Intravenous ketamine for subacute treatment of refractory chronic migraine: a case series
- Clinton Lauritsen†1Email authorView ORCID ID profile,
- Santiago Mazuera†1,
- Richard B. Lipton2 and
- Sait Ashina3
© The Author(s). 2016
Received: 19 October 2016
Accepted: 17 November 2016
Published: 22 November 2016
Refractory migraine is a challenging condition with great impact on health related quality of life. Intravenous (IV) ketamine has been previously used to treat various refractory pain conditions. We present a series of patients with refractory migraine treated with intravenous ketamine in the hospital setting.
Based on retrospective chart review, we identified six patients with refractory migraine admitted from 2010 through 2014 for treatment with intravenous ketamine. Ketamine was administered using a standard protocol starting with a dose of 0.1 mg/kg/hr and increased by 0.1 mg/kg/hr every 3 to 4 h as tolerated until the target pain score of 3/10 was achieved and maintained for at least 8 h. Visual Analogue Scale (VAS) scores at time of hospital admission were obtained as well as average baseline VAS scores prior to ketamine infusion. A phone interview was conducted for follow-up of migraine response in the 3 to 6 months following ketamine infusion.
The study sample had a median age of 36.5 years (range 29–54) and 83% were women. Pre-treatment pain scores ranged from 9 to 10. All patients achieved a target pain level of 3 or less for 8 h; the average ketamine infusion rate at target was 0.34 mg/kg/hour (range 0.12–0.42 mg/kg/hr). One patient reported a transient out-of-body hallucination following an increase in the infusion rate, which resolved after decreasing the rate. There were no other significant side effects.
IV ketamine was safely administered in the hospital setting to patients with refractory chronic migraine. Treatment was associated with short term improvement in pain severity in 6 of 6 patients with refractory chronic migraine. Prospective placebo-controlled trials are needed to assess short term and long-term efficacy of IV ketamine in refractory chronic migraine.
Chronic migraine and refractory migraine have long challenged clinicians. In the United States, chronic migraine prevalence is nearly 1% and results in enormous impact on headache-related disability, including higher Migraine Disability Assessment Test (MIDAS), reduced health-related quality of life (HRQoL), increased depression and anxiety (PHQ-4 and GAD-7 respectively), compared to episodic migraine [1–6]. Chronic migraine has also been shown to result in greater economic burden and health care resource utilization [1, 3, 7–9]. Annually, the total economic cost of chronic migraine is over three time that of episodic migraine, when consider direct medical costs and loss from decreased productivity .
Refractory migraine is included in ICHD-2  and ICHD-3 beta  but criteria for intractable headache have only recently emerged . Silberstein et al.  assesses the type and number of treatments the patient failed as well as the clinical setting and the intensity of invention for intractable headache. Multiple treatment options have been proposed for management of refractory migraine including intravenous dihydroergotamine (DHE) and intravenous divalproex sodium [13, 14].
One candidate treatment for intractable migraine is ketamine. Intravenous ketamine has been studied in various refractory pain conditions including complex regional pain . Intranasal ketamine reduced the severity of aura in migraine with prolonged aura in a small randomized trial . The use of intravenous ketamine has only been reported in case series. Krusz et al.  demonstrated improvement in pain scores in patients with refractory migraine as well as few side effects associated with treatment.
Ketamine is a dissociative anesthetic that acts on glutamate binding sites at the N-methyl-D-aspartate (NMDA) receptor as well as at opioid, monoaminergic, cholinergic, nicotinic, and muscarinic receptors . There is a theory of functional and electrophysiological dissociation between thalamo-neocortical and limbic systems: sensory inputs may reach cortical receiving areas, but fail to be observed in some of the association areas with the use of ketamine . Analysis of the dose-dependent ketamine effects on pain processing showed a decreasing activation of the secondary somatosensory cortex, insula, and anterior cingulate cortex, which has been linked to the affective pain component that underlines the potency of ketamine in modulating affective pain processing . This theoretical mechanism of action of ketamine has shown to decrease central sensitization and allodynia in pain conditions, which has motived clinicians to use it as treatment for migraine. Ketamine also reduces cortical spreading depression in animal models . Most common known side effects of ketamine may include cardiovascular instability, respiratory changes and psychiatric symptoms including acute psychosis, hallucinations, anxiety but are usually dose-dependent.
Herein, we report the effect of IV ketamine on a series of six patients with intractable migraine treated with escalated doses on an inpatient basis.
We performed a retrospective chart review study. From 2010 until 2014, a total of six patients were admitted for treatment with continuous intravenous ketamine to Mount Sinai Beth Israel Hospital in New York. Data were collected from charts obtained from the medical record department and electronic medical records (PRISM). The study was approved by the Mount Sinai Institutional Review Board. Prior to admission, a diagnosis of chronic migraine without aura based on ICHD-2 criteria was made by a headache specialist (Sait Ashina). Demographics, number of prior migraine treatments and current use of medications such as opioids, antidepressants, beta blockers, antiepileptic medications and nonsteroidal anti-inflammatory drugs (NSAIDs) were documented, as well as onset age of migraine diagnosis.
All the patients received information regarding side effects and risks associated with the treatment and informed written consent was obtained prior to infusion. Monitoring of the treatment was done according to the ketamine infusion procedure policy of the Department of Pain Medicine and Palliative Care at Mount Sinai Beth Israel (see Additional file 1 for sources used in protocol development). Following an initial electrocardiogram (EKG) for all patients and a pregnancy test for female patients, ketamine was administered using a standard protocol starting with an initial intravenous infusion of 0.1 mg/kg/hr. The infusion was increased by 0.1 mg/kg/hr every 3 to 4 h as tolerated until the goal pain score of 3/10 was maintained for 8 h. The eight-hour designation was made based on standard pain assessment intervals in the institution. Thereafter, the infusion was decreased by 0.2 mg/kg/hr every 3to 4 h until the infusion rate reached 0 mg/kg/hr. The dose of ketamine escalated as needed until maximal response or until undesirable side effects including psychomimetic and dysphoric effects.
Visual Analogue scale (VAS) score was used at the moment of admission and follow-up VAS scores at different ketamine infusion rates were assessed from nursing and infusion records. We defined a pain response as a reduction in the initial VAS to a score of three or less. Side effects were identified and reported.
We attempted to contact the patients in this retrospective study for telephone follow-up; however, we were only able to reach two of the six patients. During telephone interview, a questionnaire including MIDAS  was administered.
The demographic and clinical data and intravenous (IV) ketamine infusion rates at which 6 patients achieved a VAS pain score of 3 or less
Age at migraine onset
Duration of Illness
Psychiatric and Pain Comorbidities
IV Ketamine Rate VAS < 3
Time to maintain VAS of 3 or less for duration of 8 h
Depression, Panic Attacks, Chronic Back Pain
Complex Regional Pain Syndrome
Depression, Borderline Personality Disorder, Chronic Neck Pain
Outpatient medical regimen in patients with chronic migraine cases at time of scheduled treatment with intravenous ketamine
Number of previously failed medications for each patient
Abortive Medications Failed
Preventive Medications Failed
In this small cases series, all six patients with refractory migraine met the target pain relief endpoint with ketamine over a mean infusion of 44 h (range 12–82). Mean ketamine infusion rate at the time of pain relief endpoint was 0.34 mg/kg/hour (range 0.12–0.42). Patients achieved pain relief without substantial adverse effects. One patient reported a brief dissociative experience, which reversed.
Intravenous ketamine use in treating refractory depression has recently been well established [22, 23]. Studies have also suggested a role for ketamine in the treatment of intractable chronic pain including long-term analgesic effect persisting beyond the duration of infusion . Long-term ketamine infusion (4–14 days) has been shown to decrease pain for up to 3 months . Allodynia, a marker of chronic pain and central sensitization of nociceptive pathways, has also been shown decrease with intravenous ketamine infusion. Interestingly, this effect was not achieved until 4–5 days of continuous infusion .
The existing literature on IV ketamine for the treatment of headache is limited. Though our case series is modest in size, and in the absence of a contemporaneous placebo group, causal inferences are not possible, we demonstrated short-term success in pain relief in intractable migraine patients with one significant but short-lived adverse event. It is biologically plausible that ketamine could be an effective treatment for intractable headache. Ketamine is an antagonist at NMDA receptors, blocking the excitatory action of glutamate (Glu), a neurotransmitter long implicated in the pathophysiology of migraine . Glu has been shown to be implicated in induction of cortical spreading depression (CSD), activation of trigeminal nociceptive neurons as well as play a role in central sensitization. Previous studies have identified variants in the gene for GluA receptors in persons with migraine .
To date, there has been a lack of treatments with reliable abortive effect on migraine aura, the phenomenon attributed to CSD. In the rat-model, both ketamine and the non-specific NMDA antagonist, MK-801 have been shown to block CSD, demonstrated electrophysiologically and by fMRI . In a double-blinded, randomized parallel-group controlled study of 18 patients with migraine with aura, Afridi et al. tested the effect of intranasal ketamine compared to midazolam on aura. Ketamine was shown to reduce severity of aura but not duration, whereas midazolam had no effect . Intranasal ketamine has been shown to consistently improve aura symptoms in some patients with familial hemiplegic migraine, although without significant reduction of headache severity . Note: Broadly blocking CSD with long term administration is viewed as a model for preventive treatment . Memantine is a voltage-dependent noncompetitive antagonist at the glutamatergic NMDA receptor, which inhibits the prolonged influx of calcium associated with neuronal excitotoxicity. In order to identify an agent with preventive activity against refractory and chronic migraine, Bigal, et al. administered daily memantine to 28 patients in an unblinded protocol. Compared to baseline, at 3 months, memantine decreased headache frequency severe headaches and MIDAS scores . Ketamine may be a particularly beneficial treatment option for patients that have failed memantine. Because ketamine is the most potent competitive antagonist at the NMDA-type glutamate receptor whereas memantine is a weaker and noncompetitive antagonist, ketamine may have greater impact on central sensitization . Also of interest, in patients concomitantly treated with opioids, ketamine has been shown to increase pain relief. This may suggest a role for ketamine in the treatment of medication overuse headache.
Of the patients that completed follow up questionnaires, none reported lasting benefit from ketamine 3–6 months post infusion. Prior publications have reported lasting effects on chronic non-headache pain reduction following long term infusions of more than 4 days. Of note, none of the patients included in this case series received ketamine infusion for more than 4 days. Thus, we propose that future studies target ketamine infusions for at least this duration. Once placebo controlled studies on acute headache relief are performed, studies assessing long-term benefits should begin. Strategies for maintaining the effect of intravenous ketamine infusion should also be studied, such as the ongoing administration of a daily or as needed NMDA receptor antagonist. Researchers have used similar strategies in prior studies, such as with the use of mexiletine following lidocaine infusion for chronic daily headache. In this fashion, agents including dextromethorphan-quinidine, memantine, oral or intranasal ketamine could be used to maintain the benefit from NDMA receptor antagonism following ketamine infusion [35, 36].
This study highlights the need for further research regarding new treatment options for patients who suffer daily consequences of refractory migraine and have failed many abortive and preventive medications. Our IV ketamine infusion protocol, based on gradually dose escalation, relieves pain without substantial adverse effects. However, future study of this benefit on short-term headache relief needs to be conducted in a placebo-controlled fashion and this publication may serve as the basis for the design of such a trial.
Please note a preliminary version of this research was presented as an abstract at the Congress of the International Headache Society in May 2015 .
CL, SM, SA, and RL were responsible for the conception and design and the study. CL and SM performed chart reviews with analysis of data. CL, SM, SA, and RL were resposible for interpretation of data, drafting of the manuscript and making intellectual contributions to its content. All authors read and approved the final manuscript.
Clinton Lauritsen, Santiago Mazuera and Sait Ashina previously worked at Mount Sinai Beth Israel Hospital. Clinton Lauritsen and Santiago Mazuera have no disclosures. Sait Ashina received honoraria for lecturing from Allergan, Teva Pharmaceuticals, Avanir Pharmaceuticals and served as a consultant for Avanir Pharmaceuticals. Richard Lipton received research support from the NIH [PO1 AG03949 (Program Director), RO1AG025119 (Investigator), RO1AG022374-06A2 (Investigator), RO1AG034119 (Investigator), RO1AG12101 (Investigator), K23AG030857 (Mentor), K23NS05140901A1 (Mentor), and K23NS47256 (Mentor)], the National Headache Foundation, and the Migraine Research Fund; serves on the editorial board of Neurology; has reviewed for the NIA and NINDS; holds stock options in eNeura Therapeutics; and serves as consultant, advisory board member, or has received honoraria from Allergan, American Headache Society, Autonomic Technologies, Boston Scientific, Bristol Myers Squibb, Cognimed, Colucid, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, MAP, Merck, Nautilus Neuroscience, Novartis, NuPathe, Pfizer, and Vedanta.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Blumenfeld AM et al. (2011) Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS). Cephalalgia 31(3):301–15View ArticlePubMedGoogle Scholar
- Buse DC et al. (2012) Chronic migraine prevalence, disability, and sociodemographic factors: results from the American migraine prevalence and prevention study. Headache 52(10):1456–70View ArticlePubMedGoogle Scholar
- Lipton RB et al. (2011) OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine. Neurology 77(15):1465–72View ArticlePubMedGoogle Scholar
- Schulman EA et al. (2008) Defining refractory migraine and refractory chronic migraine: proposed criteria from the Refractory Headache Special Interest Section of the American Headache Society. Headache 48(6):778–82View ArticlePubMedGoogle Scholar
- Adams AM et al. (2015) The impact of chronic migraine: the chronic migraine epidemiology and outcomes (CaMEO) study methods and baseline results. Cephalalgia 35(7):563–78View ArticlePubMedPubMed CentralGoogle Scholar
- D’Amico D et al. (2013) Disability and quality of life in headache: where we are now and where we are heading. Neurol Sci 34(Suppl 1):S1–5View ArticlePubMedGoogle Scholar
- Lipton RB et al. (2016) OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine over one year of treatment: pooled results from the PREEMPT randomized clinical trial program. Cephalalgia 36(9):899–908View ArticlePubMedPubMed CentralGoogle Scholar
- Messali A et al. (2016) Direct and indirect costs of chronic and episodic migraine in the united states: a Web-based survey. Headache 56(2):306–22View ArticlePubMedGoogle Scholar
- Wang SJ et al. (2013) Comparisons of disability, quality of life, and resource use between chronic and episodic migraineurs: a clinic-based study in Taiwan. Cephalalgia 33(3):171–81View ArticlePubMedGoogle Scholar
- Headache Classification Subcommittee of the International Headache, S (2004) The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24(Suppl 1):9–160Google Scholar
- Headache Classification Committee of the International Headache, S (2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33(9):629–808View ArticleGoogle Scholar
- Silberstein SD, Dodick DW, Pearlman S (2010) Defining the pharmacologically intractable headache for clinical trials and clinical practice. Headache 50(9):1499–506View ArticlePubMedGoogle Scholar
- Norton J (2000) Use of intravenous valproate sodium in status migraine. Headache 40(9):755–7View ArticlePubMedGoogle Scholar
- Peterlin BL et al. (2008) Rational combination therapy in refractory migraine. Headache 48(6):805–19View ArticlePubMedGoogle Scholar
- Goldberg ME et al. (2005) Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician 8(2):175–9PubMedGoogle Scholar
- Afridi SK et al. (2013) A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology 80(7):642–7View ArticlePubMedGoogle Scholar
- Krusz J, Cagle J, Hall S (2008) Efficacy of IV ketamine in treating refractory migraines in the clinic. J Pain 9(4):30Google Scholar
- Corssen G, Domino EF (1966) Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg 45(1):29–40View ArticlePubMedGoogle Scholar
- Sprenger T et al. (2006) Imaging pain modulation by subanesthetic S-(+)-ketamine. Anesth Analg 103(3):729–37View ArticlePubMedGoogle Scholar
- Sanchez-Porras R et al. (2014) The effect of ketamine on optical and electrical characteristics of spreading depolarizations in gyrencephalic swine cortex. Neuropharmacology 84:52–61View ArticlePubMedGoogle Scholar
- Stewart WF et al. (1999) An international study to assess reliability of the migraine disability assessment (MIDAS) score. Neurology 53(5):988–94View ArticlePubMedGoogle Scholar
- Coyle CM, Laws KR (2015) The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol 30(3):152–63View ArticlePubMedGoogle Scholar
- Swiatek KM, K Jordan, J. Coffman (2016) New use for an old drug: oral ketamine for treatment-resistant depression. BMJ Case Rep, 2016Google Scholar
- Niesters M, Dahan A, van Kleef M (2016) Safety and efficacy of ketamine for pain relief. Ned Tijdschr Geneeskd 160:D58PubMedGoogle Scholar
- Niesters M, Martini C, Dahan A (2014) Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol 77(2):357–67View ArticlePubMedPubMed CentralGoogle Scholar
- Puchalski P, Zyluk A (2016) Results of the treatment of chronic, refractory CRPS with ketamine infusions: a preliminary report. Handchir Mikrochir Plast Chir 48(3):143–147View ArticlePubMedGoogle Scholar
- Vikelis M, Mitsikostas DD (2007) The role of glutamate and its receptors in migraine. CNS Neurol Disord Drug Targets 6(4):251–7View ArticlePubMedGoogle Scholar
- Ramadan NM (2014) Glutamate and migraine: from Ikeda to the 21st century. Cephalalgia 34(2):86–9View ArticlePubMedGoogle Scholar
- Shatillo A et al. (2015) Involvement of NMDA receptor subtypes in cortical spreading depression in rats assessed by fMRI. Neuropharmacology 93:164–70View ArticlePubMedGoogle Scholar
- Kaube H et al. (2000) Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 55(1):139–41View ArticlePubMedGoogle Scholar
- Ayata C et al. (2006) Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol 59(4):652–61View ArticlePubMedGoogle Scholar
- Bigal M et al. (2008) Memantine in the preventive treatment of refractory migraine. Headache 48(9):1337–42View ArticlePubMedGoogle Scholar
- Grande LA et al. (2008) Ultra-low dose ketamine and memantine treatment for pain in an opioid-tolerant oncology patient. Anesth Analg 107(4):1380–3View ArticlePubMedGoogle Scholar
- Sveticic G et al. (2003) Combinations of morphine with ketamine for patient-controlled analgesia: a new optimization method. Anesthesiology 98(5):1195–205View ArticlePubMedGoogle Scholar
- Taylor CP et al. (2016) Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (nuedexta(R)) clinical use. Pharmacol Ther 164:170–82View ArticlePubMedGoogle Scholar
- Marmura MJ, Passero FC Jr, Young WB (2008) Mexiletine for refractory chronic daily headache: a report of nine cases. Headache 48(10):1506–10View ArticlePubMedGoogle Scholar
- Mazuera S, Ashina S, Lipton RB. (2015) Intravenous Ketamine for the Subacute Treatment of Refractory Chronic Migraine: Case Series: PF24. [Abstract] Headache. 55 Supplement 3:144Google Scholar