Effect of ketamine combined with magnesium sulfate in neuropathic pain patients (KETAPAIN): study protocol for a randomized controlled trial
Delage et al. Trials
Effect of ketamine combined with magnesium sulfate in neuropathic pain patients (KETAPAIN): study protocol for a randomized controlled trial
Noémie Delage 3
Véronique Morel 0 2
Pascale Picard 3
Fabienne Marcaillou 3
Bruno Pereira 1
Gisèle Pickering 0 2 4
0 Centre de Pharmacologie Clinique , Bâtiment 3C, CIC Inserm 1405, CHU Clermont-Ferrand, BP 69, F-63003 Clermont-Ferrand, Cedex 1 , France
1 CHU de Clermont-Ferrand, Délégation Recherche Clinique & Innovation - Villa annexe IFSI , 58 Rue Montalembert, F-63003 Clermont-Ferrand, Cedex , France
2 Centre de Pharmacologie Clinique , Bâtiment 3C, CIC Inserm 1405, CHU Clermont-Ferrand, BP 69, F-63003 Clermont-Ferrand, Cedex 1 , France
3 Centre d'Evaluation et de Traitement de la Douleur, CHU de Clermont-Ferrand , F-63003 Clermont-Ferrand , France
4 Inserm, U1107 Neuro-Dol, Pharmacologie Fondamentale et Clinique de la Douleur, Laboratoire de Pharmacologie, Faculté de Médecine, Université Clermont Auvergne , F-63000 Clermont-Ferrand , France
Background: Neuropathic pain is difficult to treat, and the efficacy of recommended drugs remains limited. N-methyl-Daspartate receptors are implicated, and antagonists are a pharmacological option. Ketamine is widely used in French pain clinics, but without consensus or recommendations. Furthermore, the association of ketamine with magnesium has been poorly studied. The aim of the present study is to evaluate the benefit of ketamine with or without magnesium in refractory neuropathic pain. Methods/design: A randomized, double-blind, crossover, placebo-controlled study will be performed in ClermontFerrand University Hospital, Clermont-Ferrand, France. The aim is to evaluate the effect of ketamine with or without magnesium in 22 patients with neuropathic pain. Intravenous ketamine/placebo, ketamine/magnesium sulfate, or placebo/placebo will be administered consecutively to each patient, in random order, once at 5week intervals. The primary endpoint is the AUC of pain intensity assessed on a 0-10 Numeric Pain Rating Scale for a 5-week period. Data analysis will be performed on an intention-to-treat basis, and all statistical tests (except primary analysis) will be performed with an α risk of 5% (two-sided). Discussion: Considering the poor efficacy of the drugs available for neuropathic pain, ketamine with or without magnesium sulfate may be a valuable therapeutic option that needs to be standardized.
Ketamine; Neuropathic pain; Magnesium sulfate; N-methyl-D-aspartate receptor; Placebo
Neuropathic pain (NP), whatever the etiology or
topography, presents with a number of clinical
characteristics: sensory deficit, hypoesthesia, electric shock-like
pain, allodynia, or hyperalgesia [
N-methyl-D-aspartate receptors (NMDARs) are involved in the
development of NP and may provide an avenue to a
pharmacological tool for treatment. Ketamine, an
NMDAR antagonist, has been used for a number of
years for the treatment of NP. In animals, it decreases
NP symptoms [
]. In humans, ketamine at
infraanesthetic doses has shown some efficacy in
postoperative pain [
], refractory pain [
], phantom limb pain
], postherpetic neuralgia [
], and complex regional
pain syndrome (CRPS) [
]. Most clinical studies
showing efficacy were retrospective [
], or clinical reports [
]. However, a
few randomized, placebo-controlled, double-blind
studies have also been published [
]. Ketamine appears
to be well tolerated at low doses, with little
psychodysleptic effect [
16, 19, 20, 22, 23
Another NMDAR modulator, magnesium sulfate, is a
physiological blocker of NMDAR and has also been
shown to be effective in the treatment of NP. In animal
NP models, it decreased cold allodynia and thermal and
mechanical hyperalgesia [
] and increased the
analgesic effect of morphine [
]. In humans, it is
well tolerated and has shown efficacy against NP in
patients with cancer [
], headache [
postoperative pain [
], as well as in the frequency of pain
paroxysms and in the emotional component [
Concerning the ketamine-magnesium sulfate
interaction, a preclinical study showed a synergistic effect,
blocking the hyperthermia caused by systemic
administration of morphine [
]. A recent randomized,
prospective, double-blind study [
] of patients undergoing
scoliosis surgery showed that magnesium sulfate
combined with ketamine had a greater beneficial effect on
postoperative pain and morphine consumption than
ketamine alone. Furthermore, patients receiving
ketamine combined with magnesium sulfate reported better
sleep. Magnesium sulfate and ketamine act on different
sites of the NMDAR channel, and this could explain
their synergistic role. This combination is hypothesized
to reduce ketamine dosage and diminish its adverse
events, although another randomized, double-blind,
controlled trial [
] showed no significant difference in
the occurrence of adverse events among patients
receiving ketamine either alone or combined with
magnesium sulfate. Given the lack of randomized clinical
trials of ketamine or the combination of ketamine and
magnesium, the objective of the present randomized,
controlled, double-blind trial is to assess the efficacy of
intravenous ketamine with or without magnesium in
patients with NP.
This is a randomized, placebo-controlled, double-blind,
crossover, single-center clinical study with intravenous
ketamine/placebo, ketamine/magnesium sulfate, and
placebo/placebo injections given to each patient. This
clinical trial is reported according to the Standard
Protocol Items: Recommendations for Interventional
Trials (SPIRIT) guidelines (see Additional file 1) and
performed in Clermont-Ferrand University Hospital,
Clermont-Ferrand, France. Patients meeting the
inclusion criteria will sign a consent form after receiving
oral and written information from a physician
investigator involved in this project. During this
consultation, they will fill out a Numeric Pain Rating Scale
(NPRS), as well as the Diagnosing Neuropathic Pain 4
] in order to detect NP, and they will
be asked to keep a daily pain diary (mean daily pain
and maximum pain on NPRS, and concomitant
analgesic treatment) for 14 days before the first course of
treatment. After inclusion, patients will be randomly
assigned to ketamine-placebo, ketamine-magnesium
sulfate, or placebo-placebo for 1 month, in random
order, with a washout period of 5 weeks between
every treatment (Fig. 1). At each injection, the
patients will undergo a number of tests for assessment
of (1) pain (NPRS, Brief Pain Inventory [BPI] [
McGill Pain Questionnaire [
], and Patient Global
Impression of Change [PGIC] [
]), (2) NP (Neuropathic
Pain Symptom Inventory [NPSI] [
]), (3) anxiety and
depression (Hospital Anxiety and Depression Scale
], (4) quality of life (36-item Short Form Health
Survey [SF-36] [
]), and (5) quality of sleep (Pittsburgh
Sleep Quality Index [PSQI] [
]). All questionnaires will be
administered before each ketamine injection in order not
to influence the results because of the possible ketamine
adverse events. To check for any adverse events, subjects
will be called by phone on the day following each injection.
Ketamine will be administered in ampoules of 50 mg/5 ml
intravenously with an electric syringe at the dose of
0.5 mg/kg diluted in 45 ml of physiological saline (0.9%
NaCl) according to the usual procedures of the pain clinic.
Ketamine and magnesium sulfate
Ketamine will be given according to the protocol
described above combined with an infusion of two ampoules
of 0.15 g/ml of magnesium sulfate (1.5 g per 10 ml)
diluted in 250 ml of physiological saline (0.9% NaCl),
Physiological saline will be administered in injectable
form (0.9% NaCl) in a 250-ml or 45-ml infusion via the
electric syringe pump.
Each patient will receive successively in random order
each of the three products with a period of washout
between every administration. The duration of the washout
will be 5 weeks (35 days). The duration of each infusion
is 2½ h per patient as follows:
Ketamine-placebo group: Ketamine will be
administered for 2 h and placebo for 30 minutes.
Ketamine-magnesium sulfate group: Ketamine will
be administered for 2 h and magnesium sulfate for
Placebo-placebo group: Placebo will be administered
for 2 h and placebo for 30 minutes.
The drugs used in the study (ketamine,
ketaminemagnesium, and placebo) are prepared, conditioned, and
released in the hospital pharmacy by one qualified
person according to good manufacturing principles. Once
the treatment is completed, the empty infusion bags are
then returned to the packaging box, and the number of
infusion bags in each dispensed container is verified and
recounted at the end of the treatment by two persons
totally independent of the protocol.
The primary objective of this study is to compare, using
a crossover design, the analgesic efficacy of intravenous
ketamine with that of placebo in patients with
intractable NP. Secondary objectives are as follows:
To compare the additive analgesic efficacy of
magnesium and ketamine
To study the time course of pain and analgesia after
intravenous administration of ketamine,
ketaminemagnesium, and placebo
1. Patients ≥ 18 years old
2. Patients with chronic pain (for > 3 months), having
the characteristics of a peripheral or central
neuropathy justifying implementation of a
therapeutic program with courses of intravenous
3. Patients who have never received ketamine infusion
for care of their NP
4. History of illness compatible with an injury or
disease of the somatosensory system
5. Localized pain in a neuroanatomical territory
6. Neurological examination shows sensory
7. For women of childbearing age, they will be enrolled
in the study after a negative urine pregnancy test; in
case of suspicion of pregnancy, a blood pregnancy
test should be performed.
8. Cooperation and willingness to follow the study
9. Acceptance to give written consent
10.Affiliated with the French social security system
11.Inscription or acceptance of inscription in the
national register of volunteers involved in trials
1. Patients who have received an intravenous ketamine
2. Patients with one or many contraindications to
ketamine administration: known hypersensitivity to
ketamine in which one of the constituents of the
product, uncontrolled high blood pressure, severe
3. Patients with one or many contraindications to
magnesium sulfate administration: patients with
severe renal impairment
4. Patients with one or many contraindications to
administration of sodium chloride: water inflation,
5. Patients with a medical history and/or surgical
history judged by the investigator not to be
consistent with the clinical trial
6. Patients with drug treatments judged by the
investigator not to be consistent with the clinical
7. Pregnant or lactating women
8. Patient who participated in another clinical trial,
located in the exclusion period, or received
benefits > €4500 during 12 months before the
beginning of the trial
9. Patients with cooperation and understanding not
strictly adherent to the conditions of the clinical trial
10. Patients receiving a measure of legal protection
11. Patients not affiliated with the French social
Definition of outcome measures
The primary outcome is the AUC of pain intensity
assessed on a 0–10 NPRS for a period of 5 weeks
(35 days) from the day of intravenous treatment.
Secondary outcome measure
Secondary endpoints are the evaluation of pain (NPRS,
NPSI, BPI, McGill Pain Questionnaire, PGIC), anxiety
and depression (HADS), quality of life (SF-36), and
quality of sleep (PSQI) using a variety of scales and
questionnaires. Furthermore, the intensity of the average and
maximum pain scores as well as concomitant analgesic
treatments will be reported in a daily pain diary. The
various assessments and questionnaires are summarized
in Fig. 2.
This clinical trial will be carried out by the physicians of
the pain clinic and of the clinical pharmacology center/
CIC Inserm 1405 of CHU Clermont-Ferrand in charge
of the project. The number of subjects needed (n = 22) is
quite realistic according to the recruitment capacities of
the pain clinic. The duration of recruitment is expected
to be 2 years.
On the day of the first visit, inclusion and exclusion
criteria are verified, and written informed consent is
obtained by the physician. A clinical nurse independent from
the protocol obtains the randomization number from the
hospital pharmacy, and the patient is then randomized
into one of the three groups. The assignment to the
treatments will follow a predetermined randomization list and
is generated using random blocks by a clinical research
associate totally independent from the protocol. The
randomization list and a copy will be edited, placed in a
sealed envelope, and handed over to the
ClermontFerrand University Hospital Pharmacy and to the
coordinating center, the Clinical Research Center of
ClermontFerrand University Hospital.
In order to maintain blinding, packaging will be
identical. The clinical research center and the pain clinic are
situated on the same floor of the Clermont-Ferrand
University Hospital. A clinical nurse of the clinical
research center independent from the protocol prepares
and gives the treatment to the patient in a room in the
pain clinic. The persons who administer and provide
clinical supervision are the medical team affiliated with
the pain clinic of the University Hospital of
ClermontFerrand. The person who performs all questionnaires
and analyses is not involved in other aspects of the
protocol. Furthermore, only ketamine-naïve patients
are included in this trial in order to avoid detection of
the placebo or the active substance, taking into account
the dysphoric effects (even minor) that may accompany
ketamine infusion. If an adverse event occurs (e.g.,
hospitalization or prolonged hospitalization, incapacity
or disability), treatment of the enrolled patients will
immediately be suspended. The drug dose will not be
changed, and treatment will be continued only upon
agreement of the sponsor and the investigators if they
conclude that the cause of the adverse event is not
related or unlikely to be related to the study products.
Unblinding will be allowed only in case of a serious
adverse event. Only a doctor involved in the protocol but
not in the administration or evaluation of the drug will
be dealing with such events. All these steps will be
conducted and documented according to the procedures of
the University Hospital of Clermont-Ferrand and the
current regulatory requirements. If an adverse event
persists at the end of the study, the investigator will
follow the patient until the event is resolved.
Concerning missing data, if the participant misses one of
the three treatment blocks, the patient will be excluded
from the study. If missing data occur, a sensitivity
analysis will be proposed in order to define the level of
attrition and the statistical nature of the missing data, and
the last data obtained will be reported.
Data handling and record keeping
We have not established a data and safety monitoring
board for this study. However, in order to improve
adherence to the intervention, the case report forms will
be monitored by a clinical research associate
independent from the protocol and will address any safety or
other concerns that may arise. During these visits, the
following elements will be reviewed: informed consent;
compliance with the study protocol and the procedures
defined; and quality of data collected in the case report
form, including accuracy, missing data, consistency of
data with source documents (e.g., medical records,
appointment sheets, laboratory results), and
management of the pharmaceutical drugs. Then the monitored
case report forms will be retained at the data
management center (CIC-Inserm 1405, Clermont-Ferrand,
France) in a secure, locked room. Then data will be
entered by double data entry by two people independent
from the protocol. The blocked database will be
transferred to the statistician responsible for the statistical
analysis. All original records (consent forms, case report
forms, questionnaires, and pain diaries) will be kept at
the trial site for 15 years. All data will be anonymized
and identified by a participant code.
Sample size calculation
To highlight the analgesic efficacy of intravenous
ketamine in patients with intractable NP, sample size
estimation was based on a pilot study done at the pain clinic of
the University Hospital of Clermont-Ferrand
(administration of intravenous ketamine in a similar open-label
population), showing an AUC (28 days) of the intensity
of pain of 164 ± 38 (unpublished data). Furthermore, in a
study comparing similar treatments (ketamine and
placebo) in a different chronic pain setting (CRPS), the
AUC graph estimate suggested a 35% reduction in AUC
(at 28 days), that 18 patients are needed to detect a
minimum difference of 57 in the primary outcome, with
a two-sided type I error of 1.67% (to take account of
multiple comparisons), statistical power of 90%, and an
intraindividual correlation coefficient of 0.5 (owing to
the crossover design and no carryover effect assumed)
]. Considering data from our center, a recent study
] (NCT01602185) currently submitted to a
peerreviewed journal but not yet published clearly shows that
pain evaluation remains the same from 28 days to
60 days. Ultimately, allowing for patient dropout for
adverse events or premature withdrawal, we plan to
recruit 22 subjects.
Statistical analysis will be performed on an
intention-totreat basis using Stata software (version 13; StataCorp,
College Station, TX, USA) for a two-sided type I error at
α = 5%. Continuous data will be described as mean ± SD
or median (IQR) according to the statistical distribution
(assumption of normality studied by Shapiro-Wilk test).
Categorical parameters will be described as number and
percent. The primary endpoint (AUC of pain intensity
based on NPRS) will be compared between groups by
repeated measures analysis of variance (ANOVA) for
crossover designs, taking account of the following
effects: treatment group (ketamine versus placebo),
sequence, subject (as random effect), and carryover. Then,
the “sequence × treatment” interaction will be tested; if it
is significant, statistical analysis will cover only the first
period of the crossover study. The normality of residuals
will be studied. When quantitative endpoints do not
meet the normality assumption, a nonparametric paired
Wilcoxon test will be used. Sensitivity analysis will
determine the statistical nature of missing data to apply the
most appropriate imputation approach.
Statistical analyses of secondary outcomes (NPSI, BPI,
HAD, SF-36, PSQI and McGill Pain Questionnaire scores)
will be performed similarly to those for the primary
endpoint. For categorical parameters (PGIC, analgesic
response), the Stuart-Maxwell test for proportion paired
data or a generalized linear mixed model will be used,
taking the above effects into account. Random-effects
models, useful to model between- and within-subject
variability, will be performed for the effects described for the
crossover ANOVA, to compare the additive analgesic
efficacy of associating magnesium sulfate versus placebo to
ketamine, and to study the evolution of pain and analgesia
with the waning of the intravenous administration. In case
of omnibus p value < 0.05, a post hoc analysis for multiple
comparisons (inflation of type I error) will be applied
using the Tukey-Kramer test. For non-crossover
comparisons, the usual statistical tests will be performed: (1) for
quantitative parameters, ANOVA or Kruskal-Wallis test if
the conditions for parametric tests are not met (normality
and homoscedasticity on Fisher-Snedecor test); and (2) for
categorical variables, the chi-square test or Fisher’s exact
test. When appropriate (p < 0.05), an appropriate post hoc
test will be applied: Tukey-Kramer post hoc ANOVA or
Dunn post hoc Kruskal-Wallis. As discussed by Feise [
type I error (α) will not be adjusted systematically, but
rather on a case-by-case basis, in the light of clinical rather
than exclusively statistical considerations.
Persistent pain is difficult to treat, and a range of evidence
indicates that NMDARs play an important role in
sensitization, windup, and neuroplastic changes in the
central nervous system [
]. Ketamine may reduce NP
symptoms via its antagonistic action on NMDARs [
Magnesium, a physiological blocker of the NMDAR
calcium channels, has also been shown to be effective in the
treatment of NP, such as postherpetic neuralgia, CRPS, and
phantom limb pain [
]. Researchers in two studies
examined the effect of these antagonists, and the results
were contradictory. Felsby et al.  reported that ketamine
was more effective than magnesium in the treatment of
chronic NP, whereas Kim et al. [
] did not find a
significant difference between the two. This discrepancy may have
been due to a difference in magnesium dose and
administration time. Ketamine and magnesium were given
separately but never in combination, and the major limitation of
these clinical studies is that they had no placebo group. The
objective of the present study is to compare three different
forms of injection (ketamine alone, ketamine-magnesium,
and placebo) to optimize analgesia in patients with severe
NP. Although ketamine, associated with magnesium sulfate
or not, is often administered for NP, physicians have no
reliable guidelines for prescribing it.
Furthermore, it is also widely reported that NP is
known to impact quality of life with psychological
discomfort, anxiety, and/or depression . Recently,
an open-label study showed that oral administration
of ketamine improved both depression and anxiety
symptoms ; a single injection was sufficient to
reduce refractory depressive symptoms after 2 h and for
1 week . The present clinical trial will also
evaluate the efficacy of the three injections on the
emotional component of pain and on the comorbidities
associated with chronic pain.
The benefit expected for participating patients lies in
better follow-up of pain and quality of life, with no
additional risk. This double-blind randomized controlled
clinical trial will provide objective data on the efficacy of
ketamine in the treatment of NP and comorbidities
associated with chronic pain, such as anxiety and depression.
It will enrich good practice recommendations for
ketamine, an anesthetic that is often used off-label for NP.
Recruitment started in November 2015 and is currently
Additional file 1: SPIRIT 2013 checklist: recommended items to address
in a clinical trial protocol and related documents. (DOC 121 kb)
ANOVA: Analysis of variance; BPI: Brief Pain Inventory; CRPS: Complex
regional pain syndrome; DN4: Diagnosing Neuropathic Pain 4 Questions;
HADS: Hospital Anxiety and Depression Scale; NMDAR: N-methyl-D-aspartate
receptor; NP: Neuropathic pain; NPRS: Numeric Pain Rating Scale;
NPSI: Neuropathic Pain Symptom Inventory; PGIC: Patient Global Impression
of Change; PSQI: Pittsburgh Sleep Quality Index; SF-36: 36-item Short Form
Health Survey; SPIRIT: Standard Protocol Items: Recommendations for
This work is supported by University Hospital Clermont-Ferrand, France.
Role and responsibilities of the sponsor: Clermont-Ferrand University Hospital,
Clermont-Ferrand, France, manages the study. It is the interlocutor with the
French Research Ethics Committee and the guarantor of the quality and
confidentiality of the trial, the safety of participants, and the funding of this
Role and responsibilities of the coordinating center: The CPC/CIC Inserm 1405,
University Clermont-Ferrand Hospital, Clermont-Ferrand, France, participated
in the study conception and design, contributed to the writing of the study
protocol and elaboration of the protocol, developed all the material of the
study (elaboration of the case report forms, informed consent, investigative
brochure). It ensures the proper organization of the study (e.g., logistics,
study materials, safety data, monitoring). It also sets up the study and
ensures its smooth functioning in collaboration with the regulatory affairs
department and quality assurance.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from
the corresponding author on reasonable request. Results will be communicated
and published in peer-reviewed journals.
GP is the overall study principal investigator. GP participated in study conception
and design and contributed to the writing of the study protocol as well as the
drafting and editing of the manuscript. ND, PP, FM, and BP participated in the
study design. BP contributed to the writing of the study protocol, carried out all
statistical calculations, and wrote the “Statistical analysis” section of the manuscript.
BP, GP, ND, and VM drafted and edited the manuscript. All authors read and
approved the final manuscript.
Ethics approval and consent to participate
The study received approval from the French Research Ethics Committee on
April 13, 2015 (IRB number AU 1173). The trial is registered with ClinicalTrials.gov
(NCT0246751). Patients meeting the inclusion criteria will sign a consent form
after receiving oral and written information.
Consent for publication
All authors have consented to publication of this article.
The authors declare that they have no competing interests.
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