Abstract
Dear Sir
In early 1993 we observed that octreotide (a synthetic analogue of somatostatin) caused a remission of headache in three patients suffering from idiopathic intracranial hypertension (IIH). Three years later, in an open-label study, we showed that in IIH octreotide lowers intracranial pressure (ICP), improves headache and reverses visual field defects (1). Here we discuss the molecular underpinnings of the effects of octreotide in IIH, migraine and cluster headache (CH) and we lay out questions that remain to be answered, focusing on IIH.
Octreotide is a potent inhibitor of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), while it downregulates serotonin, gastrin, vasoactive intestinal peptide (VIP) and substance P (SP). It is currently approved for the treatment of acromegaly, carcinoid tumours and VIP-secreting tumours.
These effects are mediated by somatostatin receptors subtype 2 (SSTR2s), which the drug binds with high affinity. The observation that their density is increased at central nervous system (CNS) areas related to cranial nociception prompted researchers to investigate its use in migraine and CH (2). In migraine, a single 100 µg subcutaneous dose did not improve response rate over placebo (3), while in CH the same dose induced a significant improvement (2). Among the many downstream effects of SSTR2 inhibition, suppression of VIP is more relevant to CH and could explain these different outcomes; VIP increases during both migraine and CH attacks (4). However, in migraine exogenous VIP causes cephalic vasodilation without provoking attacks (4), while in CH its elevation is related to hypothalamic dysfunction, which is pathogenic of this disorder (5).
The remission of IIH-induced headache caused by octreotide, on the other hand, cannot be a result of VIP suppression, since VIP levels are low, when ICP is elevated, and increase parallel to clinical improvement after shunt operations. Here, reduction of ICP seems to be the main mechanism of action. Indeed, in our IIH trial, ICP decreased significantly post treatment (p < 0.001; mean reduction 20.72 ± 10.7 cmH2O). Headache and papilloedema subsided in 24 of 26 patients (92%), while visual disturbances improved in 18 of 20 patients (90%). We administered octreotide subcutaneously, at an initial dose of 100 µg three times a day, and subsequently increased it (by 100 µg every third day) until the symptoms subsided or a maximum dose of 1000 µg/day was reached. Treatment continued at the effective dose for 6 months, and then the dose was slowly tapered, over another 2 months. In eight additional patients we used long-acting depot (LARDepot; LAR) octreotide once monthly after determining the effective dose, in an attempt to avoid daily injections. Here the overall response rate was lower (75%), which could be a result of the lower steady-state plasma concentration attained by this formulation.
How octreotide reduces ICP is not entirely clear. Somatostatin receptors (SSRs) have been detected at high densities in human choroid plexuses and arachnoid villi, a localization leading to the hypothesis that they might be related to cerebrospinal fluid (CSF) production and absorption (6). SSTR2s have also been linked to obesity, an established risk factor for IIH (6).
Octreotide was well tolerated in our study. Mild and transient nausea and diarrhoea were the most common adverse events. Elevated transaminase levels were observed in one patient, treated with the LAR formulation. Cholelithiasis and hair loss were also frequently observed in clinical trials (2).
In light of these initial results, octreotide seems to be a promising therapeutic option for IIH. Questions that remain to be answered in further clinical trials include the optimal treatment duration, the efficacy and safety of the drug in IIH patients carrying a shunt and the comparative efficacy of the different formulations.