3.1 Pain free after 15 minutes (SPG)

3.2 Pain reduction after 15 minutes (SPG)

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

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.  Two studies were found on SPG (Goadsby, 2019; Schoenen, 2013).

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.

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.

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

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:

2.3.1. ONS for prophylactic treatment; or

2.3.2. NVS for acute or prophylactic treatment; or

2.3.3. SPG for acute or prophylactic treatment

C: Usual care, different intensity of neuromodulation, placebo/sham

O: For acute treatment (SPG, NVS): Pain free after 15 minutes, pain reduction after 15 minutes and adverse events (device related, patient related).

For prophylactic treatment (ONS, SPG, NVS): attack-frequency (per week), use of acute/abortive medication, severity of the attack, 50% responder rate, 30% responder rate, quality of life, patient satisfaction, and adverse events

Relevant outcome measures

The guideline development group considered attack frequency (for prophylactic treatment), pain free after 15 minutes (for acute treatment) and pain reduction after 15 minutes (for acute treatment) as critical outcome measures for decision making; and use of acute/abortive medication, severity of the attack, 50% responder rate, 30% responder rate, quality of life, patient satisfaction and adverse events as an important outcomes measure for decision making.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies. Patient satisfaction and quality of life had to be assessed using validated instruments.

Per outcome, the working group defined the following differences as a minimal clinically (patient) important differences:

Dichotomous outcomes (relative risk; yes/no):

• Pain free after 15 minutes: ≥10%
• Pain reduction after 15 minutes: for NVS ≥10%; for SPG: ≥30%
• Use of acute/abortive medication: ≥25%
• 50% responder rate: 30%
• 30% responder rate: 30%
• Adverse events (device related, patient related): ≥10%

Continuous outcomes:

• Pain reduction after 15 minutes: ≥20%; 2 points on a 0-10 scale
• Attack frequency: ≥30% (prophylactic treatment) and n.a. for acute treatment
• Use of acute/abortive medication: ≥25%
• Severity of the attack: ≥20%; 2 points on a 0-10 scale (prophylactic treatment) and ≥30%; 3 points on a 0-10 scale (acute treatment)
• Quality of life: ≥10% difference on a scale, or previously defined minimal importand differences (e.g. 0.07 for EQ-5D-3L, 1 on SF-12 physical scale, 4 on SF-12 mental scale (Hao, 2019))
• Patient satisfaction: ≥10% difference on a validated scale

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until 5 October 2021. The detailed search strategy is depicted under the tab Methods. Due to overlap between the subjects of module 1 ‘greater occipital nerve-injections’ and module 2 ‘neuromodulation’ in this guideline, the two subjects were combined in one search strategy. The systematic literature search resulted in 451 hits. Studies were selected based on the following criteria:

• systematic review (searched in at least two databases, and detailed search strategy, risk of bias assessment and results of individual studies available), randomized controlled trial, or observational comparative studies;
• full-text English language publication;
• including ≥ 20 (ten in each study arm) patients; and
• studies according to the PICO.

Based on titles and abstracts, 54 studies were initially selected. After reading the full text, 48 studies were excluded (see the table with reasons for exclusion under the tab Methods), and six studies were included.

Results

Six studies were included in the analysis of the literature, of which six randomized controlled trials. No observational studies with comparative character were a match with the PICO. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.

One study was found regarding ONS (Wilbrink, 2021), three studies reported data on VNS (Gaul, 2016; Goadsby, 2018; Silberstein, 2016), and two studies were found on SPG (Goadsby, 2019; Schoenen, 2013).