Chronic Migraine with Medication Overuse and OnabotulinumtoxinA: Two Positive Case Reports of a Modified Injection Protocol

This correspondence proposes a modified injection protocol for OnabotulinumtoxinA (BoNT-A) in chronic migraine, whenever first time treated patients experience local adverse events but good clinical response. BoNT-A is approved as a prophylactic treatment for chronic migraine with/without medication overuse; its safety and efficacy were evaluated in the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) study, which established the optimal total dose to maximize efficacy and tolerability between 150 UI and 200 UI.1 Treatment is usually safe and well tolerated; the most frequent adverse event is muscular weakness. Ptosis, local pain, paresthesia/hypoesthesia, erythema, ecchymosis are common; tearing and photophobia are less common. The exact mechanism of BoNT-A in pain control is still debated; according to the leading hypothesis, it inhibits the release of neurotransmitters from peripheral nociceptors blocking sensitization of painconducting nerve fibers and reducing peripheral pain signals to the central nervous system (CNS); moreover, a recent preclinical study suggested the role of BoNT-A in the processing of mechanical pain by selective inhibition of trigeminal meningeal nociceptors (C-fibers).2 However, the pre-clinical observation that BoNT-A can reduce secondary mechanical hyperalgesia not only on the injection side but also on the contralateral side,3 supports a possible additional central mechanism that could contribute to BoNT-A efficacy.We report two cases of patients, treated for the first time with BoNT-A for chronic migraine following the standard procedure, who experienced tearing and bilateral photophobia. Both patients were female (51- and 54-year-old, respectively), with a diagnosis of chronic migraine according to International Classification of Headache Disorders (ICHD-III); they reported medication overuse and met clinical criteria for refractory migraine, since more than two classes of first-line prophylactic drugs (beta-blockers,antiepileptics, and antidepressants) resulted ineffective and poorly tolerated.4 In both cases pain was olecranic. The first injection with BoNT-A was practiced following the standard procedure (155 UI, 31 fixed injection sites: 7 anterior injections – which include 4 sites in the frontalis muscle, 2 in the corrugator muscle and 1 in the procerus muscle – and, for each side, 4 injections into the temporalis muscle, 3 into the occipitalis muscle, 2 into cervical paraspinal muscles, 3 into trapezius muscle). No periprocedural adverse events were reported. A few days after injections, both patients complained of bilateral tearing and severe photophobia. Relevant ophthalmic pathologies were ruled out with specialized consulting. Symptoms progressively improved with complete remission within a month. Despite side effects, dramatic reduction in the mean number of headache-days per month (Patient 1: from 30 to 8-10 days; Patient 2: from 30 to 4-5 days) was noticed in both cases, and associated improvement in pain intensity was reported; medication overuse ceased. We decided to practice a second treatment with BoNT-A, modifying the injection protocol to avoid side effects. No injections were performed on frontalis, corrugator, and procerus muscles; cervical injection points remained unchanged whereas the number of remaining sites was increased as follows: 10 (5 right15 left) injection sites into temporal muscles, 8 (4 right14 left) into occipital muscles, and 10 (5 right15 left) into trapezius muscles. The points of injection were all those specified by both the standard and “follow the pain” protocols, avoiding the anterior approach. After the procedure no adverse events were reported and the clinical benefit was confirmed; further treatments were performed with similar results. The prolonged positive effect (1 year followup) observed in both patients suggests that a different approach with selected sites of injection of BoNT-A may be equally effective if adequate dose of neurotoxin is used (32 sites, 160 UI). Our alternative protocol, if validated by further reports, could be considered in patients with moderate to severe local adverse events related to anterior injections, reporting remarkable clinical improvement. This observation in patients with olecranic pain reinforces the hypotesis of a central action of BoNT-A, possibly by its retrograde axonal transport from the nerve trunk to CNS.