Terug naar zoekresultaten

Hoofdpijn

Volgen
Initiatief: NVN Aantal modules: 21
Bijlagen
Download richtlijn

Clusterhoofdpijn: Neuromodulatie

Beoordeeld: 18-10-2023

Uitgangsvraag

Wat is de plaats van neuromodulatie in de behandeling bij patiënten met clusterhoofdpijn?

 

De module 'neuromodulatie' bestaat uit de volgende submodules:

Occipitale zenuwstimulatie (ONS)

Nervus vagus stimulatie (NVS)

Sphenopalatine ganglion stimulatie (SPG)

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

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

Het doel van deze uitgangsvraag was om te achterhalen wat de toegevoegde waarde van neuromodulatie is als behandeling bij clusterhoofdpijn. In totaal zijn er zes RCT’s gevonden die neuromodulatie vergeleken met standaard zorg, verschillende intensiteit van neuromodulatie of placebo. Naast enkele methodologische beperkingen waren de studiepopulaties relatief klein. Gezien het feit dat dit een relatief zeldzame aandoening betreft, lijken grotere studiepopulaties niet haalbaar. Bewijskracht voor de kritieke uitkomstmaten (aanvalsfrequentie per week, afname van pijn of vrijheid van pijn binnen 15 minuten) was laag tot zeer laag. Dit betekent dat andere studies kunnen leiden tot nieuwe inzichten. Er kunnen op basis van de literatuur geen harde conclusies getrokken worden over de toegevoegde waarde van neuromodulatie voor patiënten met clusterhoofdpijn.

 

Veranderingen ten opzichte van baseline wordt niet GRADE beoordeeld, inherent aan de methodiek. Wilbrink (2021) rapporteert in beide groepen een statistisch significant verschil na 24 weken (ten opzichte van baseline). Dit gold voor zowel de primaire als secundaire uitkomstmaten. Het significante, klinisch relevante en consistente effect ten opzichte van baseline impliceert volgens de auteurs een positief effect van ONS (Wilbrink, 2021). Hoewel patiënttevredenheid niet was onderzocht met een gevalideerde schaal, raadde > 90% van de patiënten de behandeling aan. De werkgroep stelt dat ONS effectief lijkt bij lage en hoge stimulatie in tot nu toe onbehandelbare patiënten met chronische clusterhoofdpijn en de behandeling overwogen kan worden voor deze patiëntengroep. Gezien de significante, snelle en aanhoudende afname van de aanvalsfrequentie wordt er wel een relevant biologisch effect aangenomen (Wilbrink, 2021). Op basis van deze within-group verschillen, adviseert de werkgroep om met lage intensiteit te stimuleren: de batterij gaat langer mee en de stimulatie wordt minder snel als vervelend ervaren.

Mogelijke nadelen of risico’s dienen vanzelfsprekend goed overwogen te worden (zoals bijvoorbeeld kosten, invasief met bijbehorend risico op subcutane infectie/bloeding, pijn/ongemak ter plaatse, defecte elektrode, batterijvervanging). Bijwerkingen worden over het algemeen als mild ervaren en zijn meestal ‘hardware related’, zoals een lege batterij of een elektrode die verschuift. Deze kunnen meestal verholpen worden met een kleine operatie (Wilbrink, 2021). Patiënten kunnen met een neurostimulator niet in een MRI (magnetic resonance imaging) scanner. Dat kan nadelige gevolgen hebben als patiënten vanwege een andere indicatie een MRI scan moeten krijgen.

 

ONS is tevens een potentiële behandeloptie bij vrouwen met een zwangerschapswens en medicamenteus onbehandelbare chronische clusterhoofdpijn (de Coo, 2016). Er is namelijk een te grote onzekerheid over de veiligheid van frequente subcutane injecties met sumatriptan en orale profylactische medicatie is niet veilig tijdens zwangerschap.

 

De conclusies over NVS als aanvalsbehandeling of als profylaxe ten opzichte van placebo laten een klinisch relevant en significant effect zien in pijn vermindering in de studie van Silberstein (2016). In de studie van Goadsby (2018) is het verschil niet klinisch relevant. Een studie (Gaul, 2016) onderzocht het effect op de aanvalsfrequentie en liet een niet klinisch relevant verschil zien. De bijwerkingen acht de werkgroep als mild. Het betreffende apparaat wordt in Nederland niet vergoed en is niet makkelijk beschikbaar.

 

De studies over SPG als aanvalsbehandeling versus placebo stimulatie laten een klinisch relevant en significant effect zien in ‘pijnvrij zijn na 15 minuten’ en ‘pijnreductie na 15 minuten’ (Goadsby, 2019; Schoenen, 2013). Deze behandeling is echter niet beschikbaar in Nederland.

 

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

ONS is een invasieve behandeling die een hoge mate van therapietrouw vereist: direct na implantatie krijgt de patiënt te maken met specifieke leefstijladviezen gedurende drie maanden, daarnaast worden de stimulatie instellingen zeker in het begin regelmatig gecontroleerd. Soms kan het een periode duren voordat de juiste instellingen worden bereikt om dit doel te bewerkstelligen. Dit vergt voor de patiënt geduld en meerdere fysieke consulten binnen zijn/haar behandelcentrum. Het belangrijkste doel is minder aanvallen en medicatie kunnen afbouwen in verband met frequente bijwerkingen (Wilbrink, 2021). Ook wordt er een vermindering van intensiteit of duur van de aanvallen gezien zodat aanvallen beter te behandelen zijn. Patiënten geven ook dan aan dat hun kwaliteit van leven toeneemt, ook als het aantal aanvallen hetzelfde zijn gebleven. Het individuele effect per patiënt is niet vooraf in te schatten. Subgroepen ten aanzien van effect zijn nog niet bekend. Veel patiënten ervaren door het invasieve karakter en de onzekerheid ten aanzien van het effect een drempel voor start van deze behandeling. Tevens zijn er een aantal leefstijl beperkingen waar men rekening mee moet houden: bepaalde fysieke, intensieve sporten zoals boksen en andere vechtsporten kunnen een verhoogde kans geven op verschoven of gebroken elektroden. Patiënten kunnen op langere termijn beperkingen ervaren door een houdingsafhankelijke pijn in het gebied van de geïmplanteerde batterij (bil). Ook kunnen metaaldetectors, bijvoorbeeld op het vliegveld, alarmeren op het systeem. Naast een goede educatie voorafgaand aan de behandeling, is daarom ook de begeleiding tijdens de behandeling van belang. Omdat veel patiënten deze behandeling zien als laatste optie, zijn patiënten over het algemeen erg gemotiveerd en therapietrouw. Wanneer er geen effect is na 6 á 12 maanden, kan indien gewenst het neuromodulatiesysteem worden verwijderd.

 

SPG is tevens een invasieve behandeling. Dit neuromodulatie-systeem kan niet meer worden verwijderd (Schoenen, 2013). NVS is geen invasieve behandeling en heeft daarvoor minder nadelen.

 

Kosten (middelenbeslag)

Op basis van de eerste berekeningen die zijn uitgevoerd in opdracht van Zorginstituut Nederland (Zorginstituut Nederland, 2019), is besloten dat occipitale zenuwstimulatie voor patiënten met medicamenteus onbehandelbare clusterhoofdpijn wordt vergoed uit het basispakket, omdat de behandeling kosteneffectief is. De resultaten van de kosteneffectiviteitsanalyse op basis van de ICON studie zullen hier in de toekomst meer inzicht in geven.

 

Aanvaardbaarheid, haalbaarheid en implementatie

De centra die neuromodulatie uitvoeren bij clusterhoofdpijn, moeten expertise hebben in neuromodulatie bij clusterhoofdpijn, maar ook bij andere indicaties (failed back surgery syndrome, diabetische neuropathie, Complex Regionaal Pijn Syndroom). De groep clusterhoofdpijn-patiënten die in aanmerking komt is namelijk te klein om alleen met deze indicatie voldoende ervaring met neuromodulatie te krijgen. Er zijn daarom volumenormen vastgesteld door de Nederlandse vereniging voor Anesthesiologie (NVA). Het is van belang dat er gespecialiseerde verpleegkundigen zijn die ervaring hebben met patiënten met chronische pijn en het instellen van de stimulator. Daarom zijn er nu drie centra die neuromodulatie mogen uitvoeren. De werkgroep is hiermee akkoord.

 

Implementatie van SPG en NVS is niet haalbaar momenteel, beide interventies zijn niet beschikbaar in Nederland.

 

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

Hoewel de bewijskracht voor het effect van ONS als ‘matig tot laag’ en niet effectief bestempeld wordt, laat de ICON studie zien dat 50% van de patiënten 50% of meer aanvalsreductie had gedurende 1 jaar follow-up (Wilbrink, 2021). Een aantal open label studies ondersteunen deze bevinding (Burns, 2009; Fontaine, 2011; Magis, 2011; Mueller, 2011). De werkgroep hecht waarden aan deze within-group verschillen en praktijk ervaringen. Omdat ONS een invasieve behandeling is met een geïmplanteerd systeem wat na implantatie de nodige controles vereist, kunnen de kosten redelijk hoog zijn. Daarom adviseert de werkgroep ONS als laatste optie (na verapamil, lithium en topiramaat) bij medicamenteus onbehandelbare chronische clusterhoofdpijn. Ter overbrugging kan een GON-injectie overwogen worden (zie module 1 ‘GON injecties). Indien SPG of NVS weer beschikbaar zijn, kunnen deze interventies overwogen worden als aanvalsbehandeling of als profylaxe (NVS), met name bij patiënten bij wie sumatriptan en/of O2 niet werkzaam of gecontra-indiceerd zijn.

Onderbouwing

Neuromodulatie (ook wel neurostimulatie genoemd) kan door middel van elektriciteit de werking van het zenuwstelsel beïnvloeden, hierdoor kan de werking van het zenuwstelsel veranderen met een mogelijk therapeutisch effect als gevolg hebben. Er zijn verschillende vormen van neuromodulatie beschikbaar voor patiënten met clusterhoofdpijn. Occipitale zenuwstimulatie (ONS) wordt sinds 1 januari 2020 vergoed door de zorgverzekeraar bij patiënten met refractaire chronische clusterhoofdpijn. Non-invasieve nervus vagus stimulatie (NVS) lijkt in praktijk een effectieve acute therapie bij episodische clusterhoofdpijn, maar niet bij chronische clusterhoofdpijn. Hierbij wordt met een apparaat de nervus vagus gestimuleerd in de hals. Er is mogelijk een profylactisch effect bij chronische clusterhoofdpijn. Non-invasieve nervus vagus stimulatie wordt momenteel niet vergoed en niet toegepast in Nederland. Echter bestellen sommige patiënten soms zelf een apparaat. Sphenopalatine ganglion stimulatie (SPG) is mogelijk effectief zowel als acute behandeling en profylactische behandeling in chronische clusterhoofdpijn, echter is dit nog onvoldoende onderzocht.

Samenvattend, er zijn verschillende nieuwe therapieën beschikbaar waarbij de toegevoegde waarde nog niet goed onderzocht is bij clusterhoofdpijn. De invasieve behandelingen gaan gepaard met relatief hoge kosten. Een eenduidig beleid ontbreekt momenteel in de Nederlandse praktijk. In deze module worden aanbevelingen gedaan over de rol van de verschillende vormen neuromodulatie (ONS, NVS, SPG) in de behandeling van clusterhoofdpijn.

1.3 Attack frequency per week (ONS)

Low GRADE

Stimulation with 100% ONS may result in little to no difference in change of attack frequency per week when compared to 30% ONS in patients with medically resistant chronic cluster headache.

 

Source: Wilbrink (2021)

 

1.5 Severity of the attack (ONS)

Moderate GRADE

Stimulation with 100% ONS probably results in little to no difference in severity of the attack when compared to 30% ONS in patients with medically resistant chronic cluster headache.

 

Source: Wilbrink (2021)

 

1.6 50% responder rate (ONS)

Low GRADE

Stimulation with 100% ONS may result in little to no difference in 50% responder rate when compared to 30% ONS in patients with medically resistant chronic cluster headache.

 

Source: Wilbrink (2021)

 

1.7 30% responder rate (ONS)

Moderate GRADE

Stimulation with 100% ONS probably results in little to no difference in 30% responder rate when compared to 30% ONS in patients with medically resistant chronic cluster headache.

 

Source: Wilbrink (2021)

 

1.8 Quality of life (ONS)

Low GRADE

Stimulation with 100% ONS may result in little to no difference in quality of life when compared to 30% ONS in patients with medically resistant chronic cluster headache.

 

Source: Wilbrink (2021)

 

1.10 Adverse events (ONS)

Low GRADE

Stimulation with 100% ONS may increase adverse events when compared to 30% ONS in patients with medically resistant chronic cluster headache.

 

Source: Wilbrink (2021)

 

1.11 Device related adverse events (ONS)

Low GRADE

The evidence is very uncertain about the effect of 100% ONS on device related adverse events when compared to 30% ONS in patients with medically resistant chronic cluster headache.

 

Source: Wilbrink (2021)

 

1.1 Pain free after 15 minutes, 1.2 Pain reduction after 15 minutes, 1.4 Use of acute medication, 1.9 Patient satisfaction (ONS)

- GRADE

No evidence was found regarding the effect of 100% ONS on pain, use of acute medication, or patient satisfaction when compared with 30% ONS in patients with cluster headache.

 

Source: -

 

Comparison with placebo/sham or usual care only

- GRADE

No evidence was found regarding the effect of ONS when compared with placebo/ sham or usual care only, in patients with cluster headache.

 

Source: -

 

2. 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.
2. 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).

 

2. 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)

 

3. SPG: Results

3.1 Pain free after 15 minutes (critical)

Two studies reported on freedom of pain after 15 minutes (Goadsby, 2019; Schoenen, 2013).

In the RCT of Goadsby (2019), freedom of pain after 15 minutes was measured on a five-point ordinal scale (0-4), on which a reduction of pain from 2-4 to 0 without use of medication, was considered freedom of pain. In the four-week experimental phase, 30% of all treated attacks (n=410) in the SPG group, resulted in pain free status in 15 minutes. In the control group, 21% of all treated attacks (n=582) reached pain-free status in 15 minutes. Odds ratios were calculated using a generalized estimated equation model. The odds ratio was 2.32 (95%CI 1.06 to 5.08), favouring the SPG group. Since no raw data were provided, risk ratios could not be calculated. Despite the high amount of events, the clinical relevance of this OR was estimated using the minimal clinical important difference of 10%. This effect was considered clinically relevant.

 

In the RCT of Schoenen (2013), freedom of pain after 15 was measured on a five-point ordinal scale (0-4). Freedom of pain was defined as a reduction from pain scores (scores 2-4) to a score of 0. Freedom of pain was measured in all participants with at least one treated attack (n=22) during the experimental phase. At the end of the experimental phase, 566 attacks were treated. After full stimulation, 65 out of 190 the treatments resulted in freedom from pain at 15 minutes. After sham stimulation, 3 out of 192 of the treatments resulted in freedom from pain at 15 minutes. Probabilities were calculated using a generalized estimating equation model. Probability for freedom from pain 15 minutes after full stimulation was 34.1% (95%CI 18.6 to 54.1). Probability for freedom from pain 15 minutes after sham stimulation was 1.5% (95%CI 0.5 to 4.9), favouring full stimulation with SPG. Since no raw data were provided, risk ratios could not be calculated. The clinical relevance of this outcome was estimated using the minimal clinical important difference of 10%. The difference between the two probabilities implies clinical relevance.

 

3.2 Pain reduction after 15 minutes (critical)

Two studies reported on pain relive in 15 minutes (Goadsby, 2019; Schoenen, 2013).

Goadsby (2019) measured pain reduction on a five-point ordinal scale (0-4). Pain reduction in 15 minutes after treatment was defined as a reduction from pain (scores 2-4) to a score of 0 or 1 (without acute medication). In the SPG group (n=36), 189 out of 410 (46%) attacks resulted in pain relief. In the control group (n=40), 226 out of 482 (39%) attacks resulted in pain relief. Odds ratios were calculated using a generalized estimated equation model. This resulted in an odds ratio of 2.62 (95%CI 1.28 to 5.34), with a p-value of 0.008, favouring the SPG group. Since no raw data were provided, risk ratios could not be calculated. Despite the high amount of events, the clinical relevance of this OR was estimated using the minimal clinical important difference of 30%. This effect was considered clinically relevant.

 

Schoenen (2013) measured pain reduction after 15 minutes on a five-point ordinal scale (0-4: 0 no pain; 4 worst pain). Pain reduction was defined as a reduction from pain scores (scores 2-4) to a score of 0 or 1. At the end of the experimental phase, 566 attacks in 22 participants were treated. After SPG, 127 out of 190 the treatments resulted in pain reduction at 15 minutes. After sham stimulation, 15 out of 192 of the treatments resulted in pain reduction at 15 minutes. Probability for pain reduction 15 minutes after full stimulation was 67.1% (95%CI 50.2 to 80.5). Probability for pain reduction 15 minutes after sham stimulation was 7.4% (95%CI 3.9 to 13.7), favoring full stimulation with SPG. Since no raw data were provided, risk ratios could not be calculated. The clinical relevance of this oucome was estimated using the minimal clinical important difference of 30%. The difference between the two probabilities implies clinical relevance.

 

3.3 Attack frequency (critical)

Schoenen (2013) and Goadsby (2019) studied SPG as acute treatment, and were not eligible for this outcome measure.

 

3.8 Quality of life

Difference between two groups in quality of life were not reported in the RCT by Schoenen (2013). Also Goadsby (2019) did not include this outcome measure.

 

3.4 Use of acute medication, 3.5 severity of the attack, 3.6 50% responder rate, 3.7 30% responder rate and 3.9 patient satisfaction

The outcome measures use of acute medication, severity of the attack, 50% responder rate, 30% responder rate, quality of life and patient satisfaction were not reported in the included studies on SPG.

 

3.10 Adverse events

In the RCT by Schoenen (2013), at 30 days after implantation, a total of 92 adverse events were reported. After one year, 36 adverse events were reported. Five serious adverse events were reported in five patients (16%). No information was provided which proportion of the adverse events were considered device related, and comparisons between groups were not reported.

 

In the RCT by Goadsby (2019), at day 30 of the stabilization phase, 340 adverse events were reported, of which 23 events were not assumed to be device or procedure related. At the end of the open label phase, another 171 adverse events were reported, of which 110 were not device or procedure related. Of these adverse events, nine were serious adverse events (measured in nine participants). The amount of participants reporting adverse events was not specified per group. Comparisons between groups were not reported.

 

3.11 Device related adverse events

Device related adverse events were reported by one study (Goadsby ,2019). Of the 340 adverse events which occurred within 30 days after implantation of the device, 317 were assumed to be device or procedure related. Of the 171 adverse events which occurred 31 days after implantation, 61 were assumed to be device or procedure related. Four out of nine serious adverse events were considered device related. The amount of participants reporting adverse events was not specified per group. Comparisons between groups were not reported.

 

3. SPG: Level of evidence of the literature

3.1 Pain free after 15 minutes (acute treatment)

The level of evidence regarding the outcome measure pain free after 15 minutes started as high and was downgraded by three levels to very low because of much influence by sponsoring manufacturer in both studies and unknown carry-over effects (Schoenen, 2013) (-2 risk of bias, and confidence intervals including no effect (Goadsby, 2019) (-1 imprecision).

 

3.2 Pain reduction after 15 minutes (acute treatment)

The level of evidence regarding the outcome measure pain reduction after 15 minutes started as high and was downgraded by three levels to very low because of much influence by sponsoring manufacturer in both studies and unknown carry-over effects (Schoenen, 2013) (-2 risk of bias) and confidence intervals including no effect (Goadsby, 2019) (-1 imprecision).

 

3.3-3.10 Attack frequency, use of acute medication, severity of the attack, 50% responder rate, 30% responder rate, quality of life, patient satisfaction, and (device related) adverse events

The level of evidence regarding the outcome measures severity of the attack, 50% responder rate, 30% responder rate, quality of life, patient satisfaction, and (device related) adverse events were not assessed for treatment with SPG.

 

3. SPG: Conclusions

3.1 Pain free after 15 minutes (SPG)

Very low GRADE

The evidence is very uncertain about the effect of SPG as an acute treatment on freedom of pain after 15 minutes when compared with sham treatment in patients with cluster headache.

 

Sources: Goadsby (2019) and Schoenen (2013)

 

3.2 Pain reduction after 15 minutes (SPG)

 Very low GRADE

The evidence is very uncertain about the effect of SPG as an acute treatment on pain reduction after 15 minutes when compared with sham treatment in patients with cluster headache.

 

Sources: Goadsby (2019) and Schoenen (2013)

 

3.3-3.11 Attack frequency, use of acute medication, severity of the attack, 50% responder rate, 30% responder rate, quality of life, patient satisfaction and (device related) adverse events

- GRADE

No evidence was found regarding the effect of SPG on attack frequency, use of acute medication, severity of the attack, 50% responder rate, 30% responder rate, quality of life, patient satisfaction and (device related) adverse events were not assessed for treatment with SPG in patients with cluster headache.

 

Sources: -

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.

 

  1. Occipital nerve stimulation (ONS)

Regarding treatment with ONS, one RCT was found (Wilbrink, 2021). In this RCT, 131 participants with medically resistant chronic cluster headache (international classification of headache disorders; ICHD-3) were randomly assigned to the intervention-group (100% ONS, n=65, mean age ± SD: 44 ± 13, 57% male) or the control-group (30% ONS, n=66, mean age ± SD: 44 ± 13, 71% male). The intervention-group received 100% occipital nerve stimulation (ONS) as prophylactic treatment and the control-group received 30% ONS. The use of acute medication or other preventive medication was allowed in both treatment groups. After a baseline phase of 12 weeks in which baseline variables were collected, patients were randomized and devices were implanted. During the intervention phase of 24 weeks, participants received the treatment as allocated.

Relevant outcome measures include mean attack frequency per week (weeks 1-4 compared to weeks 21-24), severity of the attack (scale 0-10 with 10 the worst pain possible), responder rate (both 50% and 30%), use of acute medication, quality of life and (device related) adverse events. The follow-up was 24 weeks.

 

  1. 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.

 

  1. Stimulation of the sphenopalatine ganglion (SPG)

Two studies were found (Goadsby, 2019; Schoenen, 2013). In Schoenen (2013) 28 participants with chronic cluster headache (ICHD-2) were randomized between full stimulation of the SPG, sub-perception stimulation or sham as the acute treatment for every new attack (n=566). Mean age was 45 years (range 20-63) and 85% of the participants were male. Since all participants received multiple interventions, the baseline characteristics were not reported per group. Baseline values were retrospectively collected, for four weeks pre-implant. A stabilization phase of minimal three weeks followed implantation. After this phase, stimulation parameters and electrodes were further adjusted over a period of six weeks (therapy titration phase) before start of the experimental phase. Three weeks after initiation of the experimental phase or after the 30th attack, the experimental period ended. Relevant outcome measures include pain reduction in 15 minutes and freedom from pain in 15 minutes. The follow-up was up to three weeks. 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.

 

In the RCT by Goadsby (2019), 93 participants with chronic cluster headache (ICHD-3) were randomly assigned to either SPG for the acute treatment of attacks (n=45, mean age ± SD: 48 ± 11, 73% male), or sham stimulation (n=48, mean age ± SD: 48 ± 11, 73% male). All randomized participants underwent implantation of the device. After a baseline phase of at least 4 weeks, a stabilization phase of 12 weeks followed implantation. The 4-week experimental phase started afterwards. Relevant outcome measures include pain reduction and freedom from pain after 15 minutes. The follow-up was four weeks. The trial was funded by the manufacturer, which had roles in design, collecting, analysing and interpretation of data, and writing.

 

1. ONS: Results

1.1 and 1.2 Pain free after 15 minutes and pain reduction after 15 minutes

Wilbrink (2021) studied ONS as prophylactic treatment and was not eligible for these outcome measures.

 

1.3 Attack frequency (critical)

Wilbrink (2021) measured attack frequency every four weeks. Baseline data were skewed, thus medians and interquartile ranges (IQR’s) were provided. Median attack frequency in the 100% ONS group (n=65) was 17.58 (IQR 9.83 to 29.33) at baseline and 9.50 (IQR 3.00 to 21.25) in week 21-24. Median attack frequency in the 30% ONS group (n=65) was 15.00 (IQR 9.25 to 22.33) at baseline and 6.75 (IQR 1.50 to 16.50) in week 21-24. A linear regression analysis was performed using the logarithms of the mean attack frequency as dependent variable, the logarithm of baseline mean attack frequency as covariate and treatment as fixed variable. The difference between change scores was -2.42 (95%CI -5.17 to 3.33). This between-group difference was not clinically relevant.

 

1.4 Use of acute medication

Wilbrink (2021) did not report this outcome.

 

1.5 Severity of the attack

Wilbrink (2021) measured severity of the attack on a scale from 0-10, with 10 indicating the worst pain. The baseline Mean Attack Intensity (5.96, 95%CI 5.54 to 6.38) was the mean of the first four weeks for the complete population (n= 130). At week 21-24, the Mean Attack Intensity change-score in the 100% ONS group (n=65) was -1.85 (SD 2.51). Mean attack intensity change-score in the 30% ONS group (n=65) was -2.18 (SD 3.45). 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 0.33 (95%CI -0.71 to 1.37). This between-group difference was not clinically relevant.

 

1.6 50% responder rate

Wilbrink (2021) defined the 50% responder rate as participants with an experienced reduction in Mean Attack Frequency of 50% or more. At week 21-24, the percentage 50% responders in both groups was estimated 44.6% (n=29, 95%CI 36.3 to 53.2). This resulted in a risk ratio of 1 (95%CI 0.68 to 1.47), the difference between the groups was not clinically relevant.

 

1.7 30% responder rate

In the RCT of Wilbrink (2021), 30% responder rates were defined as participants with an experienced reduction in Mean Attack Frequency of 30% or more. This outcome was analysed post-hoc. At week 21-24, the percentage 30% responders in the 100% ONS group was estimated 53.8% (95%CI 41.9 to 65.4). This percentage translates to 35 participants. The percentage of 30% responders in the 30% ONS group was estimated 56.9% (44.8 to 68.2). This percentage translates to 37 participants. The risk ratio was 0.95 (95%CI 0.69 to 1.29), this difference was not clinically relevant.

 

1.8 Quality of life

Wilbrink (2021) measured quality of life using the mean physical health summary score, and the mean mental health summary score from the SF-36. Scores for this outcome were assessed from figure 1A and 1B, in the supplemental material of Wilbrink (2021). At week 21-24, mean physical health summary score in the 100% ONS group (n=65) was 56 (95%CI 49 to 63, SD 28.25). Mean physical health summary score in the 30% ONS group (n=65) was 61 (95%CI 56 to 66, SD 20.18). The mean difference between the groups was -5.00 (95%CI -13.44 to 3.44). This difference was not clinically relevant.

At week 21-24, mean mental health summary score in the 100% ONS group was 58 (95%CI 52 to 64, SD =4.21). Mean mental health summary score in the 30% ONS group was 57 (95%CI 51.5 to 62.5, SD 22.20). The mean difference between the groups was 1.00 (95%CI -6.99 to 8.99). This difference was not clinically relevant.

 

1.9 Patient satisfaction

Wilbrink (2021) did not report on this outcome using a validated scale.

 

1.10 Adverse events

In the RCT by Wilbrink (2021), both non-serious and serious adverse events were reported.

In the 100% ONS group (n=65), 48 participants reported one or more non-serious adverse events, and 15 participants reported one or more serious adverse events. In the 30% ONS group (n=65), 43 participants reported one or more non-serious adverse events, and 7 participants reported one or more adverse events. The RR for non-serious adverse events was 1.12 (95%CI 0.89 to 1.40). The RR for serious adverse events was 2.14 (95%CI 0.94 to 4.91).

 

1.11 Device related adverse events

In the RCT of Wilbrink (2021), in the 100% ONS group (n=65), 8 participants reported one or more hardware related adverse events. In the 30% ONS group (n=65), 4 participants reported one or more hardware related adverse events. The RR for hardware related adverse events was 2.00 (95%CI 0.63 to 6.32). This ratio was clinically relevant.

 

1. ONS: Level of evidence of the literature

1.1 and 1.2 Pain free after 15 minutes and pain reduction after 15 minutes

Wilbrink (2021) studied ONS als profylactic treatment, and was not eligible for these outcome measures.

 

1.3 Attack frequency

The level of evidence regarding the outcome measure attack frequency started as high as it was based on a RCT and was downgraded by two levels to low because of a small number of included patients and the confidence interval included beneficial effect for 100% stimulation and 30% stimulation. (-2 imprecision).

 

1.4 Use of acute medication

The level of evidence regarding the outcome measure use of acute medication was not assessed for treatment with ONS.

 

1.5 Severity of the attack

The level of evidence regarding the outcome measure severity of the attack started as high and was downgraded by one level to moderate because of a small number of included patients (-1 imprecision).

 

1.6 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 a small number of included patients and the confidence interval included both clinically relevant harm and benefit (-2 imprecision).

 

1.7 30% responder rate

The level of evidence regarding the outcome measure 30% responder rate started as high and was downgraded by one level to moderate because of a small number of included patients and the confidence interval included clinically relevant harm (-1 imprecision).

 

1.8 Quality of life

The level of evidence regarding the outcome measure quality of life (physical health summary score) started as high and was downgraded by two levels to low because of a small number of included patients and both confidence intervals crossed borders of clinical relevance (-2 imprecision).

 

The level of evidence regarding the outcome measure quality of life (mental health summary score) started as high and was downgraded by one level to moderate because of a small number of included patients (-1 imprecision).

 

1.9 Patient satisfaction

The level of evidence regarding the outcome measure patient satisfaction could not be assessed for treatment with ONS due to lack of data.

 

1.10 Adverse events

The level of evidence regarding the outcome measure adverse events started as high and was downgraded by two levels to low because of a small number of included patients and the confidence interval included both clinically relevant harm and benefit (-2 imprecision).

 

1.11 Device related adverse events

The level of evidence regarding the outcome measure device related adverse events started as high and was downgraded by two levels to low because of a small number of included patients and events, and the confidence interval included both clinically relevant and benefit (-2 imprecision).

A systematic review of the literature was performed to answer the following questions:

1. What is the effect of neuromodulation with ONS compared to standard care, different intensity of neuromodulation, or placebo/sham in the treatment of patients with chronic cluster headache?

2. 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?

3. What is the effect of neuromodulation with SPG 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:

  1. ONS for prophylactic treatment; or

  2. NVS for acute or prophylactic treatment; or

  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.

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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

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)

Autorisatiedatum en geldigheid

Laatst beoordeeld  : 18-10-2023

Laatst geautoriseerd  : 18-10-2023

Geplande herbeoordeling  :

Initiatief en autorisatie

Initiatief:
  • Nederlandse Vereniging voor Neurologie
Geautoriseerd door:
  • Nederlandse Vereniging voor Neurologie
  • Verpleegkundigen en Verzorgenden Nederland
  • Patiëntenvereniging Hoofdpijnnet

Algemene gegevens

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Kwaliteitsgelden Medisch Specialisten (SKMS). De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodules is in 2021 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de ‘samenstelling van de werkgroep’) die betrokken zijn bij de zorg voor patiënten met migraine of clusterhoofdpijn.

 

Samenstelling van de werkgroep

 

WERKGROEP

  • Mevr. prof. dr. Gisela Terwindt (voorzitter), neuroloog, Leids Universitair Medisch Centrum, Leiden; NVN
  • Dhr. dr. Wim Mulleners (voorzitter), neuroloog, Canisius-Wilhelmina Ziekenhuis, Nijmegen; NVN
  • Mevr. drs. Judith Pijpers, neuroloog-in-opleiding, Leids Universitair Medisch Centrum, Leiden; NVN (tot oktober 2022)
  • Dhr. dr. Guus Schoonman, neuroloog, Elisabeth-Tweesteden Ziekenhuis, Tilburg; NVN
  • Mevr. dr. Natalie Wiendels, neuroloog/somnoloog, Zaans Medisch Centrum, Zaandam; NVN
  • Dhr. dr. Rolf Fronczek, neuroloog/somnoloog, Leids Universitair Medisch Centrum, Leiden en Slaap-Waakcentrum, SEIN, Heemstede; NVN
  • Mevr. dr. Poldi Wilbrink, neuroloog, Zuyderland ziekenhuis, Heerlen; NVN
  • Mevr. Jennifer Trouerbach, verpleegkundige, Leids Universitair Medisch Centrum, Leiden; V&VN
  • Mevr. Mieke Heitkamp, verpleegkundig specialist , Canisius Wilhelmina Ziekenhuis; V&VN
  • Mevr. Lisette Verharen, verpleegkundig specialist (MANP), Elisabeth-TweeSteden Ziekenhuis, Tilburg; V&VN
  • Mevr. dr. Attie Tuinenburg, ervaringsdeskundige; Patiëntenvereniging Hoofdpijnnet
  • Mevr. Esmee Mulder, ervaringsdeskundige; Patiëntenvereniging Hoofdpijnnet

KLANKBORDGROEP

  • Dhr. prof. dr. Frank Huygen, anesthesioloog, Erasmus MC, Rotterdam; NVA
  • Mevr. dr. Fleur Sprangers, kinderneuroloog, Elisabeth-Tweesteden Ziekenhuis, Tilburg; NVK
  • Mevr. drs. Arianne Verburg-Oorthuizen, huisarts; NHG

Met ondersteuning van:

  • Dhr. drs. Toon Lamberts, senior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
  • Mevr. dr. Charlotte Michels, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
  • Mevr. drs. Beatrix Vogelaar, junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten

Belangenverklaringen

De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.

Inbreng patiëntenperspectief

Er werd aandacht besteed aan het patiëntenperspectief door afgevaardigden van de patiëntenvereniging Hoofdpijnnet te betrekken in de werkgroep. De verkregen input is meegenomen bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen (zie kop “Waarden en voorkeuren van patiënten”). De conceptrichtlijn is tevens voor commentaar voorgelegd aan Hoofdpijnnet en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

 

Achternaam werkgroeplid

Hoofdfunctie

Nevenwerkzaamheden

Gemelde belangen

Ondernomen actie

Mulleners (voorzitter)

Functie: neuroloog
Werkgever: CWZ, Nijmegen
  • Lid deskundigen Regionaal Tuchtcollege Eindhoven (betaald)
  • Bestuurslid Nederlandse Hoofdpijnvereniging (onbetaald)

 
  • Projectleider ZonMw Goed Gebruik Geneesmiddelen “Efficacy and safety of minidosing lysergic acid diethylamide (LSD) for chronic cluster headache: a randomized placebo-cotrolled study” (projectnummer: 10140262110004).
  • Medeaanvrager ZonMw subsidie Goed Geneesmiddelen gebruik (toegekend – herhaalde GON injecties; co-promotor en onderzoeker, REGON-trial), zie link ZonMw (projectnummer: 10140022010004).
  • Galcanezumab (Lilly) adviesraad cluster hoofdpijn: eenmalige ad-hoc bijeenkomst (03-12-2019). Medicijn valt buiten richtlijn.
  • Lokale onderzoeker bij diverse industry sponsored trials (Novartis, Lilly, Abbvie, Allergan, TEVA).
  • Eerste auteur bij publicatie over monoklonale antilichamen: Mulleners, et al. "Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial." The Lancet Neurology (2020). DOI: 10.1016/S1474-4422(20)30279-9.

Geen restrictie

Terwindt (voorzitter)

Functie: neuroloog, hoogleraar neurologie

Werkgever: LUMC, Leiden
  • Consultancy voor Novartis, Teva, Abbvie/Allergan, Lilly, Lundbeck (betaald, consultancy gericht op Hoofdpijn).
  • Hoofdpijn-applicatie in ontwikkeling samen met Interactive Studios (betaald)

Betrokken bij:

  • Hoofdpijnnet/ Hoofdpijnalliantie (onbetaald)
  • Bestuurslid Nederlandse Hoofdpijnvereniging (onbetaald)
  • Lid van meerdere commissies van IHS (voorzitter en/of lid) (onbetaald)
  • Grants voor wetenschappelijk onderzoek gehonoreerd (investigator initiated, wetenschappelijk onderzoek: Nederlandse hartstichting, Hersenstichting - HA2017.01.05, ZonMW/NWO - projectnummer: 849200007, Dioraphte, IRRF).
  • Alnylam and Biogen: Both companies contribute to a consortium that funds the running costs of a natural history study on D-CAA (consortium pays to institution). Onderwerp valt buiten richtlijn.
  • Up to date: stuk over Retinale Vasculopathie met Cerebrale Leukoencefalopathie en Systemische manifestaties (RVCL-S).
  • Dutch Neurology Handbook (betaald).
  • Presentaties/colleges: Spring Media, Ashfield MedComms, Remedica, Cygnea (betaald).
  • Laatste auteur bij publicatie over e-diaries: van Casteren, et al. "E-diary use in clinical headache practice: A prospective observational study." Cephalalgia (2021). doi:10.1177/03331024211010306.

Extra kritisch commentaar gevraagd van onafhankelijke reviewers tijdens commentaarfase

Fronczek

Functie: 0.8fte - neuroloog (LUMC). 0.2fte - neuroloog/somnoloog

Werkgever: LUMC, Leiden en Slaap-Waakcentrum, SEIN, Heemstede

 
  • Lid adviesraad Editie Migraine (betaald, Teva)
  • Lid adviesraad Lundbeck (betaald)
  • Lid adviesraad Lilly (betaald)
  • Bestuurslid Europees Narcoiepsie Netwerk (EUNN) (onbetaald)
  • Management groep lid European Academy of Neurology (EAN) - Sleep Wake Panel (onbetaald)
  • Hoofdredacteur 'De Neuroloog' (NVN) (onbetaald)
  • Lid beroepsbelangen commissie (NVN) (onbetaald)
  • Lid bestuur International Sleep Medicine Course (ISMC) (onbetaald)
  • Presentaties gegeven voor Teva en Novartis (betaald)
  • PI van de CHIANTI-trial (betreft: onderzoek naar GON injecties, sponsor: Hersenstichting en Innovatiefonds Zorgverzekeraars, zie link)
  • PI van de REGON-trial (sponsor: ZonMw Goed Gebruik Geneesmiddelen, zie link ZonMw (projectnummer: 10140022010004).

CHIANTI en REGON trial: De middelen zijn nog niet geregistreerd voor clusterhoofdpijn in Nederland; trials zijn nog niet gepubliceerd.

Extra kritisch commentaar gevraagd van onafhankelijke reviewers tijdens commentaarfase

Heitkamp-van Deursen

Functie: Verpleegkundig Specialist (specialisatie Hoofdpijn)

Werkgever: CWZ, Nijmegen

Geen

Geen

Geen restrictie

Huygen (klankbord groep)

Functie: hoogleraar anesthesiologie pijngeneeskunde

Werkgever: 0.9fte ErasmusMC Rotterdam, 0.1fte UMC Utrecht
  • Centraal Tuchtcollege Den Haag (betaald)
  • Voorzitter educational committee EFIC (onbetaald)
  • Lid scientific committee IASP congres Toronto 2022 (onbetaald)
  • Lid scientific committee INS congres Barcelona 2022 (onbetaald)
  • Wetenschappelijke adviesraad patiëntenvereniging CRPS Nederland (onbetaald)
  • Wetenschappelijke adviesraad patiëntenvereniging CRPS USA (onbetaald)
  • Lid board of directors International CRPS research consortium (onbetaald)

Geen

Geen restrictie

Mulder

Ervaringsdeskundige; Hoofdpijnnet

 

Geen

Geen

Geen restrictie

Pijpers (tot oktober 2022)

Functie: AIOS Neurologie

Werkgever: LUMC, Leiden

PhD kandidaat Neurologie bij het LUMC (onbetaald)

Titel: 'The clinical aspects and management of chronic migraine'

Financiering: werd betaald vanuit een persoonlijke LUMC beurs en een VIDI beurs van Gisela Terwindt (91711319).

Geen

Geen restrictie

Schoonman

Functie: Neuroloog

Werkgever: ETZ, Tilburg

Onderzoeker digitale communicatie in de zorg, TU Tilburg (onbetaald)

Aantal jaar geleden local PI bij twee clinical trials naar het effect van CGRP Antagonisten:

Geen restrictie

Sprangers (klankbord groep)

Functie: Kinderarts, kinderneuroloog

Werkgever: Spaarne Gasthuis, Haarlem

Geen

Geen

Geen restrictie

Trommelen-Verharen

Functie: verpleegkundig specialist

Werkgever: ETZ, Tilburg
  • Bestuurslid Landelijke vereniging Masters MS (onbetaald)
  • Lid landelijke scholingscommissie MS (gedeeltelijk betaald door multisponsoring)

Geen

Geen restrictie

Trouerbach-Kraan

Functie: verpleegkundig consulent

Werkgever: LUMC, Leiden
  • Verpleegkundig adviesraad Lundbeck (betaald)
  • Verpleegkundig adviesraad Novartis (betaald)
  • Verpleegkundig adviesraad Teva (betaald)
  • Bestuurslid hoofdpijnverpleegkundige VNHC (onbetaald)
  • Bestuurslid internationale forum voor hoofdpijnverpleegkundige (IFHN) (onbetaald)

Geen

Geen restrictie

Tuinenburg

Ervaringsdeskundige; Hoofdpijnnet

 
  • Onafhankelijk epidemioloog (ZZP)
  • Methodoloog bij het Zorginstituut Nederland, project Uitkomstgerichte Zorg (betaald)

Als ZZP’er literatuuronderzoek gedaan m.b.t. meest recente richtlijnen over de behandeling van hemofilie en van immuun trombocytopenie (ITP).

 

 

Geen restrictie

Verburg-Oorthuizen (klankbord groep)

Functie: 0.4fte - huisarts, 0.4fte - senior wetenschappelijk medewerker NHG

Geen

Geen

Geen restrictie

Wiendels

Functie: neuroloog

Werkgever: Zaans Medisch Centrum, Zaandam
  • Redactielid nascholingstijdschrift Nervus (betaald)
  • EEG examinator LOI (betaald)

Geen

Geen restrictie

Wilbrink

Functie: neuroloog

Werkgever: Zuyderland, Heerlen

lid adviesraad Teva (betaald)

Geen. Eerste auteur bij publicatie over ONS: Wilbrink, et al. "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 Neurology (2021). DOI: 10.1016/S1474-4422(21)00101-0.

Extra kritisch commentaar gevraagd van onafhankelijke reviewers tijdens commentaarfase

Wkkgz & Kwalitatieve raming van mogelijke substantiële financiële gevolgen

Bij de richtlijn is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling zijn richtlijnmodules op verschillende domeinen getoetst (zie het stroomschema op de Richtlijnendatabase).

 

Uit de kwalitatieve raming blijkt dat er waarschijnlijk geen substantiële financiële gevolgen zijn, zie onderstaande tabel.

Module

Uitkomst raming

Toelichting

Module 1 Gon-injecties

Geen financiële gevolgen

Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (5.000-40.000 patiënten), volgt ook uit de toetsing dat het overgrote deel (±90%) van de zorgaanbieders en zorgverleners al aan de norm voldoet en het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft. Er worden daarom geen financiële gevolgen verwacht.

 

Module 2 Neuromodulatie

Geen financiële gevolgen

Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (5.000-40.000 patiënten), volgt ook uit de toetsing dat het overgrote deel (±90%) van de zorgaanbieders en zorgverleners al aan de norm voldoet en het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft. Er worden daarom geen financiële gevolgen verwacht.

 

Module 3 Beeldvorming

Geen financiële gevolgen

Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (5.000-40.000 patiënten), volgt ook uit de toetsing dat het overgrote deel (±90%) van de zorgaanbieders en zorgverleners al aan de norm voldoet en het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft. Er worden daarom geen financiële gevolgen verwacht.

 

Module 4 organisatie van zorg - clusterhoofdpijn

Geen financiële gevolgen

Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (5.000-40.000 patiënten), volgt ook uit de toetsing dat het overgrote deel (±90%) van de zorgaanbieders en zorgverleners al aan de norm voldoet en het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft. Er worden daarom geen financiële gevolgen verwacht.

 

Module 5 Monoklonale antilichamen - migraine

Geen financiële gevolgen

Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (>40.000 patiënten), volgt uit de toetsing dat het overgrote deel (±90%) van de zorgaanbieders en zorgverleners al aan de norm voldoet en het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft, het geen toename in het aantal in te zetten voltijdsequivalenten aan zorgverleners betreft en het geen wijziging in het opleidingsniveau van zorgpersoneel betreft. Er worden daarom geen financiële gevolgen verwacht.

 

Module 6 organisatie van zorg - migraine

Geen financiële gevolgen

Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (>40.000 patiënten), volgt uit de toetsing dat het overgrote deel (±90%) van de zorgaanbieders en zorgverleners al aan de norm voldoet en het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft, het geen toename in het aantal in te zetten voltijdsequivalenten aan zorgverleners betreft en het geen wijziging in het opleidingsniveau van zorgpersoneel betreft. Er worden daarom geen financiële gevolgen verwacht.

 

 

Werkwijze

AGREE

Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).

 

Knelpuntenanalyse en uitgangsvragen

Tijdens de voorbereidende fase inventariseerde de werkgroep de knelpunten in de zorg voor patiënten met migraine of clusterhoofdpijn. Tevens zijn er knelpunten aangedragen door het Nederlands Huisartsen Genootschap, Vereniging innovatieve Geneesmiddelen, Hoofdpijnnet, Nederlandse Vereniging voor Kindergeneeskunde, Inspectie Gezondheidszorg en Jeugd, Nederlandse Vereniging van Ziekenhuizen, Zelfstandige Klinieken Nederland, Zorgverzekeraars Nederland, via enquête. Op basis van de uitkomsten van de knelpuntenanalyse zijn door de werkgroep concept-uitgangsvragen opgesteld en definitief vastgesteld.

 

Uitkomstmaten

Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.

 

Methode literatuursamenvatting

Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. Indien mogelijk werd de data uit verschillende studies gepoold in een random-effects model. Review Manager 5.4 werd gebruikt voor de statistische analyses. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.

 

Beoordelen van de kracht van het wetenschappelijke bewijs

De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).

GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).

 

GRADE

Definitie

Hoog
  • er is hoge zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • het is zeer onwaarschijnlijk dat de literatuurconclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Redelijk
  • er is redelijke zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • het is mogelijk dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Laag
  • er is lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • er is een reële kans dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Zeer laag
  • er is zeer lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • de literatuurconclusie is zeer onzeker.

 

Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).

 

Overwegingen (van bewijs naar aanbeveling)

Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE methodiek.

 

Formuleren van aanbevelingen

De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.

In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.

 

Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers

 

Sterke aanbeveling

Zwakke (conditionele) aanbeveling

Voor patiënten

De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet.

Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet.

Voor behandelaars

De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen.

Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren.

Voor beleidsmakers

De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid.

Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen.

 

Organisatie van zorg

In de knelpuntenanalyse en bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen. Meer algemene, overkoepelende, of bijkomende aspecten van de organisatie van zorg worden behandeld in de module Organisatie van zorg.

 

Commentaar- en autorisatiefase

De conceptrichtlijnmodule werd aan alle betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.

 

Literatuur

Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.

 

Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

 

Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.

 

Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.

 

Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.

 

Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html

 

Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.

 

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

Zoekverantwoording

Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.

Volgende:
Migraine