Ketamine is a drug used for anesthesia but at low doses it is a very effective pain reliever in several chronic conditions. Preliminary studies have shown that ketamine might be effective for patients with refractory chronic migraine, which is a severe type of headache for which patients usually have tried and failed many medications and can cause severe disability to their lives. This study will evaluate ketamine prospectively when given to patients who have "failed" an initial inpatient treatment.

This study is a comparison between ketamine, used in the standard fashion at Thomas Jefferson University Hospital (TJUH) for 5 days, and past data collected from inpatient treatment at Methodist Hospital. The collection of blood samples is the only experimental part of the study.

Eligible patients will be identified by a study team member at the end of inpatient treatment at Methodist Hospital. The study will be explained to patients at that time. Patients who express interest in participation will be given a consent packet to take home and bring to their office visit at Jefferson Headache Center prior to admission to TJUH for ketamine infusions. Patients will be given the time to read over the study information and have all questions answered to their satisfaction. The will provide informed consent at the end of the office visit if they choose to participate. Baseline demographic information and past medical history including current medications and medications previously tried will be collected. Patients and assessors will not be blinded to treatment.

When the patient is admitted to the hospital for treatment, the neurology team will be the admitting team and will consult the Acute Pain Service (APS) for assistance with management of ketamine, which is standard practice when ketamine is used for headache treatment at TJUH. Patients will be admitted for a total of 5 full days from the time of admission until discharge. Adjustments to ketamine infusion will be made according to standard APS protocol and data will be collected by the research coordinator or other study team personnel. A standard 11-point numeric rating scale (NRS) will be used to obtain pain ratings and they will be collected twice daily. A 4-point pain assessment scale (0=none, 1=mild, 2=moderate, 3=severe) will also be used. Blood samples will be collected at baseline and at 24 hours, 72 hours, and the final day of treatment. They will be performed at external laboratories. A daily headache diary will be used for all patients and they will be given instructions how to use one prior to discharge. A depression screening will be performed on day of admission to TJUH.

Follow-up office visits at approximately 2 weeks and 2 months will be used for collection of pain ratings and medication use. Headache diaries will be collected. If telephone visits occur, assessments will be done over the phone in place of an office visit.

Inclusion Criteria:

• All adult patients (age 18 years and older) who meet the criteria of refractory chronic migraine as defined by the International Classification of Headache Disorders-II definition who present to the Jefferson Headache Center after failing an inpatient course of treatment at Methodist.

Exclusion Criteria:

• Schizophrenia
• active psychosis
• pregnancy
• poorly controlled cardiovascular disease
• cirrhosis
• previous treatment with intravenous ketamine

These criteria are all consistent with the 2018 Consensus Guidelines for Ketamine. Patients who are deemed poor candidates for ketamine by a study team member for any reason, such as intolerance of prior neuroleptic medications, may be excluded.

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