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Medical Journals - CH Medication options & limits

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Where do I get copies of Medical Papers discussing CH medications and limits? I've discussed and tried multliple expermental propholactic options with my provider with varying degrees of success over the past 25 years. Each of my CH cycles seem to be somewhat unique and can be resistent to previously successfuly treatments. I'm open to any avenue to the propholactic meds.... as long as I can manage my pain with abortive meds......what I would like to know is....where is the evidence that imitrex has any long term or rebound impact on the patient? And if there is a rebound impact, who cares? Just manage my pain until the cycle is broken and I then don't have to worry about the rebound!. My CH's started in 1984. Bless the doctor who 1st prescribed imitrex to me in 1995. This is the first year anyone has suggested rebound headaches. Before I just had to stay within my limit of 12 mg injectable per day - I cheated with mini doses of 2-3 mg. There was also a limitation per month or quarter but the neurologist would override the limit.....

So my question is.....Where is the documentation that my health is at risk? Are there long term health risks? I've been using Imitrex during my clusters since 1995 with no ill effects.  I'm in perfect health (except the CHs) at perfect weight with a perfect heart - so why can't I be allowed to manage my pain until they break my CH cycle?

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what I would like to know is....where is the evidence that imitrex has any long term or rebound impact on the patient? So my question is.....Where is the documentation that my health is at risk? Are there long term health risks?

Hello RonRutan,

Is this of any help.

By Nicholas Regush

September/October 1995 Issue (Mother Jones)

On the morning of Feb. 4, 1994, Dianne Riley joked nervously with her

husband and one of her four children about a dream she'd had the night

before in which someone had died. This wasn't a pleasant way to begin

the day, because once before Riley had actually forecast a death in

this manner.

To make matters worse, Riley had a miserable headache. For five days

running, the 41-year-old assistant manager for a Ramada Inn in Kansas

City, Mo., had felt the pain in her head build to the point where she

would be overpowered by nausea.

Later that morning, Riley had an appointment with Dr. Samuel Ho, a

specialist in internal medicine. He diagnosed migraine, a slowly

developing headache with throbbing pain that is usually felt on only

one side of the head. The condition is believed to affect between 15

and 25 million Americans, mostly women.

Ho recommended Riley try Imitrex, the brand name for sumatriptan

succinate, a heavily marketed new drug for migraines. At 12:25 p.m.,

Riley was given a six-milligram injection of the drug. Within minutes,

she began to sweat, vomit, and experience chest pains.

Technicians managed to hook her up to an electrocardiograph and

quickly discovered that she had an abnormal heart rhythm. They called


An emergency team reached Ho's clinic at 12:56 p.m., and transported

Riley to St. Luke's Northland Hospital where she arrived with

resuscitation efforts in progress. At 1:58 p.m., a doctor pronounced

Riley dead. An autopsy performed the

next day indicates Riley's cause of death was "a result of adverse

effect of Imitrex."

On April 15, two months after Dianne Riley's death, her family filed a

lawsuit in the Circuit Court of Jackson County, Mo., charging that

Glaxo, the British-based manufacturer of Imitrex, had been aware that

the drug could cause serious harm or even death. The lawsuit accuses

the multinational and its Cerenex division in North Carolina of not

adequately labeling Imitrex and not disclosing the drug's true risks,

"in order to collect substantially higher profits." Glaxo will not

comment on the lawsuit because it is under litigation. The case, still

in the legal discovery phase, is expected to go to trial sometime in


Dr. Vincent Di Maio, one of the country's leading forensic

pathologists and editor of the American Journal of Forensic Medicine

and Pathology, intends to testify on the Rileys' behalf. He says he

has examined all the microscopic slides of tissues and organs from the

Riley autopsy and has no doubt that its conclusion was correct.

Although Dianne Riley had some risk factors for heart disease (e.g.,

smoking, family history of heart disease), Di Maio says her heart and

coronary arteries were healthy; the heart attack that killed her was

precipitated by Imitrex.

"It is a very complete autopsy," Di Maio says. "This is a simple case

where a young woman took Imitrex, started to react to it badly,

developed an irregular heartbeat, and died. The autopsy shows clearly

that there was no evidence of hardening of her arteries, no evidence

of infection, no evidence of an enlarged heart, no evidence of stroke,

no evidence of meningitis or encephalitis, no evidence of a blood

clot, no evidence of lung disease, no evidence of asthma or allergic

reaction, no evidence whatsoever of disease. If there is no other

cause of death, by deductive reasoning she died of a coronary

vasospasm following the use of Imitrex."

Imitrex, a top-line Glaxo drug, is used by more than two million

people worldwide. The drug's sales in fiscal year 1993-94 were $365

million. Both of those numbers are likely to increase when the tablet

version of the drug becomes available on the U.S. prescription market

this month.

To date, the Food and Drug Administration has received 3,526 voluntary

reports of possible side effects, ranging from mild to severe,

associated with the use of Imitrex. Included are reports of 83 deaths

and at least 273 life-threatening complications.

Earlier this year, Glaxo became the world's largest pharmaceutical

company when it bought Wellcome, another British multinational. Glaxo

and Wellcome sold a combined $11.6 billion worth of products last

year, to fight everything from asthma and ulcers to heart disorders,

infections, and migraines.

In the high-stakes pursuit of competitive advantage, drug giants like

Glaxo must sometimes spend hundreds of millions of dollars to develop

new drugs. To see returns on these investments, companies push hard to

get the drugs through the regulatory approval process and promote them

vigorously when they are first released. Glaxo's push of Imitrex was

no exception.

The history of Imitrex goes all the way back to 1972, when Glaxo

launched a research program to develop a new migraine drug. The

company's goal was to find a chemical that could narrow swollen blood

vessels in the head, thereby stopping the pain of migraine headaches.

But it was also important that the drug not narrow or squeeze blood

vessels in the heart, because this could cause spasm in those vessels

and trigger a heart attack.

More than a decade passed before Glaxo scientists came up with

Imitrex. The drug mimicked serotonin, a chemical produced naturally in

the body. Serotonin contracts blood vessels by acting on their cells

via the gateways or "receptors" known as 5HT. Glaxo researchers

thought that Imitrex would affect only the type of 5HT receptor known

as 5HT-1, which they believed was rarely found in heart vessels, and

therefore the drug would not cause heart spasm.

Glaxo believed it had a blockbuster drug in the making, one with a

potential market of hundreds of millions of dollars.

Looking back, however, some fundamental research data contradicted the

presumption that 5HT-1 receptors were generally absent from heart

vessels. In one small laboratory study, Glaxo researchers found that

Imitrex caused small contractions in coronary artery samples from

explanted human hearts, indicating the presence of 5HT-1 receptors in

heart vessels. An independent study also supported this hypothesis by

demonstrating that Imitrex could cause temporary narrowing in the

coronary arteries of patients with or without signs of heart disease.

Glaxo, however, emphasized other research that supported Imitrex's

safety. Specifically, one Glaxo study showed that Imitrex did not

affect the cardiovascular systems of dogs, indicating that 5HT-1

receptors were not present in the dogs' heart vessels and suggesting

that this might be true for human beings as well. The company also

assured regulatory agencies that the drug was safe because its

heart-monitoring tests during clinical trials showed that very few

patients suffered heart disturbances.

Strong indications that these assurances were hollow first surfaced in


On Dec. 20, 1991, Dr. Michele Brill-Edwards, then the assistant

director of the Bureau of Human Prescription Drugs at Health and

Welfare Canada, wrote a memo to the bureau's assistant director of

operations, Peter Jeffs, expressing her suspicion that Glaxo was

pressuring one of her reviewers to move faster on getting approval for


After Brill-Edwards reviewed the file herself, she believed that there

were potential problems with Imitrex. She was particularly concerned

that Glaxo had only thin documentation to show that Imitrex was not a

danger to heart vessels.

Brill-Edwards also wondered about Imitrex's recommended dosage of six

milligrams. Glaxo studies had shown that a one-milligram dose was

enough for some patients and three milligrams worked for up to 60

percent of patients. Only an additional 10 to 20 percent benefited

from the six-milligram dose. Yet contrary to standard medical

practice, which recommends tailoring dosage to a patient's needs,

Glaxo recommended six milligrams for everyone. (A Glaxo spokesperson

told Mother Jones that the company chose the six-milligram dose as

"the best balance between efficacy and safety.")

For more than two weeks, Brill-Edwards (who is under orders not to

discuss Imitrex with the media) raised concerns within her bureau

about Imitrex's safety, and questioned Glaxo's efforts to expedite the

drug's approval. In a Jan. 7, 1992 memo, she described the situation

to her boss, Dr. Claire Franklin, then the director of the Bureau of

Human Prescription Drugs:

At 5:15 p.m. [Jan. 6], Ms. Gita Lingam, [then the] head of regulatory

affairs for Glaxo, telephoned.a Threatening remarks were made

courteously. Ms. Lingam noted that Mr. Randall Chase [then a senior vice president of Glaxo Canada] intends to take the matter "to a

higher level" if there are further delays. Legal action was


[T]he product monograph remains less than adequate in its

characterization of safe usage of this valuable new product. My

recommendation is that the clinical division should be required to

remedy the deficiencies in the product monograph.--This action should

be undertaken notwithstanding substantial pressure to the contrary

from the manufacturer.

The deficiencies in the monograph were not remedied. On Jan. 16, 1992,

nine days after Brill-Edwards wrote her memo, Glaxo announced that it

would construct a $70 million manufacturing facility in Canada,

promising more jobs and research spending.

Four days later, on Jan. 20, senior managers at Health and Welfare

Canada approved Imitrex.

The next month, when Glaxo launched its promotional campaign for

Imitrex in Canada, it claimed the drug "works only on the painfully

swollen blood vessels in the head." The labeling for Imitrex, however,

recommended that people with serious heart problems shouldn't be

prescribed the drug, indicating that Glaxo was, in fact, aware of its

potential effect on heart vessels.

But when reports began to file in at Health and Welfare about side

effects following an injection of Imitrex, Glaxo officials took the

public position that these reactions were rare and unexplainable. As

of July 1992, Health and Welfare had received only 20 voluntary

reports of adverse side effects associated with the use of Imitrex,

including severe chest pain and breathing difficulties. But by

November, an additional 70 reports had been filed, again including

chest symptoms. That month, Health and Welfare and Glaxo quietly

cooperated in rewording the product labeling. The new labeling advised

doctors to take a careful medical history to avoid prescribing Imitrex

to anyone with heart disease.

Meanwhile, in Britain (where Imitrex had been available since 1991), a

new chapter in the drug's story had begun. A case report was published

in May of 1992 in the British Medical Journal concerning a 47-year-old

man with no sign of heart disease who developed severe chest pain

after injections of Imitrex. Further tests with the patient showed

that within six minutes of receiving a shot, his heart vessels began

constricting. A month after this case was reported, the U.K. Committee

on Safety of Medicines, Britain's drug regulatory group, reported that

Imitrex could cause heart vessels to constrict.

Glaxo, however, continued to maintain that severe side effects were

rare, and that those patients who suffered heart-related complications

must have had some underlying heart problem.

In the United States, the FDA had the advantage of looking at several

months' worth of cases of side effects associated with Imitrex in

Canada, Britain, and the Netherlands before deciding whether to

approve the drug for the American market. Dr. Paul Leber, chief of the

FDA's Division of Neuropharmacological Drug Products, clearly

struggled with the decision. In an August 1992 memo to Dr. Robert

Temple, director of one of the FDA's three Offices for Drug

Evaluations, Leber questioned the value of Imitrex, writing that its

benefit was difficult to determine because of the absence of compariso

ns with alternative treatments (such as painkillers, anti-inflammatory

drugs, narcotics, and medications derived from a common fungus). "It

is particularly difficult to get a clear view," Leber wrote, "because

the product has been promoted worldwide with considerable vigor.

Indeed, one expert has privately communicated his belief that the

utility and advantages of Imitrex have been considerably inflated."

Four months later, with Imitrex on the verge of approval, Leber voiced

deep concerns about the drug's safety, particularly for patients who

might have undiagnosed heart conditions. In another memo to Temple,

dated Dec. 28, 1992, Leber wrote that if the drug is "widely used once

marketed, a sizable number of patients with significant, but

unrecognized, coronary vessel disease will be inadvertently exposed.a

If this occurs, it is probable, if not certain, that some of these

individuals will suffer serious harm, even death, following their use

of Imitrex injection. In fact, postmarketing reports from countries in

which Imitrex is available indicate that such events have already


But despite this danger, Leber didn't want to stop FDA approval of

Imitrex. "What counts more?" he wrote. "The rights of millions of

otherwise healthy migraineurs to have access to an effective and, for

them, safe treatment, or the rights of those who may be inadvertently

injured by its marketing?--If there are to be potent drugs like

[imitrex]--society must be willing to tolerate the injury they will

cause to some proportion of those who use them."

The FDA approved Imitrex for sale the next day.

As part of its Imitrex information package to the press, the FDA

stated that "people with underlying heart disease should not take the

drug because of its potential to cause constriction of coronary

arteries." As a precautionary measure, the agency also recommended

that doctors consider giving the first injection in their office to

patients who might have underlying coronary heart disease.

But the drug's labeling included no recommendation to doctors to

exclude patients whom they only suspected could be at risk for

underlying heart disease. And there was no recommendation for how to

treat patients who seemed to be suffering a negative reaction.

Imitrex's reputation as a breakthrough migraine treatment was largely

made in the initial burst of promotion upon its release. It wasn't

until August 1994a20 months after the drug's approval--that the FDA

and Glaxo cooperated in making the first significant labeling change

for Imitrex. By this time, the number of reported deaths possibly

related to Imitrex had grown to at least 33. A new section was added

to the Imitrex label. Titled "Drug-Associated Fatalities," it

discloses that some of the reported deaths had occurred within a few

hours of Imitrex's use and that the drug's "specific contribution--to

most of these deaths cannot be determined." The death of Dianne Riley

is noted, though not by name, among them. (The notation, however, does

not mention that Riley's autopsy showed her to be free of heart

disease. Instead, it lists her risk factors for heart

disease--"positive family history, postmenopausal woman, and

smoking"--implying that she might have had heart disease.) The FDA

also asked Glaxo to send out what is known as a "Dear Doctor" letter,

to inform physicians of the labeling change.

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Each of my CH cycles seem to be somewhat unique and can be resistent to previously successfuly treatments.

This is fairly typical.

what I would like to know is....where is the evidence that imitrex has any long term or rebound impact on the patient?

There are a couple studies out there that show this to be the case. I'll try to dig them out unless someone beats me to it.

And if there is a rebound impact, who cares? Just manage my pain until the cycle is broken and I then don't have to worry about the rebound!.

The reason it is an issue is because many people report increased frequency of attacks and extension of their cycles, that occurred after beginning Imitrex.

Did you keep any records/headache diaries from the early years of your cycles?

Everyone doesn't experience this rebound effect but many report that the cycles that used to last 6 weeks with 2 attacks per day, are now in cycles that last 3 months with 4 or 5 attacks per day...(examples only)

My CH's started in 1984. Bless the doctor who 1st prescribed imitrex to me in 1995. This is the first year anyone has suggested rebound headaches.

That's because for years, there were no studies proving the rebound effect. Not surprisingly, most headache research is funded by pharmaceutical companies. Just about all of which today offer one form or another of triptans like Imitrex.

so why can't I be allowed to manage my pain until they break my CH cycle?

Who is telling you that you can't?


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As an ex meds junkie due to CH, from experience I can tell you that Imitrex gives rebound headaches and causes CH periods to be longer, more frequent and more intense.

But don't take my word for it.  Try it yourself and after years of more intense and frequent attacks then come back for help... if you didn't suffer a heart attack in the meantime?

This site will still be here to help you and any other people who know when it is time.

Good luck on your ventures

Hope to see you and be of help


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There are a couple studies out there that show this to be the case. I'll try to dig them out unless someone beats me to it.

Headache. 2000 Jan;40(1):41-4.

Alteration in nature of cluster headache during subcutaneous administration of sumatriptan.

Hering-Hanit R.

Headache Unit, Department of Neurology, Meir General Hospital, Kfar Sava, and the Sackler Faculty of Medicine, Tel Aviv University, Israel.

OBJECTIVES: To document the relationship between the 5-HT receptor agonist sumatriptan and a change in the nature of cluster headache in four cases. To relate the findings to the literature on the use of sumatriptan in both cluster headache and migraine.

BACKGROUND: Studies of the efficacy and adverse effects of long-term treatment with

sumatriptan in cluster headache are limited and report conflicting findings.

METHODS: Four cases are described.

RESULTS: All four patients developed a marked increase in the frequency of attacks 3 to 4 weeks after initiating treatment with the drug for the first time. Three patients also developed a change in headache character, and 2 experienced prolongation of the cluster headache period. Withdrawal of the drug reduced the frequency of headaches and eliminated the newly developed type of headache.

CONCLUSIONS: Determination of the effects of long-term use of sumatriptan will result in more precise guidelines for the frequency and duration of treatment with this otherwise extremely beneficial drug.

And more recently Â…

Headache: The Journal of Head and Face Pain

Volume 44 Issue 7 Page 713 - July 2004


Brief Communication

Subcutaneous Sumatriptan Induces Changes in Frequency Pattern in Cluster Headache Patients

Paolo Rossi, MD, PhD; Giorgio Di Lorenzo, MD; Rita Formisano, MD,

PhD; M. Gabriella Buzzi, MD, PhD


To document the relationship between the use of  subcutaneous (SQ) sumatriptan (sum) and a change in frequency pattern of cluster headache (CH) in six patients. To discuss the clinical and pathophysiological implications of this observation in the context of available literature.


Treatment with SQ sum may cause an increase in attack frequency of CH but data from literature are scant and controversial.


Six CH sum-naïve patients (three episodic and three chronic according to the International Headache Society (IHS) criteria) are described.


All six patients had very fast relief from pain and accompanying symptoms from the drug but they developed an increase in attack frequency soon after using SQ sum. In all patients, the CH returned to its usual frequency within a few days after SQ sum was withdrawn or replaced with other drugs. Five patients were not taking any prophylactic treatment and SQ sum was the only drug prescribed to treat their headache.


Physicians should recognize the possibility that treatment of CH with SQ sum may be associated with an increased frequency of headache attacks.

And this study (albeit French and retrospective – and I love the translation of primary to primitive!):

Does repeated subcutaneous administration of sumatriptan produce an unfavorable evolution in cluster headache?

Virginie Dousset1 , Virginie Chrysostome1, Bruno Ruiz1, S. Irachabal1, Magalie Lafittau1, Françoise Radat1, Bruno Brochet1 and Patrick Henry1

(1)  Chronic Pain Treatment Center, Federation of Clinical Neurosciences, Pellegrin Hospital, Place Amélie Raba Léon, 33076 Bordeaux Cedex, France

Received: 11 September 2003  Accepted: 10 February 2004 


Cluster headache (CH) is one of the most painful primitive headaches that exists. Since 1991, the subcutaneous administration of sumatriptan (SCS) in the treatment of acute attacks has proved to be rapid and effective. Moreover, SCS has an excellent safety-efficacy ratio. To date, there is no information on the modalities of SCS use by CH patients, and on its possible overuse. In fact, some patients have noticed that the use of this drug on a regular basis modifies the evolution of attacks. We retrospectively studied, in 67 patients admitted for CH, the modalities of self-administering SCS the subjective feeling of medication overuse and its repercussions on attacks. A total of 47 patients used exclusively SCS as an acute treatment, 30 of whom had used more than two injections daily. Four patients whose use of SCS was the highest had also been drug addicts. Twenty-two patients using exclusively SCS thought that sumatriptan could have modified the evolution of attacks: 20 patients thought that the attacks occurred more frequently; 11 commented that the attacks became more intense, and the remaining 11 patients stated that sumatriptan had become less efficient. In CH, overuse of sumatriptan could aggravate the evolution of attacks. Further research is needed to corroborate this argument.


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