Neurol Sci (2014) 35 (Suppl 1):S37–S39 DOI 10.1007/s10072-014-1739-z
SYMPOSIUM BOTULINUM TOXIN IN CLINICAL PRACTICE
Botulinum toxin A: a new option for treatment of chronic migraine with medication overuse Licia Grazzi • Susanna Usai
Ó Springer-Verlag Italia 2014
Abstract The application of Botulinum toxin for several pathological conditions has been largely debated in the last decades and its use has been definitively consolidated for disorders related to increased muscle tone and hyperidrosis. Botulinum neurotoxin (BoNT-A) is a potent toxin produced by an anaerobic bacterium, Clostridium botulinum, which presents several pharmacological proprieties, but also different and serious contraindications. As chronic migraine (CM) is commonly reported as a serious and debilitating condition and a big challenge from the therapeutic point of view, in the last decades, after isolated observations, BoNT-A has been applied as preventive treatment for CM patients and, after randomized and rigorous studies, it has been accepted among the most effective pharmacological treatments for these problematic patients. In the present report, a group of patients suffering from CM with medication overuse was treated with BoNTA to verify its efficacy for CM. The results confirmed the efficacy of BoNT-A when used at the dosage of 155 UI, according with the PREEMPT study protocol. Although these results are preliminary, in a limited group of patients, they led to intense efforts to enforce the use of BoNT-A for CM and to assess its clinical applicability. Keywords Onabotulinum toxin A Chronic migraine Medication overuse Clinical indexes
L. Grazzi (&) S. Usai Headache Center, C. Besta Neurological Institute and Foundation, Via Celoria 11, 20133 Milan, Italy e-mail: [email protected]
Introduction Patients suffering from chronic migraine (CM) are problematic to treat as this condition is debilitating and conditioning the affective and social life of individuals. CM affects 1.4–2.2 % of the general population [1]. These patients experience headache [15 days per month for [3 months, and often they overuse medications for aborting pain for more that 15 tablets per month (generally triptans or NSAIDS). An effective prophylactic treatment, based on pharmacological and also multidisciplinary measures, often after an adequate withdrawal from offending medications, can improve significantly the clinical condition of these patients by reducing the medication consumption [2]. Onabotulinum toxin A has been reported helpful in several pain conditions, in particular patients treated by Onabotulinum toxin A for increased motor disturbances noted a decrease in pain and consequently the use of Onabotulinum toxin A to improve pain in pain conditions including migraine has been applied [3–5]. Concerning migraine treatment, different studies with different protocols of treatment have been applied with results not always significant from the clinical point of view. Only recently, studies and the PREEMPT protocol evolved from preceding paradigms, by showing definitely that Onabotulinum toxin A is a safe, well-tolerated and effective headache prophylactic treatment for CM [6]. The mechanism of action of Onabotulinum toxin A in antinociception has not been clearly clarified yet: probably, as demonstrated in some studies, Onabotulinum toxin A inhibits the release of nociceptive mediators (glutamate, substance P, CGRP) from peripheral terminals of primary afferents [7, 8]. Blocking the release of these neurotransmitters, inhibits neurogenic inflammation and consequently the peripheral
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sensitization of nociceptive nerve fibers. As result, peripheral pain signals to the central nervous system are reduced and central sensitization is blocked [7–9]. The problem concerning treatment of patients with CM and medication overuse is challenging for physicians involved in this field and, as the significant population of CM patients refractory to common therapeutic prophylaxis, Onabotulinum toxin A can be considered a new option for these problematic patients. At our headache centre, clinical experiences evidence that treatment of CM with medication overuse need a multimodal strategy where behavioural, social and affective components have to be considered and also innovative pharmacological therapies have to be developed. On the basis of the most recent clinical experiences, with specific paradigms, Onabotulinum Toxin A has been used at our headache centre at the Besta Institute of Milan as preventive treatment to treat patients suffering from CM with medication overuse after an adequate withdrawal program. Aim of this study was to evaluate a group of patients treated with 155 UI of BoNT-A to verify its efficacy for CM with medication overuse.
Patients and procedure A group of 23 patients, 18 females and 5 males, mean age 51.1 ± 7.9 suffering from CM with medication overuse (diagnosis made according with the HIS criteria 2004 revised in 2006) [10, 11] were treated. Patients underwent to a withdrawal program in a day hospital regimen for 5 days in order to stop the overuse of symptomatic medications. After that, patients were treated by Onabotulinum toxin A injection, in multiple sites, according with the protocol proposed by the PREEMPT study [6] at the dosage of 155 UI for 31 sites. Every session of local injection (155 UI per 31 sites; 5 UI per each site) has been repeated every 3 months for a period of 1 year. Totally five injections of Onabotulinum toxin A were performed. Clinical indexes, number of medication intake per month and days of headache per month, were recorded by using an headache daily diary. Patients until now achieved the 6th month of treatment.
Results Data concerning this group of patients evidenced that days of headache/month decreased significantly during the period of treatment from the first session of therapy to the third session, 6 months later (pre 22.2 ± 6.9, post 13.8 ± 9.2,
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Neurol Sci (2014) 35 (Suppl 1):S37–S39
p \ 0.005). Also medication intake decreased significantly (pre 20 ± 6.9, post 13.7 ± 9.2, p \ 0.0005).
Discussion As CM is a serious clinical condition for patients, very disabled and at risk of medication overuse, and the moderate response to treatment, so common for this category of patients, the possibility to use new therapeutic options is crucial, also if the necessity of a multimodal treatment program, based on different kinds of therapeutic measures for these patients, has been confirmed in the last clinical experiences [2]. In the past, basic science data strongly support an analgesic effect of BoNT-A. According with these evidences, many headache clinicians have seen patients with CM who have responded significantly to BoNT-A treatment. In the past decade, data from different studies were not conclusive due to the erroneous selection of patients and to the different protocols of treatment. On the other side, the most recent clinical trials have shown more positive results as more selective criteria for inclusion of patients were used. The correct selection of patients is the key to the successful use of BoNT-A in CM management [12]. Although results of our study are preliminary, as patients were treated until the 6-month follow up, they led to intense efforts to evaluate analgesic properties of Onabotulinum toxin A and to assess its clinical applicability. Moreover, the pharmacological profile of Onabotulinum toxin A makes it a good candidate for migraine prevention at the adequate dosage as proposed in the PREEMPT study. Its long duration of action (3 months) makes it particularly attractive for patients who are not compliant with the daily use of preventive medications, or if they cannot tolerate them or when they are refractory to preventive medications. Although we did not assess it specifically, all patients accepted the treatment without referring any significant side effects or unpleasant events; moreover, they reported improvement in quality of their life as they did not assume medications every day for long period of time. In conclusion, data from recent studies show encouraging results: BoNT-A seems to be effective for patients with CM; in particular the long duration of action and favourable adverse events make it a suitable therapeutic alternative for patients not compliant with oral preventive medications. The application of BoNT-A is indicated also in the early stage of the disease and this may result in better treatment outcome. Future studies have to be performed to better understand the mechanism of action of BoNT-A and to identify possible predictors of response to this innovative treatment.
Neurol Sci (2014) 35 (Suppl 1):S37–S39 Conflict of interest I certify that there is no actual or potential conflict of interest in relation to this article.
References 1. Diener HC, Limmroth V (2004) Medication-overuse headache: a worldwide problem. Lancet Neurol 3:475–483 2. Grazzi L, Andrasik F, Usai S, Bussone G (2009) Treatment of chronic migraine with medication overuse: is drug withdrawal crucial? Neurol Sci 30(S1):85–88 3. Ranoux D, Attal N, Morain F, Bouhasira D (2008) Botulinum toxin type A induces direct analgesic effects in chronic neuropatyhic pain. Ann neurol 2008(64):274–283 4. Mathew N, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C (2005) Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache. A randomized, double blind, placebo controlled trial. Headache 45:293–307 5. Sandrini G, Perrotta A, Tassorelli C, Torelli P, Brighina F, Sances G, Nappi G (2011) Botulinum toxin type-A in the prophylaxis treatment of medication-overuse headache: a multi center, double blind, randomized, placebo-controlled, parallel group study. J Head pain 12:427–433
S39 6. Blumenfeld A, Silberstein S, Dodick D, Aurora S, Turkel C, Binder W (2010) Method of injection of Onabotulinum toxin A for chronic migraine: a safe, well-tolerated and effective treatment paradigm based on the PREEMPT clinical program. Headache 50:1406–1418 7. Aoki KR (2005) Review of a proposed mechanisms for the antinociceptive action of botulinum toxin type A. Neurotoxicology 26:785–793 8. Aoki KR (2003) Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache 43(Suppl 1):S9–S15 9. Gazerani P, Pedersen NS, Staahl C, Drewes AM, Arendt-Nielsen L (2009) Subcutaneous botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin. Pain 141:60–69 10. Headache Classification SubCommittee of the International Headache Society (2004) The international classification of headache disorders-2nd edition. Cephalalgia 24(suppl 1):1–160 11. Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, Goebel H, Lainez MJA, Lance JW, Lipton RB, Nappi G, Sakai F, Schoenen J, Silberstein SD, Steiner TJ (2006) New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 26:742–746 12. Ashkenazi A (2010) Botulinum toxin type A for chronic migraine. Curr Neurol Neurosci Rep 10:140–146
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SYMPOSIUM BOTULINUM TOXIN IN CLINICAL PRACTICE
Botulinum toxin A: a new option for treatment of chronic migraine with medication overuse Licia Grazzi • Susanna Usai
Ó Springer-Verlag Italia 2014
Abstract The application of Botulinum toxin for several pathological conditions has been largely debated in the last decades and its use has been definitively consolidated for disorders related to increased muscle tone and hyperidrosis. Botulinum neurotoxin (BoNT-A) is a potent toxin produced by an anaerobic bacterium, Clostridium botulinum, which presents several pharmacological proprieties, but also different and serious contraindications. As chronic migraine (CM) is commonly reported as a serious and debilitating condition and a big challenge from the therapeutic point of view, in the last decades, after isolated observations, BoNT-A has been applied as preventive treatment for CM patients and, after randomized and rigorous studies, it has been accepted among the most effective pharmacological treatments for these problematic patients. In the present report, a group of patients suffering from CM with medication overuse was treated with BoNTA to verify its efficacy for CM. The results confirmed the efficacy of BoNT-A when used at the dosage of 155 UI, according with the PREEMPT study protocol. Although these results are preliminary, in a limited group of patients, they led to intense efforts to enforce the use of BoNT-A for CM and to assess its clinical applicability. Keywords Onabotulinum toxin A Chronic migraine Medication overuse Clinical indexes
L. Grazzi (&) S. Usai Headache Center, C. Besta Neurological Institute and Foundation, Via Celoria 11, 20133 Milan, Italy e-mail: [email protected]
Introduction Patients suffering from chronic migraine (CM) are problematic to treat as this condition is debilitating and conditioning the affective and social life of individuals. CM affects 1.4–2.2 % of the general population [1]. These patients experience headache [15 days per month for [3 months, and often they overuse medications for aborting pain for more that 15 tablets per month (generally triptans or NSAIDS). An effective prophylactic treatment, based on pharmacological and also multidisciplinary measures, often after an adequate withdrawal from offending medications, can improve significantly the clinical condition of these patients by reducing the medication consumption [2]. Onabotulinum toxin A has been reported helpful in several pain conditions, in particular patients treated by Onabotulinum toxin A for increased motor disturbances noted a decrease in pain and consequently the use of Onabotulinum toxin A to improve pain in pain conditions including migraine has been applied [3–5]. Concerning migraine treatment, different studies with different protocols of treatment have been applied with results not always significant from the clinical point of view. Only recently, studies and the PREEMPT protocol evolved from preceding paradigms, by showing definitely that Onabotulinum toxin A is a safe, well-tolerated and effective headache prophylactic treatment for CM [6]. The mechanism of action of Onabotulinum toxin A in antinociception has not been clearly clarified yet: probably, as demonstrated in some studies, Onabotulinum toxin A inhibits the release of nociceptive mediators (glutamate, substance P, CGRP) from peripheral terminals of primary afferents [7, 8]. Blocking the release of these neurotransmitters, inhibits neurogenic inflammation and consequently the peripheral
123
S38
sensitization of nociceptive nerve fibers. As result, peripheral pain signals to the central nervous system are reduced and central sensitization is blocked [7–9]. The problem concerning treatment of patients with CM and medication overuse is challenging for physicians involved in this field and, as the significant population of CM patients refractory to common therapeutic prophylaxis, Onabotulinum toxin A can be considered a new option for these problematic patients. At our headache centre, clinical experiences evidence that treatment of CM with medication overuse need a multimodal strategy where behavioural, social and affective components have to be considered and also innovative pharmacological therapies have to be developed. On the basis of the most recent clinical experiences, with specific paradigms, Onabotulinum Toxin A has been used at our headache centre at the Besta Institute of Milan as preventive treatment to treat patients suffering from CM with medication overuse after an adequate withdrawal program. Aim of this study was to evaluate a group of patients treated with 155 UI of BoNT-A to verify its efficacy for CM with medication overuse.
Patients and procedure A group of 23 patients, 18 females and 5 males, mean age 51.1 ± 7.9 suffering from CM with medication overuse (diagnosis made according with the HIS criteria 2004 revised in 2006) [10, 11] were treated. Patients underwent to a withdrawal program in a day hospital regimen for 5 days in order to stop the overuse of symptomatic medications. After that, patients were treated by Onabotulinum toxin A injection, in multiple sites, according with the protocol proposed by the PREEMPT study [6] at the dosage of 155 UI for 31 sites. Every session of local injection (155 UI per 31 sites; 5 UI per each site) has been repeated every 3 months for a period of 1 year. Totally five injections of Onabotulinum toxin A were performed. Clinical indexes, number of medication intake per month and days of headache per month, were recorded by using an headache daily diary. Patients until now achieved the 6th month of treatment.
Results Data concerning this group of patients evidenced that days of headache/month decreased significantly during the period of treatment from the first session of therapy to the third session, 6 months later (pre 22.2 ± 6.9, post 13.8 ± 9.2,
123
Neurol Sci (2014) 35 (Suppl 1):S37–S39
p \ 0.005). Also medication intake decreased significantly (pre 20 ± 6.9, post 13.7 ± 9.2, p \ 0.0005).
Discussion As CM is a serious clinical condition for patients, very disabled and at risk of medication overuse, and the moderate response to treatment, so common for this category of patients, the possibility to use new therapeutic options is crucial, also if the necessity of a multimodal treatment program, based on different kinds of therapeutic measures for these patients, has been confirmed in the last clinical experiences [2]. In the past, basic science data strongly support an analgesic effect of BoNT-A. According with these evidences, many headache clinicians have seen patients with CM who have responded significantly to BoNT-A treatment. In the past decade, data from different studies were not conclusive due to the erroneous selection of patients and to the different protocols of treatment. On the other side, the most recent clinical trials have shown more positive results as more selective criteria for inclusion of patients were used. The correct selection of patients is the key to the successful use of BoNT-A in CM management [12]. Although results of our study are preliminary, as patients were treated until the 6-month follow up, they led to intense efforts to evaluate analgesic properties of Onabotulinum toxin A and to assess its clinical applicability. Moreover, the pharmacological profile of Onabotulinum toxin A makes it a good candidate for migraine prevention at the adequate dosage as proposed in the PREEMPT study. Its long duration of action (3 months) makes it particularly attractive for patients who are not compliant with the daily use of preventive medications, or if they cannot tolerate them or when they are refractory to preventive medications. Although we did not assess it specifically, all patients accepted the treatment without referring any significant side effects or unpleasant events; moreover, they reported improvement in quality of their life as they did not assume medications every day for long period of time. In conclusion, data from recent studies show encouraging results: BoNT-A seems to be effective for patients with CM; in particular the long duration of action and favourable adverse events make it a suitable therapeutic alternative for patients not compliant with oral preventive medications. The application of BoNT-A is indicated also in the early stage of the disease and this may result in better treatment outcome. Future studies have to be performed to better understand the mechanism of action of BoNT-A and to identify possible predictors of response to this innovative treatment.
Neurol Sci (2014) 35 (Suppl 1):S37–S39 Conflict of interest I certify that there is no actual or potential conflict of interest in relation to this article.
References 1. Diener HC, Limmroth V (2004) Medication-overuse headache: a worldwide problem. Lancet Neurol 3:475–483 2. Grazzi L, Andrasik F, Usai S, Bussone G (2009) Treatment of chronic migraine with medication overuse: is drug withdrawal crucial? Neurol Sci 30(S1):85–88 3. Ranoux D, Attal N, Morain F, Bouhasira D (2008) Botulinum toxin type A induces direct analgesic effects in chronic neuropatyhic pain. Ann neurol 2008(64):274–283 4. Mathew N, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C (2005) Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache. A randomized, double blind, placebo controlled trial. Headache 45:293–307 5. Sandrini G, Perrotta A, Tassorelli C, Torelli P, Brighina F, Sances G, Nappi G (2011) Botulinum toxin type-A in the prophylaxis treatment of medication-overuse headache: a multi center, double blind, randomized, placebo-controlled, parallel group study. J Head pain 12:427–433
S39 6. Blumenfeld A, Silberstein S, Dodick D, Aurora S, Turkel C, Binder W (2010) Method of injection of Onabotulinum toxin A for chronic migraine: a safe, well-tolerated and effective treatment paradigm based on the PREEMPT clinical program. Headache 50:1406–1418 7. Aoki KR (2005) Review of a proposed mechanisms for the antinociceptive action of botulinum toxin type A. Neurotoxicology 26:785–793 8. Aoki KR (2003) Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache 43(Suppl 1):S9–S15 9. Gazerani P, Pedersen NS, Staahl C, Drewes AM, Arendt-Nielsen L (2009) Subcutaneous botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin. Pain 141:60–69 10. Headache Classification SubCommittee of the International Headache Society (2004) The international classification of headache disorders-2nd edition. Cephalalgia 24(suppl 1):1–160 11. Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, Goebel H, Lainez MJA, Lance JW, Lipton RB, Nappi G, Sakai F, Schoenen J, Silberstein SD, Steiner TJ (2006) New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 26:742–746 12. Ashkenazi A (2010) Botulinum toxin type A for chronic migraine. Curr Neurol Neurosci Rep 10:140–146
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