Greek Researchers Investigate Octreotide

In 2007,  researchers at Athens General Hospital in Greece published the results of a clinical study in which 26 patients with idiopathic intracranial hypertension (IIH) were treated with octreotide, a synthetic hormone that is sometimes used in the treatment of tumors and in certain endocrine disorders. This was an expansion of an earlier study from 1993.

What Is Octreotide? How Does It Work?
Octreotide is a man-made version of a natural hormone called somatostatin. It is a long-acting, complex protein known as an octapeptide. For a substance like octreotide to have the same effects of the hormone it is mimicking, it must be able to attach to special sites on certain cells called receptor sites. Octreotide has a strong affinity for the usual somatostatin receptor sites.

Once attached to these receptors, octreotide produces pharmacological actions that mirror somatostatin’s effects. Octreotide and natural somatostatin inhibit insulin secretion to a similar degree. Octreotide, like somatostatin, also suppresses the release of gastrointestinal peptide hormones, including serotonin, gastrin, vasoactive intestinal peptide (VIP), secretin, motilin, and pancreatic polypeptide, all of which have vital gastrointestinal functions.

In some cases, octreotide is even more potent than somatostatin. For example, it has stronger inhibitory power in blocking secretion of growth hormone and glucagons—a substance that causes blood sugar to rapidly rise—than somatostatin.

There are other differences between octreotide and somatostatin. Octreotide also has a longer duration of action than somatosatin. Because of this pharmacological distinction, octreotide is used to treat various endocrinological disorders and certain gastrointestinal, colorectal and pancreatic tumors;  it is usually administered by subcutaneous injection, two or three times daily.
Octreotide is also widely recognized as an effective treatment for acromegaly—a disorder of excess body growth from excessive growth hormone secreted by a pituitary tumor.

The 2007 Study
In the study, the researchers recognized that the origin or pathophysiology of idiopathic IH is unknown. But they believe that growth
hormone plays a role, in some way. As evidence, they offer the established fact that children treated with recombinant growth hormone often develop intracranial hypertension. (Editor’s note: When growth hormone is discontinued, the intracranial hypertension usually disappears.)

They also point to presumptive evidence that in acromegaly, in which high levels of growth hormone are present, using octreotide—which inhibits the production of growth hormone—reduced the severe, chronic headaches associated with acromegaly. And they stated that, in a previous study published in 1993, 3 patients with IIH responded well to octreotide treatment.

Study Design
The authors’ plan was to expand the original study to include a larger number of patients with longer follow-up. They recruited 26 patients who met the study requirements, with the signs and symptoms of intracranial hypertension. Their inclusion criteria were:

1. Unilateral or bilateral papilledema (swollen optic nerves).
2. CSF pressures greater than 200mm H2O.
3. Normal composition of cerebrospinal fluid (CSF) (i.e. normal lab tests of CSF).
4. Absence of enlarged ventricles (indicating hydrocephalus) or an intracranial mass in brain MRI study.
5. Absence of focal neurological signs. (No neurological findings that are characteristic of specific neurological
diseases.)

Twenty-six patients were selected for the study; twenty-three were female and 3 were male. The mean age was 27.5 +/-5.1 years. Eighteen of the 26 patients were overweight (Body Mass Index (BMI) >25), mean BMI was 26.65 +/– 2.25. All patients reported headache and all had papilledema.

The study protocol required that eye examinations be performed on all 26 patients and this included the examination of visual acuity, visual fields, as well as fluoroangiography (photography of the retinal blood vessels and the optic nerve). All patients had a spinal tap in the lateral decubitus position (lying on one’s side) to determine the opening pressure prior to treatment.

Patients received subcutaneous injection of .3mg. of octreotide each day. This initial dose was increased every third day by 0.1mg. until the headache was relieved or until maximum dose of 1 mg. a day was reached. This dose was continued for six to eight months. After this period, the dosage was gradually decreased. The mean duration of treatment was 42 weeks.(The treatment range ran 5 -130 weeks.)

Patients were then examined every month, including eye exams, for the next three years. They checked the opening pressure readings (spinal taps) at the end of the first month.

Results
The authors reported that 24 of the 26 patients (92%) were significantly improved. Two patients did not have any improvement, and after 15 weeks of octreotide treatment, it was stopped. In 24 patients, headache was relieved within 10 days (median: 7 days) and papilledema subsided in all of these patients within the time period of 35 to 68 days, (median: 45 days). Th e 24 patients have remained free of signs and symptoms of intracranial hypertension for three years after cessation of octreotide treatment.

In the 26 patients, the pre-treatment mean opening pressure was 34 +/–12.5cm H2O (range: 21 to 66). After treatment, the mean CSF pressure was 14.82 +/– 4.52cm (range: 8 to 23). Th is represented, a mean pressure drop of 20.72+/–10.7cm H2O (2 to 48).
Adverse side-effects included nausea (5 patients) and diarrhea (4 patients). The symptoms were mild and did not required interruption of treatment.

Analysis Of The Study
While these initial results are impressive and encouraging, the standard, unbiased evaluation of any treatment requires,
as the researchers themselves have duly noted, a double-blind study. In this type of study, patients are given either the drug to be tested or a placebo on a random basis. Neither the patient nor the researcher knows whether the drug or the placebo was given to any patient until the end of the study. Results are often tabulated by a third party to determine if there is a significant difference in outcome between drug and non-drug treatment.

A double-blind study could also compare present treatment, such as weight reduction or weight reduction plus Diamox (acetazolamide) therapy or medical therapy alone. It’s also important to note that long, asymptomatic remissions have been described in cases of idiopathic IH, as the result of weight loss alone.

It is not clear how the study’s authors determined the duration of treatment. Patients are described as being treated with up to1mg. per day for six to eight months, although neither the number of daily injections nor the amount of octreotride required in each patient to produce the desired results are described in the study results. All 24 patients who responded to octreotide treatment were free of headache by 10 days and had their papilledema resolved by two months. No explanation is given regarding why the patients are continued for so long thereafter on octreotide or why they were able to be symptom-free after cessation of octreotide for a follow-up period of three years.

Two advantages of a double-blind study are that durations and dosage would be applied equally to all patients.At least one (or more) of the 24 patients was treated for as long as 130 weeks (2.5 years) without explanation. Did the patient (or patients) become symptomatic if octreotide was discontinued earlier and, therefore, octreotide had to be continued?

It is also difficult to reach specific conclusions about outcomes since individual patients are not separately identified and the
severity of their disorders are not delineated. Important factors like age and weight are not identified for each patient. Since approximately 50% of children with IIH under the age of 10 spontaneously get better, it is important to know whether young children were included in the group of 24 patients.

It is hard to evaluate if weight loss played a role. Did any of the 24 patients lose significant weight while on octreotide? Was this a factor in a favorable outcome? Did any patients who may have lost weight regain it and remain asymptomatic? This question is particularly important.

It would be helpful to understand if any of the 24 patients had other important medical ailments and/or were taking other medications. Was the group previously treated for IIH? Knowing ophthalmologic details such as the initial degree of papilledema and the actual visual field findings pre- and post-treatment would be of value in assessing outcomes, too.

Although the authors describe very few and mild side effects from octreotide, the issue of whether more adverse reactions would be found in a large, well-controlled study is important. If octreotide was beneficial, would patients continue long-term injections?

Since the drug cannot be used orally, could it be delivered in some other form, such as by dermal patch or by inhalation? There are many questions to be addressed, but first and foremost, octreotide must be evaluated in a controlled, double-blind study.

What It Means For IIH Patients
Overall, given the exceptionally positive results of this paper, the authors are aware of the need for additional study, which is appropriate and warranted. If a double-blind study can confirm octreotide as clinically capable of lowering intracranial pressure, it might open new avenues of investigation into its relationship with IH and its potential use as a treatment option.

Receptors for somatostatin are found in the choroid plexus, the place in the brain where cerebrospinal fluid (CSF) is formed, and in the arachnoid granulations, where CSF exits the brain.

A very important question to ask would be whether octreotide works at both sites—suppressing production and enhancing egress (or exiting) of CSF—or if another mechanism is at work. If octretide works at the CSF exiting site, it would be the first known drug to do so. Not only would this finding advance our understanding about how CSF leaves the head, it would open the door to developing other drugs to work at this location.

*This review is based on an article that originally appeared in our In Sight newsletter in 2008.