Headache Medicine, v.10, n.3, p.70-72, 2019
70
ABSTRACT
RESUMO
Descritores: cetamine, cefaleias crônicas, cefaleias refratárias
Feasibility of intravenous ketamine infusion for refractory
headache
Viabilidade da infusão intravenosa de cetamina para cefaleias
refratárias
Iron Dangoni Filho
H
álisson Flamini Arantes
Ulisses Cardoso D´Orto
Luis Sergio Fernandes Marques
Bruno Schuind Arantes
Mario Fernando Prieto Peres
HIAE - Hospital Israelita Albert Einstein
*Correspondence
Mario Fernando Prieto Peres
E-mail: marioperes@usp.br
Received: September 14, 2019.
Accepted: September 21, 2019.
Background: Ketamine intravenous infusion has been used safely to several
chronic pains and it is a good option to refractory chronic headaches. It is a
noncompetitive NMDA receptor antagonist that blocks glutamate, responsible
for the dissociation between thalamus-neocortical and limbic systems, leading
to changes in patients’ pain perception. Due to this theorical mechanism and
results in reducing cortical spreading depression, Ketamine has been proposed
as a treatment for migraine. Methods: We conducted a retrospective medical
chart review study at Hospital Israelita Albert Einstein including three patients.
All of them were diagnosed previosly with refractory chronic headache. Results:
Of participants included (n = 3), two were woman. The median duration of the
disease was 21 years and 12 previous treatment’s failures. All the patients were
currently in use of more than 4 preventive drugs. Treatment-emergent response
was seen in all patients, requiring 1, 3 and 4 sessions to complete plain remission.
They presented good tolerability to the treatment. One patient complained of
tinnitus and mild dizziness at the end of the last session, which lasted less than
30 minutes. Conclusion: Ketamine is well tolerated and an effective treatment
for patients with refractory chronic headache.
Keywords: Ketamine, chronic headache, refractory headache
Justicativa: A infusão intravenosa de cetamina tem sido utilizada com
segurança em diversas dores crônicas e é uma boa opção para dores de cabeça
crônicas refratárias. É um antagonista não competitivo do receptor de NMDA
que bloqueia o glutamato, responsável pela dissociação entre os sistemas
tálamo-neocortical e límbico, levando a alterações na percepção da dor dos
pacientes. Devido a esse mecanismo teórico e redução da depressão cortical
alastrante, a cetamina foi proposta como tratamento para enxaqueca. Métodos:
Realizamos um estudo retrospectivo de revisão de prontuários no Hospital
Israelita Albert Einstein, incluindo três pacientes. Todos foram diagnosticados
previamente com cefaleia crônica refratária, enxaqueca crônica. Resultados:
Dos participantes incluídos (n = 3), dois eram do sexo feminino. A duração
média da doença foi de 21 anos e 12 falhas do tratamento anterior. Todos os
pacientes estavam atualmente em uso de mais de 4 medicamentos preventivos.
A resposta emergente ao tratamento foi observada em todos os pacientes,
exigindo 1, 3 e 4 sessões para concluir a remissão simples. Eles apresentaram
boa tolerabilidade ao tratamento. Um paciente apresentou queixa de zumbido
e tontura leve no nal da última sessão, que durou menos de 30 minutos.
Conclusão: A cetamina é bem tolerada e um tratamento ecaz para pacientes
com cefaleia crônica refratária.
ORIGINAL ARTICLE
10(3).indb 70 21/10/2019 18:53:44
Ketamine infusion for headache
Dangoni Filho I, et al.
71
Headache Medicine, v.10, n.3, p.70-72, 2019
INTRODUCTION
Refractory chronic headache is responsible for high
nancial costs to the health system, considering the
frequent use of services and disability in the economically
active population. One of the currently used treatment
options is ketamine¹. This drug has been used to treat
several chronic pains with good results, and some reports
on refractory headaches also indicate good response
2-4
.
Ketamine is a dissociative anesthetic that acts on
glutamate binding sites at the N-methyl-D-aspartate
receptor (NMDA), as well as at opioid, monoaminergic,
cholinergic, nicotinic, and muscarinic receptors
5,6
.
There is a theory of functional and electrophysiological
dissociation between thalamus-neocortical and limbic
systems: sensory afferences may reach cortical receptor
areas, but are not observed in some areas of association
with ketamine use
7,8
. Analysis of the effects of dose-
dependent ketamine on pain processing showed reduced
activation of the secondary somatosensory cortex, insula
and anterior cingulate, which has been associated with the
affective component of pain
9
. This theoretical mechanism
of action of ketamine has been shown to decrease central
sensitization and allodynia, which has motivated physicians
to use it as a treatment for migraine. Ketamine also reduces
cortical spreading depression in animal models. The most
common known side effects may include cardiovascular
instability, respiratory changes, and psychiatric symptoms,
including acute psychosis, hallucinations, anxiety, but are
generally dose dependent
4
.
Although Ketamine infusions has been widely
used in depression and chronic pain conditions, limited
information is available in Brazil regarding this option in
refractory headache patients.
METHODOLOGY
We conducted a retrospective medical chart review
study. In 2018, a total of three patients were admitted
to a day hospital for continuous intravenous ketamine
treatment at Hospital Israelita Albert Einstein, in São
Paulo. Data were collected from medical records obtained
from electronic medical records. Prior to admission,
patients were already diagnosed with refractory chronic
headache by a specialist neurologist for headache.
Patients were evaluated by neurologists (HFA,
MFPP) monitored by a team of anesthetists (UCD, LSFM,
BSA), who repeated the same infusion procedure in all
cases. The protocol used was 30 mg IV ketamine diluted
in 0.9% saline 100 ml, with a one-hour continuous infusion
pump infusion time. Number of previous treatments,
headache history time, pain intensity before and after
infusion (visual analog scale), tolerability (adverse
effects) and number of applications were evaluated in
the patients.
RESULTS
The age ranged from 39 to 53 years and two out
of three patients were women. EVA scores at admission
were nine or ten. All patients were Brazilian, born in São
Paulo. The median duration of the disease was 21 years
(range 20-24). The average number of failures in previous
treatments was 12 and were currently in use of more
than 4 preventive treatments. Two out of three patients
receiving ketamine had a previous psychiatric diagnosis
(depression and panic syndrome). All three patients were
on at least one of the following medications: muscle
relaxant, NSAID, opioid, antiepileptic, antidepressant,
benzodiazepine, triptan, beta blocker or antiemetic.
Responses from 3 patients, one man and 2 women
were evaluated. Patient 1, 50 years old, required 3
sessions for complete pain remission, evolved with
good tolerability, no comorbidities. Patient 2, 53 years
old, previously diagnosed with depression and chronic
neck pain, required 4 sessions for complete pain relief (1
session per week), tinnitus and mild dizziness lasting less
than 30 min only at the end of the last session. Patient 3,
39 years old, previously diagnosed with panic syndrome,
underwent only 1 session of IV ketamine with complete
pain remission, with no reports of adverse events.
DISCUSSION
Intravenous ketamine has been proposed for the
treatment of headache disorders. Despite the small
number of patients in the case series and the absence
of a comparative placebo group, we have demonstrated
short-term success in pain relief in patients with chronic
headache with tolerable and short-term adverse effect. It
is biologically plausible that ketamine may be an effective
treatment for intractable headaches. Since Ketamine has
been used for depression and severe headache patients
are likely to present with comorbid depression, its use
may have multiple benets.
Ketamine use has been very effective, has variable
durability and has side effects with anomalous body
and consciousness sensations but not reported
as uncomfortable. Its application is feasible in our
environment, the use of infusion pump makes the
procedure expensive and is in our opinion unnecessary.
Despite the fear of the side effects prole, they are all
easy to handle.
CONCLUSION
Intravenous infusion ketamine protocol is feasable,
safe, and effective. It can be done in a non-hospitalized
infusional environment, alleviates pain without substantial
adverse effects. Future studies are necessary to stablish
the role of ketamine infusion in other headache conditions.
REFERENCES
1. Kaube H, Herzog J, Kaufer T, Dichgans M, Diener HC (2000)
Aura in some patients with familial hemiplegic migraine can
be stopped by intranasal ketamine. Neurology, 55(1):139–141.
2. Cohen SP, Bhatia A, Buvanendran A, et al (2018)
Consensus Guidelines on the Use of Intravenous Ketamine
Infusions for Chronic Pain From the American Society of
Regional Anesthesia and Pain Medicine, the American
Academy of Pain Medicine, and the American Society of
Anesthesiologists. Reg Anesth Pain Med, 43(5):521–546.
10(3).indb 71 21/10/2019 18:53:44
Ketamine infusion for headache
Dangoni Filho I, et al.
Headache Medicine, v.10, n.3, p.70-72, 2019
72
3. Schwenk ES, Dayan AC, Rangavajjula A, Torjman MC,
Hernandez MG, Lauritsen CG (2018) Ketamine for Refractory
Headache: A Retrospective Analysis. Reg Anesth Pain Med,
43(8):875-879.
4. Eikermann-Haerter K, Can A, Ayata C (2012)
Pharmacological targeting of spreading depression in
migraine. Expert Rev Neurother, 12(3):297–306.
5. Matue M, Edward FD (1968) Neuronal mechanisms of
ketamine-induced anestesia. International Journal of
Neuropharmacology, 7(6):557-573.
6. Jamie S, Martyn H, Logan V, Bill D (2014) Ketamine – More
mechanisms of action than just NMDA blockade. Trends in
Anaesthesia and Critical Care, 4(2-3):76-81.
7. Mion G, Villevieille T (2013) Ketamine pharmacology: an
update (pharmacodynamics and molecular aspects, recent
ndings). CNS Neurosci Ther, 19(6):370-380.
8. Cai ZJ (2018) The limbic-reticular coupling theory of
memory processing in the brain and its greater compatibility
over other theories. Dement Neuropsychol, 12(2):105–113.
9. Sprenger T, Valet M, Woltmann R, Zimmer C, Freynhagen R,
Kochs EF, Tölle TR, et al (2006) Imaging pain modulation by
subanesthetic S-(+)-ketamine. Anesth Analg, 103(3):729-
737.
10(3).indb 72 21/10/2019 18:53:44
