Chronic Cluster Headache Clinical Trial
Official title:
Occipital Nerve Stimulation in Medically Intractable Chronic Cluster Headache
Cluster headache (CH) is a primary headache disorder characterized by recurrent short-lasting
attacks (15 to 180 minutes) of excruciating unilateral periorbital pain accompanied by
ipsilateral cranial autonomic signs. The 1-year prevalence of CH is about 0.1 %, the male:
female ratio is 3:1. The majority of patients have cluster periods of weeks to months with
frequent attacks which are alternated with symptom-free periods of months to several years;
the episodic from of CH. In about 10% of patients the CH is chronic (CCH) in which either no
remission occurs within 1 year or the remissions last less than 1 month. At least 10 % of CCH
patients are refractory to medical treatment or cannot tolerate the treatments.
Recent pilot studies suggest that occipital nerve stimulation (ONS) in medically intractable
CCH (MICCH) might offer an effective alternative to medical treatment. There are no
randomised clinical trials and a placebo effect cannot be excluded. Long term tolerability is
known from other indications.
Here the investigators propose a prospective, randomised, double blind, parallel group
multi-centre international clinical study to compare the reduction in attack frequency from
baseline of occipital nerve stimulation (ONS) in patients with MICCH between two different
stimulation conditions: high (100%) and low (30%) stimulation.
Following implantation there will first be a run-in phase of 10 days of 10% stimulation
intensity, followed by a stepwise monthly increase up to either 30% or 100%. Patients will be
assessed monthly by a blinded assessor. The primary outcome measure is the mean number of
attacks over the last 4 weeks of the double blind 6 month treatment period in the 100% versus
the 30% treatment group. Hereafter, in an open extension phase of 6 months, all patients will
receive 100% stimulation or the stimulation considered optimal by the patient.
Secondary outcome measures include the rate of responders (≥ 50% reduction in attack
frequency during the last 4 weeks of each treatment period), patient's satisfaction,
medication use, quality of life, mean pain intensity, economic evaluation and whether
patients would recommend the treatment to another patient. The investigators will also
investigate whether predictive factors can be identified for efficacy.
Trigeminal autonomic cephalalgias (TACs) are characterized by frequent, short-lasting attacks
of unilateral extremely severe headaches accompanied by ipsilateral facial autonomic features
and are the most severe of the primary headache disorders. TACs include cluster headache
(CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache with
conjunctival injection and tearing (SUNCT). CH is the most common form of TAC. The 1-year
prevalence is about 1 in 1000, with the vast majority of patients having episodic CH (ECH):
periods of weeks to months with frequent attacks which are alternated with symptom-free
periods of several months to years. About 10% have chronic CH (CCH): attack free periods of
less than one month in every 12 months, unless treatment is given. The chronic form can be
primary unremitting from onset, or can be secondary, transform from the episodic form. CCH
may spontaneously become episodic.
Effective acute treatments for CH attacks are injectable or intranasal triptans and oxygen
inhalation. Steroids (only for a short period), verapamil, lithium carbonate and methysergide
are the most effective preventive therapies. At least 10% of patients with CCH is or may
become refractory to or cannot tolerate medical therapy. For patients with medically
intractable CCH (MICCH) there is no common treatment. Different experimental treatments, such
as deep brain stimulation (DBS), radiofrequency lesions, glycerol injections, gamma knife,
and surgery or root section of the trigeminal nerve are either substantially ineffective, or
have significant short-comings with serious complications such as death or neurological
deficits such as anaesthesia dolorosa or lack of efficacy.
CH has considerable impact on socio-economic and personal functions due to direct costs of
healthcare services and indirect costs of lost work days and decreased work efficacy. Higher
pain scores and a higher percentage of patients with poor health due to pain and social
functioning are found among CH patients compared with patients suffering from migraine. The
impact on social functions, quality of life and use of healthcare of patients with MICCH is
most likely even larger, although precise figures are not available. In the study of Burns et
al. patients, suffering from MICCH, had on average over four attacks per day. Attacks of CH
have been described by patients as being worse than child birth. Recently treatment of
headache was listed as one of the top priorities of US National the Institute of Medicine's
agenda for comparative-effectiveness research.
Functional imaging studies in CH identified activations in the region of the posterior
hypothalamus, which led to the use of neurostimulation therapy in MICCH. Hypothalamic DBS was
shown to be effective in some patients with MICCH but unfortunately this treatment is
associated with a high risk of (even lethal) consequences.
Structures in the occipital region of the head are mainly innervated by the greater occipital
nerve that is a branch of the C2 spinal root. Convergence of cervical, somatic trigeminal and
dural trigeminovascular afferents on second order nociceptors in the brain stem is well
documented. Stimulation of the greater occipital nerve increased metabolic activity in
cervical regions of the spinal cord and in the trigeminal nucleus caudalis in the cat. In
humans an occipital nerve blockade decreased the ipsi- and contralateral R2 response,
confirming the anatomic and functional convergence of afferent cervical and trigeminal
pathways. These studies suggest that modulation of these pathways may influence headache.
Suboccipital injection of corticosteroid with local anaesthetics was shown to be effective in
a placebo-controlled trial. In this study 4 patients suffering from CCH were included. In all
patients the attacks recurred eventually. The authors suggest that suboccipital steroid
injections ought to be tried as a single shot treatment before invasive treatments are
considered such as DBS, but in later studies this turned out to be of no predictive value of
the response to neuromodulation therapies.
Along the same line, stimulation of the greater occipital nerve (ONS) has been tried with
some success in intractable headaches including CCH. Burns et al. described 14 patients
suffering from MICCH and were treated with ONS in an open retrospective study. Ten patients
improved; three improved by 90% or more, 3 by 40%-90% and 4 by 20-30%. In a prospective open
ONS study on MICCH patients Magis et al. showed a reduction in attack frequency of 79.9%. No
serious complications were described in both studies.
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