Clusterhoofdpijn: Nervus vagus stimulatie (NVS)
Uitgangsvraag
Wat is de plaats van nervus vagus stimulatie (NVS) in de behandeling bij patiënten met clusterhoofdpijn?
Aanbeveling
Bespreek samen met de patiënt de beschikbare en mogelijke behandelopties.
ONS
Overweeg een verwijzing naar een centrum dat ONS uitvoert bij patiënten met medicamenteus (verapamil, lithium en topiramaat) onbehandelbare chronische clusterhoofdpijn (met 4 of meer aanvallen per week). Overweeg behandeling ter overbrugging bijvoorbeeld met een GON injectie.
NVS, SPG
Behandeling met niet-invasieve nervus vagus stimulatie (NVS) en sphenopalatine ganglion stimulatie (SPG) lijken alternatieven, echter zijn beide therapieën niet beschikbaar in Nederland.
Overwegingen
In de module 'neuromodulatie' staan de overwegingen gerapporteerd.
Onderbouwing
Conclusies
NVS: Conclusions
2.1 Pain free after 15 minutes
|
Low GRADE |
Nervus vagus stimulation as an acute treatment may result in little to no difference in freedom of pain in 15 minutes, when compared with standard of care in patients with cluster headache.
Sources: Goadsby (2018) and Silberstein (2016) |
2.2 Pain reduction after 15 minutes
|
Very low GRADE |
The evidence is very uncertain about the effect of NVS as an acute treatment on pain reduction after 15 minutes when compared with standard of care in patients with cluster headache.
Sources: Goadsby (2018) and Silberstein (2016) |
2.3 Attack frequency per week
|
Very low GRADE |
The evidence is very uncertain about the effect of NVS as a preventive treatment on attack frequency per week when compared with standard of care in patients with cluster headache.
Sources: Gaul (2016) |
2.4 Use of acute medication (acute/prophylactic)
|
Very low GRADE |
The evidence is very uncertain about the effect of NVS as acute or preventive treatment on use of acute medication when compared with standard of care in patients with cluster headache.
Sources: Gaul (2016) |
2.6 50% responder rate
|
Low GRADE |
NVS as a preventive treatment may increase the 50% responder rate when compared with standard of care in patients with cluster headache.
Sources: Gaul (2016) |
2.8 Quality of life
|
Very low GRADE |
The evidence is very uncertain about the effect of NVS as a preventive treatment on quality of life when compared with standard of care in patients with cluster headache.
Sources: Gaul (2016) |
2.10.1 (device related) adverse events (prophylactic treatment); 2.10.2 (Device related) adverse events (acute treatment)
|
Very low GRADE |
The evidence is very uncertain about the effect of NVS as acute or prophylactic treatment on (device related) adverse events when compared with standard of care in patients with cluster headache.
Sources: Gaul (2016), Goadsby (2018) and Silberstein (2016) |
2.5 Severity of the attack, 2.7 30% responder rate, 2.9 Patient satisfaction
|
- GRADE |
No evidence was found regarding the effect of NVS on severity of the attack, 30% responder rate, or patient satisfaction when compared with usual care in patients with cluster headache.
Sources: Gaul (2016) |
Samenvatting literatuur
Description of studies
After a randomized phase, in which assignment to treatment-arms was maintained, all RCTs reported results of an open label extension period. Since only comparative designs were used for the purpose of this guideline, only study-endpoints for the experimental phase were included. Three studies reported data on VNS (Gaul, 2016; Goadsby, 2018; Silberstein, 2016).
Vagus nerve stimulation (NVS)
Three studies reported data on VNS (Gaul, 2016; Goadsby, 2018; Silberstein, 2016). In one RCT (Gaul, 2016), 97 participants with chronic cluster headache (ICHD-3) were randomly assigned to either non-invasive VNS (nVNS) as (adjunctive) prophylactic treatment with usual care (n=48, mean age ± SD: 45.4 ± 11.0, 71% male) or usual care alone (n=49, mean age ± SD: 42.3 ± 11.00, 67% male). After a baseline phase of two weeks in which all participants received standard of care, participants received treatment as allocated for four weeks. Relevant outcome measures include attack frequency, use of acute medication, 50% responder rate and quality of life. The follow-up was four weeks. The funder of the study (ElectroCore) provided support with data analysis and writing, and two authors are employed at the funder. For acute medication use and quality of life, follow-up data were presented only for participants who completed the open-label phase (= modified intention to treat population).
In the RCT by Silberstein (2016), 150 participants were randomly assigned to either nVNS for acute treatment of attacks (n=73, mean age ± SD: 47.1 ± 13.5, 59% male, episodic/chronic: 50/23) or sham treatment (n=77, mean age ± SD 48.6 ± 11.7, 67% male, episodic/chronic: 51/26). Relevant outcome measures include pain reduction in 15 minutes, use of acute medication, average pain intensity (at 15 minutes after treatment), and patient satisfaction. The follow-up was four weeks.
In the RCT by Goadsby (2018), 102 participants were randomly assigned to either nNVS for the acute treatment of attacks (n=50, mean age ± SD: 43.9 ± 10.6, 70% male, episodic/chronic 15/35) or sham treatment (n=52, mean age ± SD: 46.9 ± 10.6, 73.1% male, episodic/chronic 15/37) as addition to their usual care. After a baseline phase of one week, the two-week experimental phase started. Relevant outcome measures include freedom of pain in 15 minutes, pain intensity at 15 minutes. The follow-up was two weeks.
NVS: Results
2.1 Pain free after 15 minutes, acute treatment (critical)
Gaul (2016) studied NVS als profylactic treatment, and was not eligible for this outcome measure. Silberstein (2016) did not include this outcome measure.
In the RCT of Goadsby (2018), pain intensity was measured on a five-point ordinal scale (0-4). Freedom of pain in 15 minutes after treatment was defined as the proportion of all treated attacks for which pain-free status (score 0) was reported in 15 minutes (without use of rescue medication). After two weeks, 13.5% of all treated attacks (n=495) in the nNVS group (n=48) resulted in pain free status in 15 minutes. In the sham group (n=44), 11.5% of the attacks (n=400) reached pain-free status in 15 minutes. ORs were calculated using a generalized estimating equations model. The OR for freedom of pain in 15 minutes was 1.22 (95%CI 0.42 to 3.51). Since no raw data were provided, risk ratios could not be calculated. Despite the high amount of events, the clinical relevance of this odds ratio was estimated using the minimal clinical important difference of 10%. Considering an overestimation of the risk ratio, this effect was not considered clinically relevant.
2.2 Pain reduction after 15 minutes, acute treatment (critical)
Gaul (2016) studied NVS als prophylactic treatment, and was not eligible for this outcome measure.
Two studies reported on pain reduction in 15 minutes (Silberstein, 2016; Goadsby, 2018).
Silberstein (2016), defined pain reduction as the proportion of subjects who achieved a pain intensity score of 0 or 1 (on a 5-point Likert scale) without the use of acute medication. The outcome was reported for the first treated cluster headache-attack. In the nVNS-group, 16 out of 60 (26.7%) participants reported pain reduction in 15 minutes after treatment. In the sham-group, 11 out of 73 (15.1%) participants reported pain reduction.
This resulted in a risk ratio of 1.77 (95%CI 0.89 to 3.52), favouring the nVNS group. This difference was clinically relevant.
Goadsby (2018) assessed pain reduction in 15 minutes on a five-point ordinal scale (0-4). Pain reduction was measured in participants with at least one treated attack without the use of rescue medication. In the NVS group (n=36), mean intensity was 2.4 at attack onset and 1.1 after 15 minutes, resulting in a mean change of -1.3 (SE 0.2, SD 1.2). In the control group (n=31), mean pain intensity was 2.1 at attack onset and 1.2 after 15 minutes, resulting in a mean change of -0.9 (SE 0.1, SD 0.56). The mean difference between the change scores was -0.41 (95%CI -0.90 to 0.07). This difference was not clinically relevant.
2.3 Attack frequency, prophylactic treatment (critical)
Silberstein (2016) and Goadsby (2018) studied NVS as acute treatment, and were not eligible for this outcome measure.
In the RCT of Gaul (2016), attack-frequency was calculated by subtracting the number of attacks assessed before baseline (divided by two) from the number of attacks at follow-up. The baseline attack frequency in the four weeks before enrolment was 67.3 (SD 43.6) in the intervention group, and 73.9 (SD 115.8) in the control group. For follow-up data, attack frequency was evaluated in the second two weeks of the experimental phase. At follow-up, the attack-frequency change-score was -5.9 (SE 1.2) in the NVS group (n=45) and was -2.1 (SE 1.2) in the control group (n= 48). The mean difference between the change-scores of both groups was 3.9 (95%CI 0.5 to 7.2). This difference was not clinically relevant.
2.4.1 Use of acute medication (prophylactic treatment)
In the RCT of Gaul (2016), mean differences between baseline abortive medication use (either subcutaneous sumatriptan or inhaled oxygen) and abortive medication use during the randomized phase were reported. The mean times abortive medication was used was 24.5 at baseline and 9.3 in the last two weeks of the intervention phase in the NVS group (n=32), and 19.4 at baseline and 18.3 in the intervention phase for the control group. According to original analyses, the change-score in the NVS group was -15 (SD 26) and in the control group -2 (SD 28.5). Standard deviations of the change-scores were calculated from 95%CIs for the purpose of this guideline. The mean difference between the change-scores of both groups was -13.00 (95%CI -25.47 to -0.53), favouring nNVS. This effect was clinically relevant.
2.4.2 Use of acute medication (acute treatment)
In the RCT of Silberstein (2016), use of acute medication was measured by whether a participant used rescue medication in the first hour after treatment of their first attack. The proportion of participants using acute medication was 23/60 (38.3%) in the nNVS group and 37/73 (50.7%) in the control group. The risk ratio was 0.76 (95%CI 0.51 to 1.12). This effect was not clinically relevant.
Goadsby (2019) did not include this outcome measure.
2.5 Severity of the attack
The outcome severity of the attack was not reported in the included studies on NVS.
2.6 50% responder rate (prophylactic treatment)
Silberstein (2016) and Goadsby (2018) studied NVS als acute treatment, and were not eligible for this outcome measure.
In the RCT of Gaul (2016), 50% responder rate was defined as the proportion of participants with an experienced 50% reduction in mean number of attacks. At baseline, the mean attack frequency was the mean frequency in the four weeks prior enrolment. The number of 50% responders was assessed in the last two weeks of the randomization phase. At follow-up, the number of 50% responders in the NVS group was 18 out of 45 (40%), and in the control group 4 out of 48 (8,3%). This translates to an RR of 4.8 (95%CI 1.76; 13.10), favouring NVS. This effect was clinically relevant.
2.7 30% responder rate (prophylactic treatment)
The outcome 30% responder rate was not reported in the included studies on NVS.
2.8 Quality of life (prophylactic treatment)
In the RCT of Gaul (2016), quality of life was measured with three different questionnaires: The EQ-5D-3L Index score, the EQ-5D-3L VAS score and the HIT-6 score. All scores were used at the end of the baseline phase. The follow-up score was assessed at the end of the experimental phase. For the EQ-5D-3L Index score, the mean change from baseline in the nVNS group (n=35) was 0.145, and -0.049 in the control group (n=46). For the EQ-5D-3L VAS score, the mean change from baseline in the nVNS group (n=35) was 9.20, and 0.27 in the control group (n=45). For the HIT-6 score, the mean change from baseline in the nNVS group (n=37) was -2.78, and -0.47 in the control group (n=45). The mean difference between change scores for the EQ-5D-3L index score was 0.194 (95%CI 0.054 to 0.334), favouring nVNS. The mean difference between change scores for the EQ-5D-3L VAS score was 8.93 (95%CI 0.47 to 17.39), favouring nVNS. Both change scores were clinically relevant. The mean difference between change scores for the HIT-6 score was not reported. Data for the HIT-6 score could not be used for GRADE evaluation and conclusions.
No other studies on nNVS reported on quality of life.
2.9 Patient satisfaction
In the RCT of Silberstein (2016), patient satisfaction was measured on the participants willingness to recommend the device to friends or family-members on a scale from 1-5. 38.3% of the NVS group was satisfied, very satisfied or extremely satisfied with treatment. For the control-group, 31.9% of the participants shared this opinion. This was not a validated scale, so these data could not be used for GRADE evaluation and conclusions.
No other studies on nNVS reported on patient satisfaction.
2.10.1 (Device related) adverse events (prophylactic treatment)
In the RCT of Gaul (2016), adverse events (both device-related and not device-related) were measured at the end of the randomized phase. During the randomized phase, 18 out of 48 (37.5%) participants in the NVS group experienced adverse events, compared to 13 out of 49 (26.5) participants in the control group. This resulted in a risk ratio of 1.41 (95%CI 0.78 to 2.56), favouring the control group. This difference was clinically relevant.
Device related adverse events were seen in 11 out of 48 (22.9%) participants in the intervention group (15 events). Of these device-related adverse events, 13 were mild-moderate, 2 were considered serious. No device related adverse events in the control group (n=49) were reported at the end of the follow-up. This resulted in a risk ratio of 23.47 (95%CI 1.42 to 387.45), favouring the control group. This difference was clinically relevant.
2.10.2 (Device related) adverse events (acute treatment)
Regarding NVS as acute treatment, two studies reported on adverse events (Goadsby, 2018; Silberstein, 2016).
In the RCT of Goadsby (2018), adverse events (both device-related and not device-related) were measured at two time points. At the end of the follow-up, in the intervention group, 20 out of 50 (40%) persons reported at least one adverse event, and 14 out of 52 (26.9%) in the control group. This resulted in a risk ratio of 1.49 (95%CI 0.85 to 2.61), favouring the control group. This difference was clinically relevant.
Adverse events were device related in 9 out of 50 (18%) participants in the intervention group. In the control group, the events were device related in 10 out of 52 (19.2%) participants. This resulted in a risk ratio of 0.94 (95%CI 0.42 to 2.11). This difference was not clinically relevant.
In the RCT by Silberstein (2016), adverse events at the end of the follow-up (both device-related and not device-related) were reported in 18 out of 73 participants (24.7%) in the intervention group (one patient with serious adverse events), and in 31 out of 77 (40.3%) participants in the sham group. This resulted in a risk ratio of 0.61 (95%CI 0.38 to 0.99), favouring the nVNS group. This difference was clinically relevant.
Device related adverse events were reported in 11 out of 73 (15.1%) participants in the nNVS group, and in 24 out of 73 (32.9%) participants in the sham group. This resulted in a risk ratio of 0.46 (95%CI 0.24 to 0.87), favouring the control group. This difference was clinically relevant.
NVS: Level of evidence of the literature
2.1 Pain free after 15 minutes (critical)
The level of evidence regarding the outcome measure pain free in 15 minutes started as high and was downgraded by three levels to very low because of unblinded trainers providing devices and unknown blinding of outcome-assessors and analysts (Goadsby, 2018) (-1 risk of bias) and a small number of included patients and the confidence interval included both clinically relevant harm and benefit (-2 imprecision).
2.2 Pain reduction after 15 minutes (critical)
The level of evidence regarding the outcome measure pain reduction in 15 minutes started as high and was downgraded by three levels to very low because of imbalanced dropout in Silberstein (2016) with improper imputation and complete case analysis in Goadsby (2018) with imbalanced missings (-2 risk of bias) and a small number of included patients and the confidence intervals included no effect (-1 imprecision).
2.3 Attack frequency (critical)
The level of evidence regarding the outcome measure attack frequency started as high and was downgraded by three levels to very low because of using a modified intention to treat population and much influence by sponsor (Gaul, 2016) (-2 risk of bias), and no clinically relevant effect (-1 imprecision).
2.4.1 Use of acute medication (prophylactic treatment)
The level of evidence regarding the outcome measure use of acute medication started as high and was downgraded by three levels to very low because using a modified intention to treat population and much influence by sponsor (Gaul, 2016) (-2 risk of bias) and a small number of included patients, and confidence intervals include no effect (-1 imprecision).
2.4.2 Use of acute medication (acute treatment)
The level of evidence regarding the outcome measure use of acute medication started as high and was downgraded by three levels to very low because improper imputation by Silberstein (-1 risk of bias) and a small number of included patients, and confidence intervals include no effect (-2 imprecision).
2.5 Severity of the attack
The level of evidence regarding the outcome measure severity of the attack was not assessed for treatment with NVS.
2.6 50% responder rate
The level of evidence regarding the outcome measure 50% responder rate started as high and was downgraded by two levels to low because of using a modified intention to treat population and much influence by sponsor (Gaul, 2016) (-2 risk of bias).
2.7 30% responder rate
The level of evidence regarding the outcome measure 30% responder rate was not assessed for treatment with NVS.
2.8 Quality of life
The level of evidence regarding the outcome measure quality of life started as high and was downgraded by three levels to very low because of using a modified intention to treat population and much influence by sponsor (Gaul, 2016) (-2 risk of bias) and a small number of included patients and one confidence interval included no effect (-1 imprecision).
2.9 Patient satisfaction
The level of evidence regarding the outcome measure patient satisfaction was not assessed for treatment with NVS.
2.10.1 (device related) adverse events (prophylactic treatment)
The level of evidence regarding the outcome measure (device related) adverse events started as high and was downgraded by three levels to very low because much influence by sponsor (Gaul, 2016) (-1 risk of bias), and confidence interval includes both harm and benefit (-2 imprecision).
2.10.2 (Device related) adverse events (acute treatment)
The level of evidence regarding the outcome measure (device related) adverse events started as high and was downgraded by three levels to very low because confidence intervals including both harm and benefit (-2 imprecision), and conflicting results (-1 inconsistency).
Zoeken en selecteren
A systematic review of the literature was performed to answer the following questions:
What is the effect of neuromodulation with NVS compared to standard care, different intensity of neuromodulation, or placebo/sham in the treatment of patients with chronic cluster headache?
P: Patients with episodic or chronic cluster headache
I: Neuromodulation with:
2.3.1. ONS for prophylactic treatment; or
2.3.2. NVS for acute or prophylactic treatment; or
2.3.3. SPG for acute or prophylactic treatment
C: Usual care, different intensity of neuromodulation, placebo/sham
O: For acute treatment (SPG, NVS): Pain free after 15 minutes, pain reduction after 15 minutes and adverse events (device related, patient related).
For prophylactic treatment (ONS, SPG, NVS): attack-frequency (per week), use of acute/abortive medication, severity of the attack, 50% responder rate, 30% responder rate, quality of life, patient satisfaction, and adverse events
Relevant outcome measures
The guideline development group considered attack frequency (for prophylactic treatment), pain free after 15 minutes (for acute treatment) and pain reduction after 15 minutes (for acute treatment) as critical outcome measures for decision making; and use of acute/abortive medication, severity of the attack, 50% responder rate, 30% responder rate, quality of life, patient satisfaction and adverse events as an important outcomes measure for decision making.
A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies. Patient satisfaction and quality of life had to be assessed using validated instruments.
Per outcome, the working group defined the following differences as a minimal clinically (patient) important differences:
Dichotomous outcomes (relative risk; yes/no):
- Pain free after 15 minutes: ≥10%
- Pain reduction after 15 minutes: for NVS ≥10%; for SPG: ≥30%
- Use of acute/abortive medication: ≥25%
- 50% responder rate: 30%
- 30% responder rate: 30%
- Adverse events (device related, patient related): ≥10%
Continuous outcomes:
- Pain reduction after 15 minutes: ≥20%; 2 points on a 0-10 scale
- Attack frequency: ≥30% (prophylactic treatment) and n.a. for acute treatment
- Use of acute/abortive medication: ≥25%
- Severity of the attack: ≥20%; 2 points on a 0-10 scale (prophylactic treatment) and ≥30%; 3 points on a 0-10 scale (acute treatment)
- Quality of life: ≥10% difference on a scale, or previously defined minimal importand differences (e.g. 0.07 for EQ-5D-3L, 1 on SF-12 physical scale, 4 on SF-12 mental scale (Hao, 2019))
- Patient satisfaction: ≥10% difference on a validated scale
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until 5 October 2021. The detailed search strategy is depicted under the tab Methods. Due to overlap between the subjects of module 1 ‘greater occipital nerve-injections’ and module 2 ‘neuromodulation’ in this guideline, the two subjects were combined in one search strategy. The systematic literature search resulted in 451 hits. Studies were selected based on the following criteria:
- systematic review (searched in at least two databases, and detailed search strategy, risk of bias assessment and results of individual studies available), randomized controlled trial, or observational comparative studies;
- full-text English language publication;
- including ≥ 20 (ten in each study arm) patients; and
- studies according to the PICO.
Based on titles and abstracts, 54 studies were initially selected. After reading the full text, 48 studies were excluded (see the table with reasons for exclusion under the tab Methods), and six studies were included.
Results
Six studies were included in the analysis of the literature, of which six randomized controlled trials. No observational studies with comparative character were a match with the PICO. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.
One study was found regarding ONS (Wilbrink, 2021), three studies reported data on VNS (Gaul, 2016; Goadsby, 2018; Silberstein, 2016), and two studies were found on SPG (Goadsby, 2019; Schoenen, 2013).
Referenties
- Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology. 2009 Jan 27;72(4):341-5. doi: 10.1212/01.wnl.0000341279.17344.c9. PMID: 19171831.
- de Coo IF, Wilbrink LA, Haan J. Effective occipital nerve stimulation during pregnancy in a cluster headache patient. Cephalalgia. 2016 Jan;36(1):98-9. doi: 10.1177/0333102415580111. Epub 2015 Apr 1. PMID: 25834272.
- Fontaine D, Christophe Sol J, Raoul S, Fabre N, Geraud G, Magne C, Sakarovitch C, Lanteri-Minet M. Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation. Cephalalgia. 2011 Jul;31(10):1101-5. doi: 10.1177/0333102411412086. Epub 2011 Jul 4. PMID: 21727143.
- Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, Liebler EJ, Straube A; PREVA Study Group. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia. 2016 May;36(6):534-46. doi: 10.1177/0333102415607070. Epub 2015 Sep 21. PMID: 26391457; PMCID: PMC4853813.
- Goadsby PJ, de Coo IF, Silver N, Tyagi A, Ahmed F, Gaul C, Jensen RH, Diener HC, Solbach K, Straube A, Liebler E, Marin JC, Ferrari MD; ACT2 Study Group. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study. Cephalalgia. 2018 Apr;38(5):959-969. doi: 10.1177/0333102417744362. Epub 2017 Dec 12. PMID: 29231763; PMCID: PMC5896689.
- Goadsby PJ, Sahai-Srivastava S, Kezirian EJ, Calhoun AH, Matthews DC, McAllister PJ, Costantino PD, Friedman DI, Zuniga JR, Mechtler LL, Popat SR, Rezai AR, Dodick DW. Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial. Lancet Neurol. 2019 Dec;18(12):1081-1090. doi: 10.1016/S1474-4422(19)30322-9. PMID: 31701891.
- Hao Q, Devji T, Zeraatkar D, Wang Y, Qasim A, Siemieniuk RAC, Vandvik PO, Lähdeoja T, Carrasco-Labra A, Agoritsas T, Guyatt G. Minimal important differences for improvement in shoulder condition patient-reported outcomes: a systematic review to inform a BMJ Rapid Recommendation. BMJ Open. 2019 Feb 20;9(2):e028777. doi: 10.1136/bmjopen-2018-028777. PMID: 30787096; PMCID: PMC6398656.
- Magis D, Gerardy PY, Remacle JM, Schoenen J. Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache. Headache. 2011 Sep;51(8):1191-201. doi: 10.1111/j.1526-4610.2011.01973.x. Epub 2011 Aug 16. PMID: 21848953.
- Mueller OM, Gaul C, Katsarava Z, Diener HC, Sure U, Gasser T. Occipital nerve stimulation for the treatment of chronic cluster headache - lessons learned from 18 months experience. Cent Eur Neurosurg. 2011 May;72(2):84-9. doi: 10.1055/s-0030-1270476. Epub 2011 Mar 29. PMID: 21448856.
- Schoenen J, Jensen RH, Lantéri-Minet M, Láinez MJ, Gaul C, Goodman AM, Caparso A, May A. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013 Jul;33(10):816-30. doi: 10.1177/0333102412473667. Epub 2013 Jan 11. PMID: 23314784; PMCID: PMC3724276.
- Silberstein SD, Mechtler LL, Kudrow DB, Calhoun AH, McClure C, Saper JR, Liebler EJ, Rubenstein Engel E, Tepper SJ; ACT1 Study Group. Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study. Headache. 2016 Sep;56(8):1317-32. doi: 10.1111/head.12896. PMID: 27593728; PMCID: PMC5113831.
- Wilbrink LA, de Coo IF, Doesborg PGG, Mulleners WM, Teernstra OPM, Bartels EC, Burger K, Wille F, van Dongen RTM, Kurt E, Spincemaille GH, Haan J, van Zwet EW, Huygen FJPM, Ferrari MD; ICON study group. Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): a randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial. Lancet Neurol. 2021 Jul;20(7):515-525. doi: 10.1016/S1474-4422(21)00101-0. PMID: 34146510.
- Zorginstituut Nederland 2019. Standpunt occipitale neurostimulatie (ONS) bij medicamenteus onbehandelbare chronische clusterhoofdpijn, via https://www.zorginstituutnederland.nl/publicaties/standpunten/2019/12/10/standpunt-ons geraadpleegd op 20-12-2022
Evidence tabellen
|
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3
|
Follow-up |
Outcome measures and effect size 4 |
Comments |
|
Gaul, 2016 |
Type of study: RCT
Setting and country: 10 European sites (five Germany, three UK, one Belgium, one Italy)
Funding and conflicts of interest: Funded by electroCore, two authors work at electroCore. Also, electrocore provided support with writing, editorial support, and data analysis. |
Inclusion criteria: 18-70 years with diagnosed chronic CH, ≥ 1 year before enrolment
Exclusion criteria: change in prophylactic medication (type/dosage), history of intracranial/carotid aneurysm/haemorrhage, brain tumors/lesions, significant head trauma, previous surgery or abnormal anatomy at nVNS treatment site, known/suspected cardiac/cardiovascular disease, implantation with electrical or neurostimulation devices, history of carotid endarterectomy/vascular neck surgery, implantation with metallic hardware and recent history of syncope/seizures
N total at baseline: Intervention: 48 Control: 49
Important prognostic factors2: age ± SD: I: 45.4 ± 11.0 C: 42.3 ± 11.00
Sex: I: 71% M C: 67% M
Groups comparable at baseline? yes |
Describe intervention (treatment/procedure/test): non-invasive VNS (nVNS) as (adjunctive) prophylactic treatment with usual care
|
Describe control (treatment/procedure/test): usual care alone
|
Length of follow-up: 4 weeks
Loss-to-follow-up: Intervention: 4 Reasons: participant decision
Control: 1 Reasons: participant decision
Incomplete outcome data: Not reported
|
Outcome measures and effect size (include 95%CI and p-value if available):
Attack frequency: mean difference 3.9 (0.5 to 7.2)
Use of acute medication: mean difference -13.00 (-25.47 to -0.53)
50% responder rate: RR 4.8 (1.76 to 13.10)
Quality of life: EQ-5D-3L index mean difference 0.194 (0.054 to 0.334) EQ-5D-3L VAS mean difference 8.93 (0.47 to 17.39)
Patient satisfaction: RR 1.41 (0.78 to 2.56) |
|
|
Goadsby, 2018 |
Type of study: RCT
Setting and country: four EU tertiary sites
Funding and conflicts of interest: all authors received grants from pharmaceutical companies |
Inclusion criteria: ≥ 18 years, diagnosis of episodic/chronic CH.
Exclusion criteria: starting new treatment or changing dose of existing treatment during run-in phase, not in a bout at the time of screening, pregnancy, nursing or thinking of becoming pregnant during the study, or abnormal baseline ECG
N total at baseline: Intervention: 50 Control: 52
Important prognostic factors2: age ± SD: I: 43.9 ± 10.6 C: 46.9 ± 10.6
Sex: I: 70% M C: 73.1% M
Groups comparable at baseline? yes
|
Describe intervention (treatment/procedure/test): nNVS
|
Describe control (treatment/procedure/test): sham treatment
|
Length of follow-up: 2 weeks
Loss-to-follow-up: Intervention: 3 Reasons: 1 protocol violation, 2 other
Control: 6 Reasons: 2 withdrawal, 2 lost to follow-up, 2 adverse events
Incomplete outcome data: Intervention: 2 Reasons: 2 missing diary
Control: 8 Reasons: 6 missing diary, 2 no attacks treated |
Outcome measures and effect size (include 95%CI and p-value if available):
Pain free after 15 minutes: OR 1.22 (0.42 to 3.51)
Pain reduction after 15 minutes: mean difference: -0.41 (-0.90 to 0.07)
Device related adverse events: RR 0.46 (0.24 to 0.87) |
|
|
Silberstein, 2016 |
Type of study: RCT
Setting and country: 20 US centers, including university-based/ academic medical centers and headache/pain/neuro- logical clinics and institutes
Funding and conflicts of interest: |
Inclusion criteria: nonpregnant/nonlactating 18-75 years old diagnosed with episodic/chronic CH
Exclusion criteria: history of aneurysm, intercranial hemorrhage, brain tumors, significant head trauma, prolonged QT interval, arrhythmia, ventricular tachycardia/fibrillation (syncope/seizure), structural intercranial/cervical vascular lesions, another significant pain disorder, cardiovascular disease, uncontrolled hypertension, abnormal baseline ECG, botulinum toxin injections in the past three mohts, nerve blocks in the past month, previous CH surger, bilateral/right cervical vagotomy, carotid endarterectomy, right vascular neck surgery, electrical device implantation, current use of prophylactic medications for indications other than CH
N total at baseline: Intervention: 73 Control: 77
Important prognostic factors2: age ± SD: I: 47.1 ± 13.5 C: 48.6 ± 11.7
Sex: I: 59% M C: 67% M
Groups comparable at baseline? yes |
Describe intervention (treatment/procedure/test): nVNS for acute treatment of attacks |
Describe control (treatment/procedure/test): sham treatment
|
Length of follow-up: 4 weeks
Loss-to-follow-up: Intervention: 2 Reasons: not reported
Control: 3 Reasons: not reported
Incomplete outcome data: Intervention: 12 Reasons: 3 nonadherence, 8 no CH/CH ended, 1 other
Control: 5 Reasons: 2 nonadherence, 1 no CH/CH ended, 2 other
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain reduction after 15 minutes: RR 1.77 (0.89 to 3.52)
Use of acute medication: RR 0.76 (0.51 to 1.12)
Adverse events: RR 0.61 (0.38 to 0.99) device related RR 0.46 (0.24 to 0.87) |
|
|
Goadsby, 2019 |
Type of study: RCT
Setting and country: 21 headache-centers in USA
Funding and conflicts of interest: The trial was funded by the manufacturer, which had roles in the design of the trial, and all authors were consultant or employee for the funder. |
Inclusion criteria: ≥22 years old, chronic CH, previously or currently inadequately controlled with available therapies.
Exclusion criteria: change in type/dose/dose frequency of preventive headache durgs within the month before enrolment, previous diagnosis of trigeminal neuralgia/other trigeminal autonomic cephalalgias
N total at baseline: Intervention: 45 Control: 48
Important prognostic factors2: For example age ± SD: I: 48 ± 11 C: 48 ± 11
Sex: I: 73% M C: 73% M
Groups comparable at baseline? yes |
Describe intervention (treatment/procedure/test): full stimulation of the SPG
|
Describe control (treatment/procedure/test): sub-perception stimulation or sham as the acute treatment for every new attack
|
Length of follow-up: up to 3 weeks
Loss-to-follow-up: Intervention: 9 Reasons: no acute attacks during experimental phase
Control: 8 Reasons: no acute attacks during experimental phase
Incomplete outcome data: Not reported
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain free after 15 minutes: OR 2.32 (1.06 to 5.08)
Pain reduction after 15 minutes: OR 2.62 (1.28 to 5.34) |
|
|
Schoenen, 2013 |
Type of study: RCT
Setting and country: in six European clinical sites
Funding and conflicts of interest: The trial was funded by the manufacturer, which had roles in design, collecting, analysing and interpretation of data, and writing. All authors have been consultants at sponsor (ATI) or are employees at ATI (n=2).
|
Inclusion criteria: 18-65 years old, with chronic CH, reporting dissatisfaction with current treatments, able to distinguish cluster headaches from other headache types
Exclusion criteria: change in type/dosage of preventive headache medications within one month of enrolment, pregnant/nursing women, or women not using contraception of childbearing age, patients who had undergone facial surgery in specified areas within the last four months, previous treatment with radiation in last six months, patients undergone lesional radiofrequency ablation of the ipsilateral SPG/block of ipsilateral SPG or botox injection in head/neck in last three months, patients with other significant pain problems which could confound (opinion of the investigator)
N total at baseline: Intervention: - Control: -
Important prognostic factors2: age ± SD: Total: mean age 45 years (range 20-63 Sex: Total: 85% M
Groups comparable at baseline? yes |
Describe intervention (treatment/procedure/test): SPG for the acute treatment of attacks
|
Describe control (treatment/procedure/test): sham stimulation
|
Length of follow-up: 4 weeks
Loss-to-follow-up: None reported
Incomplete outcome data: 4 Reasons: 1 failure to implant, 2 explanted, 1 skipped experimental period due to pregnancy
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain free after 15 minutes: probability freedom from pain 15 minutes after full stimulation: 34.1% (18.6 to 54.1) after sham stimulation 1.5% (0.5 to 4.9).
Pain reduction after 15 minutes: OR 2.62 (1.28 to 5.34) |
|
Risk of bias table for intervention studies (randomized controlled trials; based on Cochrane risk of bias tool and suggestions by the CLARITY Group at McMaster University)
|
Study reference
|
Was the allocation sequence adequately generated? |
Was the allocation adequately concealed?
|
Blinding: Was knowledge of the allocated interventions adequately prevented? |
Was loss to follow-up (missing outcome data) infrequent?
|
Are reports of the study free of selective outcome reporting?
|
Was the study apparently free of other problems that could put it at a risk of bias?
|
Overall risk of bias If applicable/necessary, per outcome measure
|
|
Wilbrink, 2021 |
Definitely yes;
Reason: randomly varying block design |
Definitely yes;
Independent statistician |
Definitely yes;
Medical professionals implanting devices, participants and outcome assessors were all masked. |
Probably no
Low loss to follow-up (1 from intervention, 1 from control, total 1.5%), risk of bias due to LOCF considered very low |
Probably no;
Use of acute medication was only reported for baseline data, while protocol suggests 6-mnt FU data. Patient satisfaction not reported per group. |
Probably yes;
“The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.” Corresponding author had final responsibility in decision for publication. |
Low (Mean attack frequency, mean attack intensity, 50% responder rate) Some concerns (use of acute medication, patient satisfaction) |
|
Gaul, 2016 |
Probably yes
Reason: participants were randomly assigned 1:1 by standard block design. |
Probably no
Reason: No information about block sizes or concealment provided. |
Definitely no
Reason: Participants were not blinded for the intervention, no sham control was used.
(blinding of data collectors, outcome assessors and analysts not reported)” |
Probably yes
Reason: for acute medication use and quality of life, follow-up data were presented for participants who completed the open-label phase (= modified ITT). Loss to follow-up was imbalanced: four persons in the NVS group withdrew without reason given, 1 person in control group dropped out for unknown reason. For attack frequency and 50% responder rate, missing data was imputed with 0. |
Probably no
Reason: analyses for differences between mean changes of HIT-6 are not provided. |
Probably no
Reason: Funded by electroCore, two authors work at electroCore. Also, electrocore provided support with writing, editorial support, and data analysis. |
HIGH (use of acute medication, quality of life) Some concerns (Attack frequency, 50% responder rate, adverse events)
|
|
Goadsby, 2018 |
Probably yes
Reason: standard design with block size 4, central randomization, using envelopes. |
Probably no
Reason: sealed envelopes were used, but trainers providing the devices were unblinded. |
Probably no
Reason: Patients were blinded, trainers were not blinded. It is not stated whether outcome assessors or analysts were blinded. |
Probably no
Reason: For all outcomes but adverse events, the ITT population was used. The ITT population did not include participants with missing diaries, since there was no efficacy assessment (-2 in NVS, -6 in sham). Also, if attacks were not treated, participants were not included in ITT population (-2 in sham). |
Probably yes
Reason: For all outcomes matching the PICO of this guideline, results were prespecified in the methods and reported in the result section. |
Probably yes
Reason: no serious bias appeared to be present. |
Some concerns (freedom of pain in 15, pain intensity in 15, adverse events) |
|
Silberstein (2016) |
Definitely yes
Reason: Using independent statistician–generated randomization sched- ules, variable block design, stratified by site |
Probably yes
Reason: a variable block design was used. |
Probably yes
Reason: Patients, investigator, study coordinators were blinded. |
Probably yes
Reason: missing data for pain reduction were imputed as failure. There were more drop-outs in the NVS group (n=13), than in the control group (n= 5) |
Probably yes
Reason: For all outcomes matching the PICO of this guideline, results were prespecified in the methods and reported in the result section. |
Probably yes
Reason: no serious bias appeared to be present. |
Some concerns: Pain reduction in 15, adverse events |
|
Schoenen (2013) |
Probably no;
Not stated whether the randomization sequence was in variable blocks or otherwise not trackable for participants. |
Probably yes;
Stimulation doses were delivered randomly (1:1:1) using pre-specified, randomization sequences that were programmed into the remote controller. |
Probably no;
Full stimulation could probably be perceived due to paraesthesia’s.
|
Probably yes;
Due to design, no disproportional dropout was reported. |
Probably yes;
Reason: For all outcomes matching the PICO of this guideline, results were prespecified in the methods and reported in the result section. |
Probably no;
All authors have been consultants at sponsor (ATI) or are employees at ATI (n=2).
Investigation/controlling for crossover effect was not mentioned by the authors. |
Some concerns (Freedom of pain after 15 minutes, pain reduction after 15 minutes) |
|
Goadsby (2019) |
Probably yes;
Computer generated (Bracket Global software) |
Probably no;
Randomization was not central, and stratified for investigational site, sex and weekly attack frequency. Might be predictable for the unblinded study coordinator |
Probably yes;
Patients, outcome assessor and statistician were blinded.
Study coordinator at sites were unblinded. |
Probably yes;
Except for the outcomes of pain relief/freedom of pain, which were not measured in 17 participants (9 SPG, 8 control). |
Probably yes,
Reason: For all outcomes matching the PICO of this guideline, results were prespecified in the methods and reported in the result section. |
Definitely no;
The funder had roles in design, collecting, analysing and interpretation of data, and writing. |
HIGH (Freedom of pain after 15 minutes, pain reduction after 15 minutes) |
Randomization: generation of allocation sequences have to be unpredictable, for example computer generated random-numbers or drawing lots or envelopes. Examples of inadequate procedures are generation of allocation sequences by alternation, according to case record number, date of birth or date of admission.
Allocation concealment: refers to the protection (blinding) of the randomization process. Concealment of allocation sequences is adequate if patients and enrolling investigators cannot foresee assignment, for example central randomization (performed at a site remote from trial location). Inadequate procedures are all procedures based on inadequate randomization procedures or open allocation schedules..
Blinding: neither the patient nor the care provider (attending physician) knows which patient is getting the special treatment. Blinding is sometimes impossible, for example when comparing surgical with non-surgical treatments, but this should not affect the risk of bias judgement. Blinding of those assessing and collecting outcomes prevents that the knowledge of patient assignment influences the process of outcome assessment or data collection (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is usually not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary. Finally, data analysts should be blinded to patient assignment to prevents that knowledge of patient assignment influences data analysis.
Lost to follow-up: If the percentage of patients lost to follow-up or the percentage of missing outcome data is large, or differs between treatment groups, or the reasons for loss to follow-up or missing outcome data differ between treatment groups, bias is likely unless the proportion of missing outcomes compared with observed event risk is not enough to have an important impact on the intervention effect estimate or appropriate imputation methods have been used.
Selective outcome reporting: Results of all predefined outcome measures should be reported; if the protocol is available (in publication or trial registry), then outcomes in the protocol and published report can be compared; if not, outcomes listed in the methods section of an article can be compared with those whose results are reported.
Other biases: Problems may include: a potential source of bias related to the specific study design used (e.g. lead-time bias or survivor bias); trial stopped early due to some data-dependent process (including formal stopping rules); relevant baseline imbalance between intervention groups; claims of fraudulent behavior; deviations from intention-to-treat (ITT) analysis; (the role of the) funding body (see also downgrading due to industry funding. Note: The principles of an ITT analysis implies that (a) participants are kept in the intervention groups to which they were randomized, regardless of the intervention they actually received, (b) outcome data are measured on all participants, and (c) all randomized participants are included in the analysis.
Overall judgement of risk of bias per study and per outcome measure, including predicted direction of bias (e.g. favors experimental, or favors comparator). Note: the decision to downgrade the certainty of the evidence for a particular outcome measure is taken based on the body of evidence, i.e. considering potential bias and its impact on the certainty of the evidence in all included studies reporting on the outcome.
Table of excluded studies
|
Author and year |
Reason for exclusion |
|
de Coo 2019 |
Geen systematische review, geen RCT, gepoolde analyse van Goadsby2018 en Silberstein2016 (wrong design) |
|
Burns 2007 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Burns 2009 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Miller 2017 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Aibar-Durán 2020 |
Dubbel (Aibar-Durán 2021) |
|
Jürgens 2017 |
Extention phase of Schoenen (2013), observationeel niet vergelijkend onderzoek (wrong design) |
|
Tronnier 2010 |
Verkeerde taal, lijkt geen systematische review (wrong language, wrong design) |
|
Magis 2011 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Magis 2007 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Láinez 2014 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Morris 2016 |
Geen match met PICO: Cost-effectiveness results of Gaul2016 (wrong outcome) |
|
Mwamburi 2018 |
Geen match met PICO: migraine population (wrong population) |
|
Mwamburi 2017 |
Geen match met PICO: cost-effectiveness results of Goadsby2018 en Silberstein2016 (wrong outcome) |
|
Fontaine 2018 |
Geen systematische review over SPG (wrong design) |
|
Marin 2018 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Barloese 2018 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Sánches-Gomez 2021 |
Dubbel (Sánches-Gomez, 2021) |
|
Fontaine 2011 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Marin 2018 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Marin 2018 |
Dubbel (Marin, 2018) |
|
Mauskop 2005 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Schwedt 2007 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Mueller 2011 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Lainez 2016 |
Geen systematische review (narrative review) |
|
Gaul 2017 |
Extention phase of Gaul (2016), observationeel niet-vergelijkend onderzoek (wrong design) |
|
Lepus 2021 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Leone 2017 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Fontaine 2010 |
Geen match met PICO: unilateral hypothalamic DBS (wrong intervention) |
|
Nowacki 2020 |
Geen match met PICO: DBS for CCH (wrong intervention) |
|
Stilling 2019 |
Geen match met PICO: TMS and tDCS (wrong intervention) |
|
Aibar-Durán 2021 |
Geen match met PICO: ONS vergeleken met DBS (wrong control) |
|
Mammis 2011 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Diaz-de-Teran 2021 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Magis 2016 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Chen 2020 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Guo 2021 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Sciacca 2014 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Kelderman 2019 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Narouze 2009 |
Observationeel niet-vergelijkend onderzoek (wrong design) |
|
Silberstein 2017 |
Geen systematische review (wrong design) |
|
Lai 2020 |
Systematic review did not include all critical/important outcome measures |
|
Cadalso 2018 |
Systematic review did not include RCTs or comparative observational studies for PICO |
|
Jasper 2008 |
Systematic review did not include RCTs or comparative observational studies for PICO |
|
Reuter 2019 |
Systematic review did not include all critical/important outcome measures |
|
Ho 2017 |
Systematic review did not include Goadsby2019 |
|
Sanchez-Gomez 2018 |
Systematic review did not include Goadsby (2019) |
|
Robbins 2016 |
Systematic review did not include Goadsby (2019) |
|
Vukovic Cvetkovic 2018 |
Systematic review did not include Goadsby (2019) and Wilbrink (2021) |
Verantwoording
Autorisatiedatum en geldigheid
Laatst beoordeeld : 18-10-2023
Laatst geautoriseerd : 18-10-2023
Geplande herbeoordeling :
Zoekverantwoording
Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.