Ketamine + Magnesium for Chronic Cluster Headache (KETALGIA) (KETALGIA)

Evaluation of the Efficacy of a Single Infusion of Ketamine Combined With Magnesium Sulfate to Treat Refractory Chronic Cluster Headache

Chronic cluster headache (CCH) is a rare primary headache disorder, defined by episodic attacks that occur for more than one year with no remission period or with remission periods lasting < 3 months (ICHD-3 criteria). In certain cases, CCH patients become drug-resistant and continue to suffer almost daily attacks. Ketamine appears to be effective in a variety of chronic pain conditions, such as refractory headache, and can show an enhanced analgesic effect when combined with magnesium. A single infusion of ketamine-magnesium combination has been described to reduce attacks in 17 patients with rCCH. The main outcome was a comparison of the number of daily attacks two weeks prior to the infusion and one week after (days 7-8). The number of daily attacks decreased from 4.3±2.4 before treatment to 1.3±1.0 after treatment (p<0.001). 13/17 had at least 50% response. Thus, the goal of this placebo-controlled study is to try to confirm these findings.

Chronic cluster headache (CCH) is a rare primary headache disorder, defined by episodic attacks that occur for more than one year with no remission period or with remission periods lasting < 3 months (ICHD-3 criteria). In certain cases, CCH patients become drug-resistant and continue to suffer almost daily attacks. Ketamine appears to be effective in a variety of chronic pain conditions, such as refractory headache, and can show an enhanced analgesic effect when combined with magnesium. A single infusion of ketamine-magnesium combination has been described to reduce attacks in 17 patients with rCCH. The main outcome was a comparison of the number of daily attacks two weeks prior to the infusion and one week after (days 7-8). The number of daily attacks decreased from 4.3±2.4 before treatment to 1.3±1.0 after treatment (p<0.001). 13/17 had at least 50% response. Thus, the goal of this placebo-controlled study is to try to confirm these findings.

infusion will be prepared by a nurse that is not blinded to the treatment and will not take part to patient evaluation. Active and control treatments are of transparent colour and will not be recognisable.

patients in the experimental group will receive 0.5mg/kg of ketamine over 2 hours, diluted in 50cc of NaCl 0.9% and 3g of magnesium sulfate over 30 minutes diluted in 250cc of NaCl 0.9%.

patients in the control group will receive 25mg of hydroxyzine over 2 hours, diluted in 50cc of NaCl 0.9% and 250cc of NaCl 0.9% over 30 minutes

Evaluate the efficacy of a single infusion of ketamine combined with magnesium sulfate compared to a control group receiving hydroxyzine (active placebo) in terms of the proportion of patients with at least 50% daily attacks decrease between the 7 days before infusion and days 7 and 8 after infusion

Evaluate the efficacy of a single infusion of ketamine combined with magnesium sulfate compared to a control group receiving hydroxyzine (active placebo) in terms of the proportion of patients with at least 50% daily attacks decrease between the 7 days before infusion and days 7 and 8 after infusion

evaluated on the electronic diary for each attack using a numeric rating scale (NRS), will be compared between the 7 days before infusion and the day 7 after infusion

evaluated on the electronic diary for each attack using a numeric rating scale (NRS), will be compared between the 7 days before infusion and the day 8 after infusion

proportion of patients in each group reporting any side effect during or in the 24 hours after infusion (together with the type and intensity of these side effects)

proportion of patients in each group reporting any side effect during or in the 24 hours after infusion (together with the type and intensity of these side effects)

magnesemia on the infusion day (D0) will be correlated with 50% response at D7-8 among patients receiving active treatment

magnesemia on the infusion day (D0) will be correlated with 50% response at D7-8 among patients receiving active treatment

Direct medical cost (treatments, consultations, hospitalisations) in each group and cost effectiveness ratio taking 50% responder rate as efficacy criteria

Inclusion Criteria: Age >= 18 years Chronic cluster headache diagnosis made according to ICHD-3 criteria A mean of at least 2 attacks/day during the 14 days before infusion Insufficient efficacy or intolerance or contra-indication to the use of the 3 main validated treatments (verapamil, lithium and sub-occipital steroids injections) Stable preventive treatment for at least 7 days before infusion Exclusion Criteria: Pregnant or lactating woman Contra-indication to ketamine use (uncontrolled high blood pressure, stoke history, severe cardiac failure) Ketamine use during the previous year Hypersensitivity to the product or their metabolites Severe renal insufficiency (creatinine clearance < 30ml/min)