Long-Term Improvement in Refractory Headache Following Ozone Therapy Bernardino Clavo, MD, PhD, 1,2,3 Norberto Santana-Rodriguez, MD, PhD, 2 Dominga Gutierrez, RN, 2,3 Juan C. Lopez, MD, 4 Gerardo Suarez, RN, 2,3 Laura Lopez, RN, 2,3 Francisco Robaina, MD, PhD, 1 and Velio Bocci, MD, PhD 5 Abstract Background: Headache afflicts approximately 10%–15% of the general population. Mixed results are obtained from various therapies, usually drugs, but also oxygen inhalation, behavioral psychology, physical therapy, and peripheral or central neurostimulation. When refractory to treatment, it has severe impact on quality of life. Objectives/subjects: Five (5) patients are presented who had suffered from severe/persistent headache refrac- tory to standard management (including 5-HT 1 agonist triptan drugs) and were treated with ozone therapy. Interventions: Ozone administration was by major autohemotherapy. The procedure involved venous blood drawn into a sterile single-use glass bottle containing anticoagulant, gently mixed with an equal volume of O 3 / O 2 gas mixture (prefiltered through a sterile 0.20-lm filter) and slowly reinfused back into the donor patient via the antecubital vein. Outcome measures: The analyzed parameters were analgesia requirements, days of sick leave due to headache, number of headache events, and pain intensity according to the visual analogue scale (VAS); these recorded at three time points: pre-ozone therapy, post-ozone therapy, and before the last follow-up (mean: 64.6 – 36.8 months). Results: The number of headache episodes pretreatment (n = 80; range 5–200) was significantly decreased during the first 6 months post-treatment (n = 0, range 0–1; p = 0.042) and over the 6 months before the last follow-up visit (n = 1, range 0–2; p = 0.043). The corresponding VAS scores were 8.7 – 0.8 pretreatment versus 1.1 – 2.5 the 6 months post-treatment ( p = 0.003) and versus 3.1 – 3.3 the 6 months before last follow-up visit ( p = 0.036). Conclusions: Ozone therapy decreased headache episodes and pain severity over a protracted period. This novel approach is effective and merits further research. Introduction H eadache afflicts approximately 10%–15% of the general population. Migraine is a frequent type of pri- mary headache. When chronic or severe, headache has high social impact related to direct and indirect financial costs (sick leave and loss of productivity) and is associated with de- creased quality of life. 1 Concerning pathophysiological ex- planations of migraine, several authors have suggested that migraine results from a spreading depression of cortical electrical activity with an increased blood flow and activation of trigeminal meningeal afferents. Brainstem dysfunction, or alterations in the neurotransmitter systems, may also be a relevant factor in the evolution of a migraine. 2,3 Other studies have presented data indicating that migraine is a genetically transmitted syndrome. 4 Several treatments have shown ben- efit in the relief of pain, but the benefits that accrue and the reduced frequency of attack are often not very substantial. Hence, prevention strategies are important components of therapy aimed at reducing the attack frequency and severity. Several drugs have been evaluated for use in the treatment (or prevention) of headache 2,3 as well as nonpharmacological treatments, 5–7 all with varying degrees of success. The use of ozonated major autohemotherapy (m-AHT) in headache has not been thoroughly investigated, to date. However, the increasing use of ozone therapy in different pain syndromes has been supported by a recent meta- analysis in disc herniation. 8 In 1997, ozone therapy was 1 Chronic Pain Unit, 2 Research Unit, 3 Departments of Radiation Oncology and 4 Neurology of the Dr. Negrin University Hospital, Las Palmas, Spain. 5 Department of Physiology, University of Siena, Siena, Italy. THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 19, Number 5, 2013, pp. 453–458 ª Mary Ann Liebert, Inc. DOI: 10.1089/acm.2012.0273 453