Occipital nerve stimulation (ONS), an invasive treatment involving implanted electrodes, reduced the frequency of medically intractable chronic cluster headache (MICCH) attacks and was well tolerated, the phase III ICON clinical trial found.
Electrical doses just below 100% of the individually determined voltage level causing discomfort, and at 30% of that level, were assessed for a primary outcome of reducing median mean weekly attack frequency between 21 and 24 weeks after stimulation began.
Mean weekly cluster headache attacks dropped from 15.75 at baseline to 7.38 attacks at 21-24 weeks (mean change of −5.21, 95% CI −11.18 to −0.19, P<0.001) in the overall cohort, including both dosing groups (n=130), reported Michel Ferrari, MD, of Leiden University Medical Center in the Netherlands, and co-authors in Lancet Neurology.
No significant difference was seen for attack frequency between the 100% (n=65) and 30% (n=65) stimulation groups.
Effects were evident within several weeks and sustained over 48 weeks. Most serious adverse effects were related to implanted electrodes (neck) and stimulator box (abdomen or buttocks).
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting MICCH, both at high and low intensity,” Ferrari and colleagues wrote. “MICCH attack frequency was halved and attack intensity was reduced by a third. At 24 weeks, roughly half the participants had a 50% or higher reduction in attack frequency and 16 (12%) of 130 had no MICCH attacks.”
“Because the results showed no significant difference between treatment groups, we cannot exclude that improvement could be partially due to the placebo effect,” they added. “However, such an abrupt, pronounced, and sustained improvement in patients so severely affected by MICCH is unlikely to be caused solely by the placebo effect.”
ICON researchers enrolled patients at seven European hospitals between October 2010 and December 2017. The cohort had mean age of 44 and a mean duration of 7 years since diagnosis; 36% were women.
All participants had four or more weekly cluster headache attacks (unilateral orbital pain and ipsilateral facial autonomic symptoms lasting 15-180 minutes). Participant attacks were chronic (no or only short attack-free periods; mean duration of chronicity 4 years) and medically intractable (all were refractory or intolerant to preventive medications verapamil and lithium and could not take or did not benefit from methysergide, topiramate, or gabapentin).
Following stimulator installation and a 10-day run-in phase, a 24-week randomized treatment period compared the 100% and 30% stimulation levels with an additional 24-week open-label treatment. All participants had paresthesias but not discomfort at both 30% and 100% stimulation levels, ideally giving a double-blind comparison between the two intensity groups.
Mean attack frequency dropped by 36.81% compared with baseline (95% CI −60.62 to −7.92) during weeks 1-4. Later, during weeks 45-48, the decrease was 50.45% (95% CI −89.73 to −1.65) versus baseline.
Mean attack intensity decreased by 21.02% (95% CI −25.99 to −16.05) from baseline during weeks 1-4, by 27.19% (95% CI −32.83 to −21.55) for the 21-24 week period, and by 31.68% for weeks 45-48 (95% CI −37.99 to −25.37).
“Short-term and long-term outcomes in this large homogeneous series of patients with intractable chronic cluster headache are concordant with those reported in previous observational studies showing that ONS substantially improves quality of life in this highly disabled population,” noted Denys Fontaine, MD, PhD, and Michel Lanteri-Minet, MD, both of the University of Cote d’Azur in Nice, France, in an accompanying editorial.
“We agree that a placebo effect is very unlikely in this situation,” they added. “Moreover, ONS complications, although frequent, are usually minor, and the overall risk-benefit ratio remains highly favorable, particularly considering the severity of disease in these patients.”
“We hope that these data will help health authorities to recognize the efficacy of occipital nerve stimulation and consider its approval for use in patients with intractable chronic cluster headache,” they concluded.
Chronicity emerges or may be present from cluster headache onset in about 15-20% of patients, and a similar proportion of those are considered medically refractory.
Treatments remain imperfect, and episodic, chronic, and refractory cluster headaches have been associated with suicidality. A 2019 study found passive suicidal ideation, active suicidal ideation, suicidal planning, and suicidal attempt reported by 64.2% 35.8%, 5.8%, and 2.3%, respectively, of patients during attacks. In periods of attack absence between clusters, the respective figures were 0%, 1.9%, 1.9%, and 0%, highlighting the need for more effective treatments.
In the ICON study, there was no difference in serious adverse events between stimulation intensity groups. About a third of participants overall had a serious adverse event, “a proportion that is similar to other ONS studies,” Ferrari and colleagues wrote. “Two thirds of these events consisted of replacing an empty implantable pulse generator or a dislocated or fractured electrode or lead,” they continued.
“In this context, it is important to realize that the hardware we used in the study was developed for epidural spinal cord stimulation,” they wrote. “However, the bending forces in ONS are much greater, increasing the risk of fracture or dislocation.”
Rechargeable implantable pulse generators are available, although not used in the initial phase of the study, they noted, and a more flexible electrode adjustable to the shape of the skull and resistant to migration recently became available.
One patient had a stroke judged non-related to the intervention, and there were no deaths.
Limitations of the study include varying electrical doses, which were defined not in absolute voltage terms, but were individualized based on the paresthesia threshold of each patient.
This, and “the fact that patients in both groups had paresthesia (to maintain blinding), suggest that this controlled study actually compared similar treatments in both groups,” the editorialists observed. “This is concordant with the common opinion of physicians who do ONS: that the lowest stimulation intensity that induces paresthesia is sufficient to obtain an effect in the patients who respond.”
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Occipital nerve stimulation, an invasive treatment involving implanted electrodes, reduced the frequency of medically intractable chronic cluster headache attacks and was well tolerated, the ICON study found.
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Effects were evident within several weeks and sustained over 48 weeks. Most serious adverse effects were related to implanted electrodes (neck) and stimulator box (abdomen or buttocks).
Paul Smyth, MD, Contributing Writer, BreakingMED™
This study was funded by the Netherlands Organization for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.
Ferrari reports grants and consultancy or industry support from Electrocore, Medtronic, Eli Lilly, Amgen, Novartis, and TEVA, and independent support from the Netherlands Organization for Scientific Research, the Netherlands Organisation for Health Research and Development, the Dutch Brain and Heart Foundations, the Dutch Ministry of Health, and the NutsOhra Foundation from the Dutch Insurance Companies.
Lanteri-Minet declares financial support to their institution from Medtronic and St. Jude and consulting fees from Medtronic. Fontaine declares financial support to their institution from Medtronic and St Jude Abbott and consulting fees and support for attending meetings or travel from Boston Scientific, Medtronic, and Abbott.
Cat ID: 130
Topic ID: 82,130,730,130,35,192,925
