Editorial

Bratbak and colleagues have conducted an open-label pilot study of the safety and effect of bilateral sphenopalatine injection of onabotulinum toxin A (BTA) in patients with chronic migraine (CM) (1). They present fairly impressive results with a 50% frequency reduction or more in eight out of 10 patients and only minor, mainly sensory side effects.

The authors should be congratulated for their careful characterisation of the included patients as the terms medically refractory patients or intractable patients are widely used in the existing literature without a specific definition. Ambiguous terms such as ‘hard to treat, difficult to treat, intolerant or medically intractable’ are also widely used in the literature, and our headache scientific community has to be absolutely precise and aware of the consequences of our definitions, especially when such new and invasive procedures are introduced. Furthermore, and very importantly, the authors excluded patients with overuse of acute medication. The vast majority of patients with CM also have medication-overuse headache (MOH). Labelling these CM/MOH patients as intractable or medically refractory is very unfortunate as treatment of MOH with detoxification with or without prophylaxis has an excellent outcome. Rule number one in headache management is to take the trigger away and in this case, with CM/MOH, the trigger is the medication overuse. However, 15–30% of the detoxified patients still have chronic headache, and they can be very difficult to treat with traditional preventives. Strategies such as local injection of BTA presented here certainly open new and interesting avenues that should be carefully tested in highly specialised centres, where the specific application system is mastered. As always, many more questions about consistency of effect, long-term adverse effects, mechanisms of action, and the histopathological outcome of repeated BTA in the sphenopalatine ganglion (SPG) arise. However, broadening the treatment armamentarium for CM is highly welcomed, especially if the effect and the positive side effect profile can be confirmed.

What is the functional basis of this therapeutical approach? The authors speculate that BTA may block neurotransmitter release (acetylcholine) in the SPG thereby reducing parasympathetic neurotransmission, which should lead to reduced postganglionic activity and reduced release of parasympathetic mediators like acetylcholine (Ach), vasoactive intestinal polypeptide (VIP), nitric oxide (NO) and pituitary adenylate cyclase activating peptide (PACAP) in meningeal structures. At first glance it appears reasonable that reducing pathological events like dilatation of cranial blood vessels and plasma protein extravasation induced by these mediators is responsible for the beneficial effect of BTA injection. However, none of these pathological events are likely to cause migraine attacks, and among the mediators only PACAP, which is increased in jugular blood during migraine attacks (2), has been shown to sensitise central trigeminovascular neurons in animal experiments (3) and dose-dependently provoke migraine-like headaches in migraineurs (4). The authors also state correctly that sensory fibres do not classically synapse in the sphenopalatine fossa; however, the SPG is nevertheless innervated by peptidergic trigeminal afferent fibres, possibly collaterals of meningeal afferents, forming basket-like structures around neurons and subserving intraganglionic signalling (5,6). These trigeminal fibres may uptake BTA and transport it retrogradely into the trigeminal ganglion or into meningeal endings of these afferents (7). Then the whole spectrum of mechanisms proposed for BTA seems possible, including inhibition of neuropeptide release within the ganglion and reduced trafficking of nociceptive channels and receptors (8,9).

Thus this completely new approach in migraine therapy is also very interesting from a pathophysiological point of view but, most importantly, a proper randomised controlled trial is now requested. The major obstacle to performing such a trial on a multicentre basis may be the highly sophisticated method of BTA injection with the navigation-guided application device described, the use of which may be restricted to specialised centres after instruction and training by the authors. It will be interesting to see if this invasive method, which has also just been tested with similar success in intractable chronic cluster headache (10), has the potency to become an established therapeutic alternative for CM.