Transcutaneous electrical stimulation of the vagus nerve as a migraine treatment: systematic review

Thomaz, Tania Gouvêa; Kouassi, Andrée Carolle Mariane Amany; Neves, Arthur dos Santos Leite Neiva; Sena, Gisele Fernandes de

doi:10.5935/2595-0118.20240061-en

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REVIEW ARTICLE • BrJP 7 • 2024 • https://doi.org/10.5935/2595-0118.20240061-en linkcopy

Transcutaneous electrical stimulation of the vagus nerve as a migraine treatment: systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

BACKGROUND AND OBJECTIVES: Migraine is a type of primary headache that is controlled mainly by drugs to treat the crisis or as prophylaxis. The side effects and high cost of the medication justify the search for non-pharmacological treatment options. There is evidence that electrical stimulation of the vagus nerve (VNS) is capable of modulating structures related to the pathophysiology of migraine. The objective of this review was to investigate the effectiveness of transcutaneous VNS (tVNS) in the acute or prophylactic treatment of migraine with and without aura.

CONTENTS: A search was carried out in the Pubmed database using all descriptors for vagus nerve stimulation and migraine, without time limit and with the filter “randomized clinical trial” (RCT). This search strategy ultimately identified 7 articles that were read in full and subjected to a quality analysis using the Oxford Center for Evidence-Based Medicine tool. Of the 7 RCTs found, 4 were prophylaxis studies and 3 were acute treatment studies.

CONCLUSION: There is some compromise in the internal validity of all studies. Migraine prophylaxis with tVNS did not present relevant benefits that justify its use, especially with a protocol with poor adherence. Acute treatment of migraine with tNVS proved to be effective in some patients and may be a non-pharmacological treatment option. These results justify the carrying out of new RCTs where there are no doubts about their internal validity.

Keywords:
Migraine disorders; Review; Vagus nerve stimulation

HIGHLIGHTS

tVNS offers the possibility of a non-pharmacological treatment for migraine with the potential to reduce the adverse effects of current therapeutic approaches.

This review also summarizes and discusses issues related to the pathophysiology of migraine.

The critical analysis of each article included in this review exposes the difficulty of interpreting the results presented to the scientific community, especially when the research is carried out in collaboration with the industry that produces the equipment in question.

Prophylactic treatment
Authors	Population	Intervention	Control	Outcomes	Results
Straube et al.²²	40 adults with chronic migraine with and without aura	Ear stimulation 4 hours of daily stimulation at 25 Hz for 12 weeks Nemos®	Ear stimulation 4 hours of daily stimulation at 1 Hz for 12 weeks Nemos®	# reduction in the number of headache days # responsive or not (50% reduction in pain days) # MIDAS # HIT 6	PP and ITT analysis # The control group had a reduction of 7 days of pain in one month, while the intervention group had a reduction of 3.3 days in one month*. # Responsive patients: Control – 29,4 % Intervention – 13,3 % # MIDAS – improved score compared to the beginning of the study in both groups: intervention and control # HIT 6 – improved score compared to the start of the study in both the intervention and control groups
Silberstein et al.²³	51 adults with chronic migraine with and without aura. 27 patients completed the 8 months of the study	Cervical stimulation 2 sessions of 2 minutes with 5 to 10 minutes rest, 25 Hz, 3x a day, for up to 8 months Gamma Core®	Cervical stimulation 2 sessions of 2 minutes with 5 to 10 minutes rest, SHAM, 3x a day, for up to 8 months Gamma Core®	# reduction in the number of headache days # use of rescue drugs	PP and ITT analysis # After 2 months of use, a reduction of 1.4 days of pain # After 4 months of use, reduction of 2.4 days of pain (open-label) # After 6 months of use, reduction of 2.8 days of pain (open-label) # After 8 months of use, a reduction of 3.6 days of pain. (open-label)* # It did not change throughout the study in both groups
Diener et al.²⁴	341 adults with migraine with and without aura (multicenter study)	Cervical stimulation 2 sessions of 2 minutes with 5 to 10 minutes rest, 25 Hz, 3x a day, for up to 9 months. Gamma Core®-Sapphire	Cervical stimulation 2 sessions of 2 minutes with 5 to 10 minutes rest, SHAM, 3x a day Gamma Core®-Sapphire	# reduction in the number of migraine days # responsive or not (50% reduction in pain days)	ITT analysis # After 3 months of use, reduction of 2.26 days of pain. # After 3 months of use, reduction of 2.27 days of pain* (mlTT) and reduction of 2.96 days of pain* (mITT) in the subgroup with aura # After 6 or 9 months (open-label), the results remained the same # Responsive patients: 3 months - 28.5% 3 months - 31.9% (mITT) 6 months - no results 9 months - no results
Najib et al.²⁵	231 adults with episodic or chronic migraine with or without aura (multicenter study)	Cervical stimulation 2 sessions of 2 minutes with 5 to 10 minutes rest, 25 Hz, 3x a day, for at least 9 weeks Gamma Core®-Sapphire	Cervical stimulation 2 sessions of 2 minutes with 5 to 10 minutes rest, 25 Hz, 3x a day, for at least 9 weeks Gamma Core®-Sapphire	# reduction in the number of headache days # responsive or not (50% reduction in pain days) # MIDAS # HIT 6	ITT analysis # Reduction of 3.12 days of pain between the 9th and 12th week of stimulation. # 44.87% of patients are responsive * (mITT) # did not present the results # did not present the results
Acute treatment
Tassorelli et al.²⁶	248 adults with migraine with and without aura (multicenter study)	Cervical stimulation 25Hz 2 minutes of stimulation on each side (D and E), 20 minutes after the onset of pain, with repetition after 15 minutes if the pain persists Gamma Core®	Cervical stimulation SHAM 2 minutes of stimulation on each side (D and E), 20 minutes after the onset of pain, with repetition after 15 minutes if the pain persists Gamma Core®	First crisis treated # no pain after 30 minutes # no pain after 60 minutes # no pain after 120 minutes # pain relief after 30 minutes # pain relief after 60 minutes # pain relief after 120 minutes All crises treated # responsive or non-responsive (absence of pain after 120 minutes in 50% of treated crises)	ITT analysis First crisis treated # 12.7% of patients * treated with tVNS # 21% of patients * treated with tVNS # 30.4% of patients treated with tVNS # 26.7% of patients treated with tVNS # 35.8% of patients treated with tVNS # 40.8% of patients* treated with tVNS All crises treated # 32.4% of patients are responsive *
Martelletti et al.²⁷	248 adults with migraine with and without aura (multicenter study)	Cervical stimulation 25Hz 2 minutes of stimulation on each side (D and E), 20 minutes after the onset of pain, with repetition after 15 minutes if the pain persists Gamma Core®	Cervical stimulation SHAM 2 minutes of stimulation on each side (D and E), 20 minutes after the onset of pain, with repetition after 15 minutes if the pain persists Gamma Core®	All crises treated # no pain after 30 minutes # no pain after 60 minutes # no pain after 120 # pain relief after 30 minutes # pain relief after 60 minutes # pain relief after 120 minutes # decrease in pain scale score after 30 minutes # decrease in pain scale score after 60 minutes # decrease in pain scale score after 120 minutes	ITT analysis # 8.6% of patients treated with tVNS # 16.3% of patients * treated with tVNS # 22.9% of patients * treated with tVNS # 21.4% of patients treated with tVNS # 29.4% of patients * treated with tVNS # 35.2% of patients * treated with tVNS # −0.33 in patients treated with tVNS # −0.42 in patients * treated with tVNS # −0.50 in patients treated with tVNS
Grazzi et al²⁸	248 adults with migraine with and without aura (multicenter study)	Cervical stimulation 25Hz 2 minutes of stimulation on each side (D and E), 20 minutes after the onset of pain, with repetition after 15 minutes if the pain persists Gamma Core®	Cervical stimulation SHAM 2 minutes of stimulation on each side (D and E), 20 minutes after the onset of pain, with repetition after 15 minutes if the pain persists Gamma Core®	First crisis treated # >=1 point reduction in pain intensity after 30 minutes # >=1 point reduction in pain intensity after 60 minutes # >=1 point reduction in pain intensity after 120 minutes # Percentage of patients without rescue drugs All crises treated # >=1 point reduction in pain intensity after 30 minutes # >=1 point reduction in pain intensity after 60 minutes # >=1 point reduction in pain intensity after 120 minutes # Percentage of patients without rescue drugs	ITT analysis First crisis treated # 32.2 % of patients* treated with tVNS # 38.8 % of patients * treated with tVNS # 46.8% of patients * treated with tVNS # 59.3 % of patients * treated with tVNS All crises treated # 25.7% of patients treated with tVNS # 33.3 % of patients* treated with tVNS # 39.4% of patients* treated with tVNS # 52.3 % of patients* treated with tVNS

	Prophylactic treatment				Acute treatment
Checklist items/Articles	Straube et al.²²	Silberstein et al.²³	Diener et al.²⁴	Najib et al.²⁵	Tassorelli et al.²⁶	Martelletti et al.²⁷	Grazzi et al.²⁸
Are the results of the study valid (Internal Validity)?
1a. Was the distribution of patients to treatment groups random?	Yes	Yes	Yes	Uncertain The allocated population was much larger than the randomized population	Yes	Yes	Yes
1b. Were the groups similar at the start of the trial?	Yes	Yes	Yes	Uncertain If the randomization was not good, it is possible that the groups were not similar	Yes	Yes	Yes
2a. Were the groups treated equally? (Apart from the allocated treatment)	No, after reviewing the stimulation data found, some patients received additional training.	Yes	Yes	Yes	No, in the intervention group, a higher proportion of participants treated their first attack when its intensity was severe and were using preventive drugs	No, in the intervention group, a higher proportion of participants treated their first attack when its intensity was severe and were using preventive drugs	No, in the intervention group, a higher proportion of participants treated their first attack when its intensity was severe and were using preventive drugs
2b. Were all the patients who entered the study counted and analyzed? - And were they analyzed within the groups to which they were randomized to?	Yes	No The text is not clear about the population analyzed by PP or ITT	No The text is not clear about the population analyzed by PP or ITT. The post hoc analysis (mITT) only evaluates patients adhering to the protocol.	No The text is not clear about the population analyzed by PP or ITT. The post hoc analysis (mITT) only evaluates patients adhering to the protocol.	Uncertain, the text does not make it clear which criteria were used for the post hoc analysis (mITT)	Uncertain, the text does not make it clear which criteria were used for the post hoc analysis (mITT)	Uncertain, the text does not make it clear which criteria were used for the post hoc analysis (mlTT)
3. Are the outcome measures objective? If not, were patients and clinicians “blinded” to which treatment they were receiving?	Yes	Yes, the outcome measures are objective. It is possible to identify the results of the blinded phase and the open phase.	Yes, the outcome measures are objective, but it doesn’t show all the results.	Yes, the outcome measures are objective, but it doesn’t show all the results.	Yes, the outcome measures are objective. It is possible to identify the results of the blinded phase and the open phase	Yes, the outcome measures are objective. It is possible to identify the results of the blinded phase and the open phase	Yes, the outcome measures are objective. The analysis was done with results from the blinded phase and the open phase together.
Which were the results?
1a. Relative Risk (RR)	Outcome: 50% reduction in pain days ITT: 0.55 PP: 0.4636363636	Outcome 50% reduction in pain days PP: 6.774193548 note: the article does not provide ITT analysis data	ITT: 1.276	ITT: 1.117647059	ITT: Outcome complete remission of pain 30min: 2.635714286 60min: 1.708333333 120min: 1.419230769	ITT: Outcome complete remission of pain 30min: 1.708333333 60min: 1.863636364 120min: 1.5375	ITT: Outcome >=1 point reduction in pain intensity First crisis treated 30 min: 1.6489133043 60 min: 1,50546875 120 min: 1.658088235 % of pcs* without rescue drugs: 1.250847458 All seizures treated 30 min: 1.310274516 60 min: 1.395442359 120 min: 1.359661786 % of pcs* without rescue drugs: 1.226567169
1b. Absolute Risk Reduction (ARR)	ITT: −0.1022727273 PP: −0.1577540107	PP: 0.09623655914 note: the article does not provide ITT analysis data	ITT: 0.069	ITT: 0.03095975232	ITT: Outcome complete remission of pain 30min: 0.09308943089 60min: 0.08638211382 120min: 0.08861788618	ITT: Outcome complete remission of pain 30min: 0.03455284553 60min: 0.07723577236 120min: 0.07865853659	ITT: Outcome >=1 point reduction in pain intensity First crisis treated 30 min: 0.1213414634 60 min: 0.131504065 120 min: 0.1819105691 % of pcs* without rescue drugs: 0.1203252033 All seizures treated 30 min: 0.06348556374 60 min: 0.100285094 120 min: 0.1077948869 % of pcs* without rescue drugs: 0.1025102178
1c. Relative Risk Reduction (RRR)	ITT: 0.45 PP: 0.5363636364	PP: −5.774193548 note: the article does not provide ITT analysis data	ITT: −0.276	ITT: −0.1176470588	ITT: Outcome complete remission of pain 30min: −1.635714286 60min: −0.7083333333 120min: −0.4192307692	ITT: Outcome complete remission of pain 30min: −0.7083333333 60min: −0.8636363636 120min: −0.5375	ITT: Outcome >=1 point reduction in pain intensity First crisis treated 30 min: -0.6489130435 60 min: -0.50546875 120 min: -0,6580882353 % of pcs* without rescue drugs: −0.2508474576 All seizures treated 30 min: −0.3102745157 60 min: −0.3954423592 120 min: −0.3596617859 % of pcs* without rescue drugs: −0.2265671693
1d. Necessary Number to Treat (NNT)	ITT: −9.777777778 PP: −6.338983051	PP: 10.39106145 note: the article does not provide ITT analysis data	ITT: 14.49275362	ITT: 32.3	ITT: Outcome complete remission of pain 30min: 10.74235808 60min: 11.57647059 120min: 11.28440367	ITT: Outcome complete remission of pain 30min: 28.94117647 60min: 12.94736842 120min: 12.71317829	ITT: Outcome >=1 point reduction in pain intensity First crisis treated 30 min: 8.24120603 60 min: 7,604327666 120 min: 5.497206704 % of pcs* without rescue drugs: 8.310810811 All seizures treated 30 min: 15.75161251 60 min: 9.971571649 120 min: 9.276877867 % of pcs* without rescue drugs: 9.755125113
2. How accurate was the estimate of the treatment effect?	The p-value was presented for each variable and is marked in table 1 when p<.05	The p-value was presented for each variable and is marked in table 1 when p<.05	The p-value was presented for each variable and is marked in table 1 when p<.05	The p-value was presented for each variable and is marked in table 1 when p<.05	The p-value was presented for each variable and is marked in table 1 when p<.05	The p-value was presented for each variable and is marked in table 1 when p<.05	The p-value was presented for each variable and is marked in table 1 when p<.05
Will the results help me to care for my patient (External validity)?
	Yes	Yes	Yes	Yes	Yes	Yes	Yes

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[TFN1] * p<0.5; MIDAS = Migraine Disability Assessment; HIT = Headache Impact Test; PP = Protocol Analysis; ITT = Intention-to-Treat Analysis; mITT = modified Intention-to-Treat Analysis