Accepted Manuscript Title: Transcranial direct current stimulation (tDCS) and its influence on analgesics effectiveness in patients suffering from migraine headache Authors: Anna Przeklasa-Muszy´nska, Magdalena Kocot-K˛epska, Jan Dobrogowski, Maciej Wiatr, Joanna Mika PII: DOI: Reference:
S1734-1140(16)30461-3 http://dx.doi.org/doi:10.1016/j.pharep.2017.02.019 PHAREP 667
To appear in: Received date: Accepted date:
19-12-2016 23-2-2017
Please cite this article as: {http://dx.doi.org/ This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) AND ITS INFLUENCE ON ANALGESICS EFFECTIVENESS IN PATIENTS SUFFERING FROM MIGRAINE HEADACHE Anna Przeklasa-Muszyńska¹, Magdalena Kocot-Kępska¹, Jan Dobrogowski¹, Maciej Wiatr², Joanna Mika3 ¹Department of Pain Research and Treatment, Chair of Anesthesiology and Intensive Therapy,
Jagiellonian University Medical College, Krakow, Poland; ²Department of Otolaryngology, Jagiellonian University Medical College, Krakow, Poland; 3Institute of Pharmacology, Polish Academy of Sciences, Department of Pain Pharmacology, Krakow, Poland Anna Przeklasa-Muszyńska Magdalena Kocot-Kępska Jan Dobrogowski Maciej Wiatr Joanna Mika
email: [email protected] email: [email protected] email: [email protected] email: [email protected] email: [email protected]
Running title: tDCS in patients suffering from migraine
Acknowledgments: The study was approved by the Bioethics Committee of the Jagiellonian University in Krakow (Opinion No KBET/267/B/2013). Supported by statutory funds of the Department of Pain Research and Treatment, Chair of Anesthesiology and Intensive Therapy, Jagiellonian University Medical College, Krakow, Poland and by statutory funds of the Institute of Pharmacology Polish Academy of Sciences. Conflict of Interests: The authors declare no conflict of interests.
Corresponding authors: Anna Przeklasa-Muszyńska, MD PhD Department of Pain Research and Treatment Chair of Anesthesiology and Intensive Therapy Jagiellonian University Medical College ul. Śniadeckich 10 31-531 Kraków, Poland Email: [email protected] Joanna Mika, Prof PAS, PhD Institute of Pharmacology Polish Academy of Sciences Department of Pain Pharmacology ul. Smętna 12 31-343 Kraków, Poland Email: [email protected]
1
MIGRAINE without aura with aura
pain intensity: 9.2 5.4 NRS duration: 23 10 hours occurrence : 7 4 days triptan use: 58-59% analgesics consumption: 49-72%
% DECREASE PAIN INTENSITY
tDCS treatment in migraine diminished: 50
### ###
40 30 20 10 0
- tDCS - tDCS
Transcranial direct current stimulation (tDCS) and its influence on analgesics effectiveness in patients suffering from migraine headache
Running title: tDCS in patients suffering from migraine
Abstract: Background: Headache is one of the most common conditions troubling nearly 45% of the world’s population. Migraine headache itself, being more common among women, affects 7-18% of people. As much as 20-30% of the population report accompanying aura and neurological symptoms. In many cases, migraine headache can be effectively treated with suitably selected pharmacotherapies which include drugs used in symptomatic treatment. Frequent occurrence of the condition is treated with prophylaxis, which often fails. Neuromodulating methods are part of the multidirectional treatment and they may be valuable complement to pharmacotherapy. Methods: Our study evaluates the impact of the transcranial direct current stimulation (tDCS) on the consumption of drugs and on pain conditions (frequency, duration, intensity). We recruited 50 patients with migraine headache (30 with aura, 20 without aura) refractory to pharmacological therapy. In 30 patients (18 with aura, 12 without aura) previous unsatisfactory treatment was supplemented with tDCS performed tenfold. 20 patients (12 with aura, 8 without aura) from a control group were treated with pharmacological methods. The observation continued for 30 days after the stimulation. Results: After tDCS, a reduction in the consumption of analgesics and triptans was reported. Additionally, we monitored pain intensity decrease during pain episodes, duration of episodes and the number of pain days. The subjective assessment of pain reduction in migraine patients encompassed 36-40% after tDCS much more effective in comparison to group with only pharmacotherapy (10-12.5%). Conclusions: The study suggests that tDCS may be safe and useful clinical tool in migraine prophylaxis and treatment. Key words: Migraine headaches; Pharmacotherapy; Neurostimulation; Transcranial direct current stimulation
3
Introduction Headache is common pain conditions of the modern era and it haunts approximately 45% of the world’s population. One of the common primary headaches is migraine and its varieties. Women (13-18%) suffer from this condition more often than men (5-10%)[1]. Migraine headache can have a significant impact on the quality of everyday life. Numerous randomized controlled studies were published, which can help to determine the most effective pharmacological treatments. Simple analgesics such as paracetamol, nonsteroidal anti-inflammatory drugs, metamizol, triptans, ergotamine derivatives and combined drugs containing aspirin, paracetamol and caffeine are often used in symptomatic treatment of migraine [2,3]. Prophylactic treatment is useful in case of patients who suffer from frequent and/or severe attacks hampering their everyday functioning[2,3]. Many different pharmacological agents with different mechanisms of action were tested in randomized controlled trials and showed beneficial effects. In many cases, however, treatments (symptomatic, preventive, pharmacological, non-pharmacological) do not meet patients’ expectations due to either adverse side effects or inefficacy[1,3]. We have been facing an ongoing search for new treatment alternatives, including both pharmacological and non-pharmacological methods, which could offer assistance to this group of patients. Invasive (nerves stimulation, brain stimulation) and non-invasive stimulation methods (peripheral: transcutaneous stimulation of supraorbital nerves, and central: transcranial magnetic stimulation, transcranial direct current stimulation) are used in migraine treatment[4]. Neuromodulation serving as a therapeutic method has been known for years. Today we can find numerous publications about this form of headache treatment. Since migraine is associated with central sensitization, transcranial direct current stimulation (tDCS) is one of potential therapeutic approaches for these patients. It is a technique which can modulate pain-related neural networks and recently, it has been one of intensively studied methods [4,5,6,7,8]. Undoubted advantages of this method distinguishing it from others are: ease of use, non-invasive nature and a low risk of side effects[4]. Additionaly, tDCS has potential advantages for headache treatments since it is portable and requires relatively low cost. In 2016 Shirahige et al.[9] suggested that tDCS has moderate to high effects and could be promising non-pharmacological alternative to pain control, mainly due to the reduction of analgesic drugs intake. Moreover, the authors strongly stressed that there is a need for more controlled trials with methodological rigor, which could increase the power of result inference[9]. Therefore, the objective of our study was to examine the effect of tDCS of the motor cortex (M1) on the following issues: frequency, intensity and duration of pain attacks in migraine patients with aura and without aura, whose medical treatment had been neither effective nor satisfying, and the consumption of drugs used during the trial was additionally assessed. The results were compared to the baseline period from before the stimulation and with a control group where no stimulation was used.
4
Materials and methods Fifty women were qualified to the study from among approximately 300 patients with migraine. The selected patients had either been undergoing ineffective treatments or had been not entirely satisfied with their therapies due to adverse side effects. The total number of subjects was divided randomly into a group treated actively and a control group (12 patients with, 8 without aura) treated with pharmacological methods. The study group consisted of 30 migraine patients with and 20 without aura. After the observation, patients from the control group were also qualified for neuromodulating procedures performed at the clinic. The study group 30 patients (18 with aura, 12 without aura) underwent ten procedures of transcranial tDCS. Each patient received ten stimulations over the course of 30 days. The duration of a single active stimulation was 20 min. Before the study (30 days) and during the observation period, the patients were to keep a "patient’s pain diary" where they recorded any pain episode, its duration and medication taken. The trials were conducted in 2015-2016. Inclusion criteria: Age 18-60 Migraine headache diagnosed according to the criteria of the International Headache Society for migraine without aura and migraine with aura [10] Written informed consent to the participation in the study No contraindications to electrotherapy Previous treatments used in line with recommended protocol No history of serious general illnesses which could limit the possibility of the treatment Exclusion criteria: Incomplete diagnostics of headache Unfulfilled diagnostic criteria for migraine headaches Arrhythmia, pacemaker, epilepsy or other factors which could prevent the use of electrotherapy No previous treatment used in line with recommended protocol No consent to treatment with stimulation The volunteers qualified to the study were informed about the purposes of the study, benefits and potential side effects, and provided their written informed consent. The patients could withdraw from the study at any time.
The method Experiments carried out in the 1960s showed that when a weak direct electrical current (2mA) passed through the cortex, it resulted in a moderate change in the degree of the cortex excitability. The nature of the induced cortical change depended on the polarity of electrodes. Anodal stimulation increased the excitability level of brain under the electrode, whereas cathodal stimulation inhibited the excitability. 5
The studies with the use of functional magnetic resonance showed that anodal stimulation of the M1 with an electric current of 2mA not only activated the cortex directly under the electrode but it also spread to adjacent areas of M1 at the side of the stimulation as well as the rear part of the parietal cortex of the opposite hemisphere[11]. tDCS is one of the non-invasive methods of brain stimulation. The procedure was conducted by means of the TCT Research device, model M101-R-2012, 021/OM101R/0000583. Active electrode (anode, 35cm²) was placed over the area corresponding to the M1 of a dominant hemisphere (left in right-handed patients). The site of the electrode placement corresponded to a C3-10/20 of EEG system. Passive electrode (cathode, 35cm²) was placed over the contralateral supraorbital area[12]. The electrodes were soaked in physiological saline solution and attached to the designated places with elastic bands. Subsequently, 20-min stimulation with a 2mA current was conducted. Treatments were performed 2-3 times per week. Pain intensity was measured on a numerical rating scale (NRS) before each treatment. Stimulation were not performed during migraine attacks. The observations were conducted during and after each treatment to detect any occurrence of side effects. It was possible to terminate the procedure at any time. The efficacy of the treatment was evaluated 30 days after the last stimulation. Within month of the follow-up we evaluated the number of pain attacks (days when pain occurred), their duration (measured in hours) and a degree of pain intensity during each attack (measured on NRS). The results were compared to the control group and to the incidence, duration and intensity of attacks from the baseline pre-treatment period. We also evaluated the amount of drugs used by the patients during the observation period. The obtained data were compared to the control group and to the amount of drugs used prior to the stimulation.
Data analysis The data are presented as mean ± SEM of 4 groups (two control:migraine with aura,n=12; migraine without aura,n=8; and two tDCS:migraine with aura,n=12; migraine without aura,n=18). Inter-group differences were statistically evaluated by ANOVA Bonferroni post-hoc test. Significance is defined as *p
S1734-1140(16)30461-3 http://dx.doi.org/doi:10.1016/j.pharep.2017.02.019 PHAREP 667
To appear in: Received date: Accepted date:
19-12-2016 23-2-2017
Please cite this article as: {http://dx.doi.org/ This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) AND ITS INFLUENCE ON ANALGESICS EFFECTIVENESS IN PATIENTS SUFFERING FROM MIGRAINE HEADACHE Anna Przeklasa-Muszyńska¹, Magdalena Kocot-Kępska¹, Jan Dobrogowski¹, Maciej Wiatr², Joanna Mika3 ¹Department of Pain Research and Treatment, Chair of Anesthesiology and Intensive Therapy,
Jagiellonian University Medical College, Krakow, Poland; ²Department of Otolaryngology, Jagiellonian University Medical College, Krakow, Poland; 3Institute of Pharmacology, Polish Academy of Sciences, Department of Pain Pharmacology, Krakow, Poland Anna Przeklasa-Muszyńska Magdalena Kocot-Kępska Jan Dobrogowski Maciej Wiatr Joanna Mika
email: [email protected] email: [email protected] email: [email protected] email: [email protected] email: [email protected]
Running title: tDCS in patients suffering from migraine
Acknowledgments: The study was approved by the Bioethics Committee of the Jagiellonian University in Krakow (Opinion No KBET/267/B/2013). Supported by statutory funds of the Department of Pain Research and Treatment, Chair of Anesthesiology and Intensive Therapy, Jagiellonian University Medical College, Krakow, Poland and by statutory funds of the Institute of Pharmacology Polish Academy of Sciences. Conflict of Interests: The authors declare no conflict of interests.
Corresponding authors: Anna Przeklasa-Muszyńska, MD PhD Department of Pain Research and Treatment Chair of Anesthesiology and Intensive Therapy Jagiellonian University Medical College ul. Śniadeckich 10 31-531 Kraków, Poland Email: [email protected] Joanna Mika, Prof PAS, PhD Institute of Pharmacology Polish Academy of Sciences Department of Pain Pharmacology ul. Smętna 12 31-343 Kraków, Poland Email: [email protected]
1
MIGRAINE without aura with aura
pain intensity: 9.2 5.4 NRS duration: 23 10 hours occurrence : 7 4 days triptan use: 58-59% analgesics consumption: 49-72%
% DECREASE PAIN INTENSITY
tDCS treatment in migraine diminished: 50
### ###
40 30 20 10 0
- tDCS - tDCS
Transcranial direct current stimulation (tDCS) and its influence on analgesics effectiveness in patients suffering from migraine headache
Running title: tDCS in patients suffering from migraine
Abstract: Background: Headache is one of the most common conditions troubling nearly 45% of the world’s population. Migraine headache itself, being more common among women, affects 7-18% of people. As much as 20-30% of the population report accompanying aura and neurological symptoms. In many cases, migraine headache can be effectively treated with suitably selected pharmacotherapies which include drugs used in symptomatic treatment. Frequent occurrence of the condition is treated with prophylaxis, which often fails. Neuromodulating methods are part of the multidirectional treatment and they may be valuable complement to pharmacotherapy. Methods: Our study evaluates the impact of the transcranial direct current stimulation (tDCS) on the consumption of drugs and on pain conditions (frequency, duration, intensity). We recruited 50 patients with migraine headache (30 with aura, 20 without aura) refractory to pharmacological therapy. In 30 patients (18 with aura, 12 without aura) previous unsatisfactory treatment was supplemented with tDCS performed tenfold. 20 patients (12 with aura, 8 without aura) from a control group were treated with pharmacological methods. The observation continued for 30 days after the stimulation. Results: After tDCS, a reduction in the consumption of analgesics and triptans was reported. Additionally, we monitored pain intensity decrease during pain episodes, duration of episodes and the number of pain days. The subjective assessment of pain reduction in migraine patients encompassed 36-40% after tDCS much more effective in comparison to group with only pharmacotherapy (10-12.5%). Conclusions: The study suggests that tDCS may be safe and useful clinical tool in migraine prophylaxis and treatment. Key words: Migraine headaches; Pharmacotherapy; Neurostimulation; Transcranial direct current stimulation
3
Introduction Headache is common pain conditions of the modern era and it haunts approximately 45% of the world’s population. One of the common primary headaches is migraine and its varieties. Women (13-18%) suffer from this condition more often than men (5-10%)[1]. Migraine headache can have a significant impact on the quality of everyday life. Numerous randomized controlled studies were published, which can help to determine the most effective pharmacological treatments. Simple analgesics such as paracetamol, nonsteroidal anti-inflammatory drugs, metamizol, triptans, ergotamine derivatives and combined drugs containing aspirin, paracetamol and caffeine are often used in symptomatic treatment of migraine [2,3]. Prophylactic treatment is useful in case of patients who suffer from frequent and/or severe attacks hampering their everyday functioning[2,3]. Many different pharmacological agents with different mechanisms of action were tested in randomized controlled trials and showed beneficial effects. In many cases, however, treatments (symptomatic, preventive, pharmacological, non-pharmacological) do not meet patients’ expectations due to either adverse side effects or inefficacy[1,3]. We have been facing an ongoing search for new treatment alternatives, including both pharmacological and non-pharmacological methods, which could offer assistance to this group of patients. Invasive (nerves stimulation, brain stimulation) and non-invasive stimulation methods (peripheral: transcutaneous stimulation of supraorbital nerves, and central: transcranial magnetic stimulation, transcranial direct current stimulation) are used in migraine treatment[4]. Neuromodulation serving as a therapeutic method has been known for years. Today we can find numerous publications about this form of headache treatment. Since migraine is associated with central sensitization, transcranial direct current stimulation (tDCS) is one of potential therapeutic approaches for these patients. It is a technique which can modulate pain-related neural networks and recently, it has been one of intensively studied methods [4,5,6,7,8]. Undoubted advantages of this method distinguishing it from others are: ease of use, non-invasive nature and a low risk of side effects[4]. Additionaly, tDCS has potential advantages for headache treatments since it is portable and requires relatively low cost. In 2016 Shirahige et al.[9] suggested that tDCS has moderate to high effects and could be promising non-pharmacological alternative to pain control, mainly due to the reduction of analgesic drugs intake. Moreover, the authors strongly stressed that there is a need for more controlled trials with methodological rigor, which could increase the power of result inference[9]. Therefore, the objective of our study was to examine the effect of tDCS of the motor cortex (M1) on the following issues: frequency, intensity and duration of pain attacks in migraine patients with aura and without aura, whose medical treatment had been neither effective nor satisfying, and the consumption of drugs used during the trial was additionally assessed. The results were compared to the baseline period from before the stimulation and with a control group where no stimulation was used.
4
Materials and methods Fifty women were qualified to the study from among approximately 300 patients with migraine. The selected patients had either been undergoing ineffective treatments or had been not entirely satisfied with their therapies due to adverse side effects. The total number of subjects was divided randomly into a group treated actively and a control group (12 patients with, 8 without aura) treated with pharmacological methods. The study group consisted of 30 migraine patients with and 20 without aura. After the observation, patients from the control group were also qualified for neuromodulating procedures performed at the clinic. The study group 30 patients (18 with aura, 12 without aura) underwent ten procedures of transcranial tDCS. Each patient received ten stimulations over the course of 30 days. The duration of a single active stimulation was 20 min. Before the study (30 days) and during the observation period, the patients were to keep a "patient’s pain diary" where they recorded any pain episode, its duration and medication taken. The trials were conducted in 2015-2016. Inclusion criteria: Age 18-60 Migraine headache diagnosed according to the criteria of the International Headache Society for migraine without aura and migraine with aura [10] Written informed consent to the participation in the study No contraindications to electrotherapy Previous treatments used in line with recommended protocol No history of serious general illnesses which could limit the possibility of the treatment Exclusion criteria: Incomplete diagnostics of headache Unfulfilled diagnostic criteria for migraine headaches Arrhythmia, pacemaker, epilepsy or other factors which could prevent the use of electrotherapy No previous treatment used in line with recommended protocol No consent to treatment with stimulation The volunteers qualified to the study were informed about the purposes of the study, benefits and potential side effects, and provided their written informed consent. The patients could withdraw from the study at any time.
The method Experiments carried out in the 1960s showed that when a weak direct electrical current (2mA) passed through the cortex, it resulted in a moderate change in the degree of the cortex excitability. The nature of the induced cortical change depended on the polarity of electrodes. Anodal stimulation increased the excitability level of brain under the electrode, whereas cathodal stimulation inhibited the excitability. 5
The studies with the use of functional magnetic resonance showed that anodal stimulation of the M1 with an electric current of 2mA not only activated the cortex directly under the electrode but it also spread to adjacent areas of M1 at the side of the stimulation as well as the rear part of the parietal cortex of the opposite hemisphere[11]. tDCS is one of the non-invasive methods of brain stimulation. The procedure was conducted by means of the TCT Research device, model M101-R-2012, 021/OM101R/0000583. Active electrode (anode, 35cm²) was placed over the area corresponding to the M1 of a dominant hemisphere (left in right-handed patients). The site of the electrode placement corresponded to a C3-10/20 of EEG system. Passive electrode (cathode, 35cm²) was placed over the contralateral supraorbital area[12]. The electrodes were soaked in physiological saline solution and attached to the designated places with elastic bands. Subsequently, 20-min stimulation with a 2mA current was conducted. Treatments were performed 2-3 times per week. Pain intensity was measured on a numerical rating scale (NRS) before each treatment. Stimulation were not performed during migraine attacks. The observations were conducted during and after each treatment to detect any occurrence of side effects. It was possible to terminate the procedure at any time. The efficacy of the treatment was evaluated 30 days after the last stimulation. Within month of the follow-up we evaluated the number of pain attacks (days when pain occurred), their duration (measured in hours) and a degree of pain intensity during each attack (measured on NRS). The results were compared to the control group and to the incidence, duration and intensity of attacks from the baseline pre-treatment period. We also evaluated the amount of drugs used by the patients during the observation period. The obtained data were compared to the control group and to the amount of drugs used prior to the stimulation.
Data analysis The data are presented as mean ± SEM of 4 groups (two control:migraine with aura,n=12; migraine without aura,n=8; and two tDCS:migraine with aura,n=12; migraine without aura,n=18). Inter-group differences were statistically evaluated by ANOVA Bonferroni post-hoc test. Significance is defined as *p
