Too 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.

Abstract:

"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.*"

Rationale:
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.

Method:
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 well.

• A room for cervical and lumbar traction, a fluoroscopy room and an EEG room that can be used for IV treatments.

• Some of these rooms already have easy chairs in them.

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 individually.

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 paradigm.*"

Conclusions of This Research:

1. "Outpatient aggressive therapy of refractory headaches and Migraines with IV therapies is highly efficacious with a very low need for re-treatment.
2. Our series successfully treated refractory Migraine and other headaches 97.5% of the time [852 of 874 patients].
3. Treatment in this manner contributes tremendously to productivity, most importantly in the workplace, at home and in personal life for the Migraine sufferer.
4. We would urge headache specialists and physicians interested in the acute management of headache disorders to explore these options in their practices.*"

Summary:
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 patients.

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).

Resources:

* 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, 2005.

© Teri Robert