
in the clinic. If it has efficacy, they place the patient on oral tramadol.
IV levetiracetam (Keppra™) - Dr. Krusz's team's data with the oral form
of this neuronal stabilizing agent was the first available anywhere in the
treatment of refractory Migraine. This agent has a unique mechanism of action
that blocks high-voltage calcium channels, another major activity of many
neuronal stabilizing agents. Subsequently, they developed an IV form of the same
agent with a compounding pharmacy and evaluated levetiracetam IV in the
treatment of refractory Migraines. More recently, cluster headache flare-ups and
trigeminal neuralgia have also been treated in the clinic. Call it somewhat
proprietary for now, but this is a powerful, non-toxic form of treatment for
many difficult pain and headache flare-ups. The manufacturer is working on an IV
preparation for commercial use to treat seizure disorders.
IV Ketamine - Some headache and pain physicians tend to think that
neuropathic pain, chronic daily headaches and Migraines are quite similar in
their biochemical mechanisms or underpinnings. The fields of pain and headache
management have become more confluent and utilize common terminologies to
describe these convergences: nociceptive pain, peripheral and central
sensitization, windup, long-term potentiation and neuroplasticity are concepts
basic to the pathophysiology, expression and maintenance of these disorders. On
the treatment side of things, why is it that medications with completely
different structures and similar mechanisms of action (i.e., propofol and
topiramate, each of which act on GABAA receptors) can both reduce Migraines and
other headaches and pain as well? One antagonist of NMDA-type glutamate
receptors shown to decrease Migraine attacks when given subcutaneously is
Ketamine. This anesthetic agent has been little studied thus far but may have
theoretical implications for preventing chronic Migraines. A recent study
administered ketamine intranasally to Migraine patients who had pronounced and
disabling aura, but less than 50% had successful resolution with ketamine.
IV methocarbamol (Robaxin) - Although methocarbamol is an older muscle
relaxant preparation with an uncertain pharmacologic mechanism(s) of action, it
is one of the very few available in an IV form and, for this reason, Dr. Krusz
sometimes utilizes it in the clinic to treat Migraines and headaches, especially
if accompanied by a lot of neck spasm. We know of no published studies looking
at effectiveness of this agent intravenously to treat headaches. All information
is anecdotal and rarely do they use it alone, it is often used after or with the
above other agents. Dr. Krusz has about 60 patients over the last four to five years for
whom addition of methocarbamol is a positive element in their overall headache
and muscle spasm relief.
Combinations - "It seems like virtually every combination of IV
medications at our disposal has been tried or given in my clinic at one time or
another for refractory Migraines, headaches or a combination of these with a
pain flare-up. Of course, we make every effort to use one medication at a time
and to document carefully the percentage reduction to that single agent. As you
can imagine, agents that have worked successfully, perhaps many times before,
might not work in the next particular situation and so we always have the next
potential treatment “game plan”. For example, one flare-up may have much more
nausea than the last three did. Or, there may be more accompanying muscle spasm, or
burning pain. One must be flexible and individualized in each treatment
Conclusions of This Research:
- "Outpatient aggressive therapy of
refractory headaches and Migraines with IV therapies is highly efficacious
with a very low need for re-treatment.
- Our series successfully treated refractory
Migraine and other headaches 97.5% of the time [852 of 874 patients].
- Treatment in this manner contributes
tremendously to productivity, most importantly in the workplace, at home and
in personal life for the Migraine sufferer.
- We would urge headache specialists and
physicians interested in the acute management of headache disorders to
explore these options in their practices.*"
It's difficult to add much to the conclusions Dr. Krusz and his colleagues
themselves have drawn from this research. The very aptly point out that
aggressive outpatient therapy of refractory headaches and Migraine with IV
therapy is highly efficacious. To that, I would add that it's also highly
desirable as such treatment in the clinic setting is achieved far more quickly
and with far more dignity than in an emergency room setting. Hopefully, this
research will lead to more doctors adopting this type of therapy for their
To view a copy of the full poster
presentation of this study presented to the annual conference of the European
Federation of Neurologic Societies, please
click HERE (Adobe
Acrobat Reader required).
* Scott-Krusz, Virginia; Belanger,
Jeanne, RN; Cagle, Jane, LVN; Krusz, John Claude, PhD, MD. "Effectiveness
of IV Therapy in the Headache Clinic for Refractory Migraines." Poster
presentation to the annual conference of the European Federation of Neurologic
Societies; Athens, Greece. September,
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