Ketamine's Efficiency in the Treatment of Chronic Pain With an Added Inflammatory Component Exploring the Kynurenin Pathway. A Randomized, Double Blind, Placebo-controlled Trial
Phase: PHASE3
Conditions: Neuralgia, Chronic Pain, Inflammation
Sponsor: Redar

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KETAMINE EFFICIENCY IN TREATMENT OF 
CHRONIC PAIN WITH AN ADDITIONAL 
INFLAMMATION: EXPLORATION OF THE 
KYNURENINE PATHWAY. A randomized, placebo-
controlled, double-blind study. 
Acronym: KEKU1 study 
 
 
NCT number: Not available yet 
 
 
 
 
Pr Valeria MARTINEZ 
Cyril QUEMENEUR 
 
 
 
 
 
V1_2 : 12 / 30 / 2017 

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KETAMINE EFFICIENCY IN TREATMENT OF CHRONIC PAIN WITH AN 
ADDITIONAL INFLAMMATION: EXPLORATION OF THE KYNURENINE 
PATHWAY. A randomized, placebo-controlled, double-blind study. 
Acronym: KEKU1 study 
  
Insurance number: No. 124-626 SHAM 
EUDRA Registration: 2017-003930-10 
Clinical trial Registration: current 
REF. CPP: CPP PARIS X 
  
Promoter 
REDAR association 
Ambroise Paré hospital 
9 avenue Charles de Gaulle 
92104 Boulogne Billancourt 
  
Investigator (s) principal (s) 

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Cyril Quemeneur: Anesthesia-Ressuscitation Resident Assistance Publique Hopitaux de Paris 
(APHP) , Master 2 of pre-clinical pharmacology, clinical pharmacology and 
pharmacokinetics, University Paris Saclay 
Pr Valeria Martinez, MD, PhD, Head of Department of anesthesia.  
Raymond Poincaré hospital. 
104 boulevard Raymond Poincaré, 92380 Garches 
 
Team 
INSERM unit U987 , Hospital Ambroise Paré 9 Avenue Charles de Gaulle, 92100 
Boulogne-Billancourt headed by Didier Bouhassira. 
Work under the responsibility of  Pr. Valeria MARTINEZ. 
  
Partners: 
Pr Launay and Dr. J. Callebert for the biology part. Laboratory of Biochemistry and 
molecular biology, hospital Lariboisière, APHP, Paris, France. 
 
APICIL Fundation, Lyon. 
 
Pr Gaillard, Head of Psychiatry department in Saint Anne’s Hospital, APHP, Paris 
 
Dr Jabbour, Head of Biochimy unit in Raymond Poincaré Hospital, APHP, Garches 
  
Study site 
Anesthesia Department.  
Raymond Poincaré hospital.  
104 boulevard Raymond Poincaré, 92380 Garches  
SUMMARY OF THE STUDY 
KE - KU1 STUDY 
Rational 
Is the kynurenine pathway involved in hyperalgesia. This pathway is 
activated by inflammation. Ketamine interacts with the kynurenine 
pathway and inflammation. Our working hypothesis are: ketamine 
clinical effects on neuropathic pain are more important in presence of 
systemic inflammation. The mechanism of action is through the 
kynurenine pathway. 
Type of study 
Interventional, randomized clinical, versus placebo 
Main objectives 
1) Show a better clinical efficiency of ketamine in chronic pain in 
patients with an inflammatory component. 
2) Explore the anti-inflammatory activity of ketamine through 
Kynurenine pathway 
Start - end of the study 
January 2018-October 2018 as part of a Pharmacology M2. 
Duration of patient follow-up 1 week. 
The study period 
6 months of inclusion. 
Population 
Adult spinal cord injured (BM), with chronic neuropathic pain (DN). 
4 groups: 
BM with DN with bedsore (ulcer pressure) Ketamine group / group 
Placebo 

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BM with DN without bedsore Ketamine group / group Placebo 
Intervention 
Infusion of ketamine 1 mg / kg in IVSE on two hours vs infusion 0.9% Nacl 
Primary endpoint 
Decrease the intensity of neuropathic pain evaluated at the moment on a 
numeric scale of 10 points to H4. Comparison by two groups. 
Criteria for secondary 
judgment 
Score of NPSI (Neuropathic pain symptom inventory) to H0, J1, J4, J7 
NPSI underscore; H0, J1, J4 J7 
Auto assessment of numeric pain scale every days from J0 to J7. 
Improvement rate of pain and mood during the week following the infusion. 
Score of depression HADS (Hospital Anxiety Depression Scale) J0, J7 
Body area pain: H0, J1, J7. 
Ketamine side effects 
Plasma dosage of serotonin (5-HT) kynurenine (KYN), indoleamine 2, 3-
dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and 
quinolinic acid (QA), as well as 3 proinflammatoire cytokyne it-1β, IL-6, 
and TNF - α before the infusion and infusion H4. 
Calculation of workforce 
The gap type of instant pain score is 1.4 on the same model. We considered 
that an improvement of 30% in the score of the intensity is significant 
clinical relief. Based on these figures and assuming a risk α = 0.05 and a 
power of 1 - β = 0.90, and using a one-sided Student's T test for a 
comparison of the 2 to 2 groups the minimum calculated sample size is 12 
patients analyzed by Group (i.e. a total of 48 patients). 
Conduct 
Inclusion of patients from the pain consultation and services of 
hospitalization of the spinal cord injured to hospital Raymond 
Poincaré 
Clinical evaluation and blood test prior to administration of ketamine 
Administration ketamine in SSPI, scopes. 
Blood test in 4 hours post end of administration 
Assessment baseline pain, H1, H4, J1, J4, J7. 
Assessment baseline depression, J0 and J7. 
Direct benefit 
Patients may benefit from treatment with Ketamine on their 
refractory neuropathic pain and monitored pain specialist  
Rational: 
1) The kynurenine pathway : a common way of hyperalgesia and depression. 
  
The kynurenine pathway is the way of tryptophan metabolism (figure 1). This path is 
involved both in depression and pain, two diseases often associated (1) . 
The indoleamine 2, 3-dioxygenase (IDO) is an enzyme modulating the kynurenine 
metabolism. It has been shown that inflammatory cytokines may activate IDO, which would 
induce a decrease tryptophan by direction preferred to the path of the kynurenines, which can 
lead a deficit in serotonin and in consequence depression (2). One of the products of 
degradation of the kynurenine is quinolinic acid, a NMDA agonist 
receptors. NMDA receptors are involved in Central sensitization of the pain with as 
consequence an amplification of the painful message manifesting by an 
hyperalgesia. 
  
2) Kynurenine pathway activation by inflammation. 
  
A large number of experimental studies showed the important role of pro-inflammatory 
factors in the pathogenesis of chronic pain and depression (3-6) . The role of the pro-

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inflammatory cytokines in the activation of the indoleamine 2, 3-dioxygenase 
(IDO) was widely reported and is a key action in the pathophysiology of the co-
morbidity of pain and depression (7-9) . 
Several experimental and clinical work related the IDO enzyme is activated by systemic 
inflammation (10). This activation is found in several chronic inflammatory diseases 
(cancers, rhumathologic, inflammatory cardiovascular diseases). More recently its 
activation was highlighted in patients with the irritable bowel syndrome (11,12) . 
This path seems to activate quickly in the early hours after tissue trauma in models of various 
surgery (coronary bypass surgery, thoracic surgery, hysterectomy) (13,14) . 
  
3) Interaction of ketamine on kynurenines. 
  
There are many mechanisms of action for ketamine. But more recently efficacy of ketamine 
in inflammatory so-called depressions and experimental studies addressing the inflammatory 
aspects common pain and inflammation have attracted our attention to the kynurenine 
pathway (15) (figure 1). Ketamine has shown a role towards the kynurenines in 
models of experimental pain (9,16,17). The ketamine has an antidepressant effect in 
fast action potentially by the inhibition of proinflammatory 
cytokines (18,19)(20). The rate of Interleukin 6 plasma would be predictive for 
efficiency of ketamine in a depressed patient population (21). Although there is a 
beam of clinical and paraclinical arguments about the role of IDO in the 
development of inflammation-induced depression, its role in pain is less explored 
in humans. However, experimental studies in animals showed the involvement of 
the path of kynurenines both in pain and depression. Kim and al (9) in a model of 
inflammatory pain in rats showed a relationship between the intensity of the 
thermal and mechanical allodynia and the concentration in mRNA of IDO, as well 
as of its enzymatic activity measured by the kynurenine/tryptophan ratio and that 
the rise of the concentration in IL6 in the brain. 
Concomitantly, ketamine would reduce the concentration of intracerebral cytokine IL-6, Il -
1 (6) , IDO, KYN/TRP ratio and increase the ratio of 5 HT / TRP.  
Finally, Wang in 2011 shows in a model of neuropathic pain in animals, the benefit 
of a single dose of ketamine on depressive behaviors induced neuropathic pain in 
the rat (16) . 
 

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Figure 1 ways of tryptophan metabolism (in blue) adapted by Walker (15) . In the 
presence of inflammation (in red), assumption of action of ketamine (in green) 
  
 
 
 
 
Information about the product being designed: ketamine 
Summary of clinical and experimental studies on the product. 
Used in low doses, ketamine has a powerful anti-hyperalgesique effect. She is the only 
powerful antagonist of the N-methyl-D-aspartate (NMDA) receptor available today 
in clinic. The NMDA receptor is known to play an important role in the phenomena 
of Central sensitization. It is widely used in perioperative to diminish the pain and 
the consumption of opioids. His action in acute pain is all the more important that 
surgery is traumatic (22) . Preventive effects of the postoperative pain required are 

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mentioned (23). On the other hand, robust and sustained antidepressant effects after 
a single intravenous infusion of low-dose ketamine in patients are reported (24) . 
Ketamine is also used off-label based on recommendations of good practices for dealing with 
the chronic pain (25) . 
However, systematic reviews recent questioning the interest ketamine in chronic pain 
rebel related a great heterogeneity in the results related to the great disparity in the 
populations studied and the administered dosages (26)(27)(28) . 
It appears that efficiency is obtained for high doses total (> 0, 5 mg/Kg) administered slowly 
over an hour on (29) . These reviews also highlight the need to better identifypatients. 
  
Information on benefits and risks of the product. 
  
The benefit expected from the product's effectiveness on refractory chronic neuropathic pain 
with a pain relief in these patients who are beyond all other types of pain treatments. 
  
Ketamine at a dose of 1 mg / kg is well tolerated in clinic and in various studies around 
ketamine. The contraindications of ketamine are allergy, severe hypertension, severe heart 
failure: patients excluded from our study. In the conditions of the study, dosage and duration 
of infusion, the risk of adverse effect is minimal. 
The most common side effects are: drowsiness, euphoria, hallucinations, tinnitus, nightmares 
and disorientation, nystagmus (rhythmic oscillation of the eyes), arterial hypertension and 
tachycardia. Patients being scoped and monitored medically in post interventionnal oversight 
room, the slightest side effect will be detected and treated. 
In our study the administration will be intravenously, it will be a single infusion of ketamine 
at a dose of 1 mg/kg, over a period of two hours. As mentioned previously, it appears that the 
effectiveness of the product in clinical studies appears to doses higher than 0, 5 mg/kg 
administered slowly on over an hour (29). Where our choice of infusion is over 2 hours. We 
have chosen a single infusion to avoid the effects of the repeated infusion over several days 
which showed liver adverse effects in the recent literature with doses regimens of ketamine 
very important. (36) 
The clinical trial will be conducted in accordance with the Protocol presented in this 
document following compliance with good clinical practices. 
  
 
 
 
Description of the study population: spinal cord injury patients with chronic pain with 
or without bedsore (ulcer pressure) 
The incidence of spinal cord injury (SCI) is about 20 / million residents in France, more than 
1,200 new cases per year, and prevalence is more than 250 / million residents, or about 20,000 
patients in France. For SCI patients, the prevalence of chronic pain is 65-85%, of which 40% 
are neuropathic and one-third are severe. Neuropathic pain are the hardest to relieve and there 
is a strong correlation between their presence and a difficult becoming both psychological, 
physical and social. Pain affects sleep, quality of life, interpersonal, socio-professional 
rehabilitation or return to work. His prognosis is not good with a low long term 

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resolution(30). There are few studies showing the effectiveness of ketamine 
administered by intra venous infusion in the treatment of refractory chronic pain 
medication (29). The recent literature reviews report the results in central 
neuropathic pain, especially in SCI patients (28,29). 
50 to 80 percent of the SCI patients will develop at least an ulcer pressure over a 
lifetime. These pressure ulcers like all chronic wounds are factors of inflammation. This 
chronic inflammation in the zone under the injury, often insensitive, is a factor of awareness 
of the central nervous system. It is common to observe an exacerbation of chronic central 
neuropathic pain patients during inflammation. On the other hand, the clinical observations 
report often spectacular efficiency of ketamine on the neuropathic pain in those patients with 
bedsores. 
Is this effect explained by a role on the kynurenine pathway in this population?  
Would ketamine be more effective in this population?   
Working hypothesis 
 The hypothesis that we raise, is : ketamine has an anti hyperalgesic action by anti 
inflammatory effects by interacting with the kynurenine pathway. 
We test this hypothesis in a clinical study with ketamine in chronic pain patients with or 
without associated inflammation. Our choice of population is patients with spinal cord injury 
with central neuropathic pain. Part of this patient population frequently suffers from pressure 
sores which leads to chronic inflammation.  
  
Trial purpose and goal: 
 Our clinical research aims to test the two following hypotheses 
(1) The ketamine clinical effects on chronic neuropathic pain are more 
important when there is an associated inflammation. 
  
(2) Its action is through interaction on the kynurenine pathway. 
 
  
  
Methods 
Population 
The selected population is a population of SCI patients with central neuropathic pain at the 
level of injury or under injury, chronic (more than three months). 
Patients are recruited through specialized consultation pain or bedscares consultation or 
through consultation and hospitalization in service of physical medicine and rehabilitation in 
hospital Raymond Poincare in Garches. This hospital is specialised in SCI management. The 

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Protocol will be proposed in a consultation of usual follow-up or hospitalization. The 
treatment will be initiated remotely, in a subsequent consultation scheduled apart of their 
follow-up. 
Four groups of patients will be included: 
Group 1: SCI with central neuropathic pain with bedsore receiving ketamine infusion.  
Group 2; SCI with central neuropathic pain with bedsore receiving placebo. 
Group 3: SCI with central neuropathic pain without bedsore receiving a ketamine 
infusion. 
Group 4: SCI with central neuropathic pain without bedsore receiving a placebo 
infusion. 
Description of treatment (dosages, forms, packaging) and preparation of the product. 
Ketamine: infusion IVSE of 1 mg/kg during 2 h in a 50 cc syringe Luer Lock BD Plastipack 
(100mg of Ketamine was 2 blisters 50mg / 5mL in a syringe of 50cc or a concentration of 2 
mg/cc, speed = weight of the patient/4 mL/h). 
A 50cc syringe Luer Lock Plastipack BD composed of Sodium chloride 0, 9% will be 
administered in the placebo group at the same rate in mL/h (weight of the patient/4 mL/h). 
The 2 products are transparent, it will be impossible to differentiate the two products with the 
same packaging or a syringe with Luer Lock Plastipack BD 50 cc with a standard Extender 
for syringe Luer Lock. 
Both products will be prepared by a nurse of SSPI, which won’t participate in the study. The 
investigator responsible for the evaluation of the patient and the patient will remain blind to 
the administration of the product. Statistics will also be blind. Each syringe will be labeled 
only with patient number inclusion. 
The infusion will be conducted in post operative monitoring room of the hospital Raymond 
Poincare in Garches,  patients will be scoped and monitored for 1 h after the end of the 
infusion. 
 Design of the study 
The study will be driving double blind, neither the patient nor the evaluator clinician will 
know product administered to the patient. The statistician who will analyze the data in the 
course of the study will be blind of the group in which the patient is located. 

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Randomization will be ensured by a randomization table created proactively using the R 
software between the two groups. The blind will be maintained through sealed envelopes. The 
post interventional monitoring room nurse will be the only one to know the contents of the 
envelope for the preparation of the drug. The investigator and the patient will remain blind to 
the treatment administered. The packaging is identical, the blind will be maintained 
throughout the study. 
To ensure maximum safety, the traceability of the product will be provided with lot number of 
Ketamine or informed administered Placebo on a pre established for each patient, form that 
you will find in the appendix to the project. 
Any potential adverse event will be supported by physicians anesthesiologists responsible 
resuscitators of  post operative monitoring of the hospital Raymond Poincaré, then transmitted 
instantaneously in pharmacovigilance and to the ANSM. 
Clinical and paraclinical evaluation during the test. 
Before administration of ketamine, we will evaluate clinical way: 
The intensity of neuropathic pain evaluated at the moment on a numeric scale of 10 
points at H0. 
The score NPSI Neuropathic Pain Symptom Inventory comprising 12 questions, each 
question will be analysed: burning pain, pain to type of vise, compression pain, 
number of hours painful in the past 24 hours, such painful crises of electrical 
discharges, painful crises in type of knife, number of painful crises in the last 24 
hours, presence of pain caused or increased pressure on the painful area, presence 
of pain caused or increased by the contact with a cold object on the painful area, 
presence of stinging, tingling presence. 
HADS depression scale with 14 questions: Seven concerning anxiety and seven 
concerning depression.  
The painful area evaluated on mapping by the subject before administration of ketamine 
then during follow-up. 
Paraclinical:  
A blood sample will be realized before the infusion of ketamine with dosage of: serotonin (5-
HT), kynurenine (KYN), indoleamine 2, 3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), 
kynurenic acid (KA) and quinolinic acid (QA). as well as 3 proinflammatoires cytokines it-

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1β, IL-6, and TNF - α. then a new dosage to 4 hours from the end of the infusion in 
the hospital or outpatient service and will include the dosage of: serotonin (5-HT), 
kynurenine (KYN), indoleamine 2, 3-dioxygenase 1 (IDO1) activity 
(ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA), as well as 3 
proinflammatoires cytokines it-1β, IL-6, and TNF - α.   
Duration of participation of the subjects: 
  
The protocol will take place in the post operative monitoring room for infusion with 2-hour 
infusion, care of one hour after the end of the infusion in post operative room and then four 
hours in the hospital.  
Either a minimum of passage to the hospital in 7 hours. 
For hospitalized patients, their usual follow-up will be resumed after the release of recovery. 
Inclusion in the study lasts 7 days in total, with a follow-up by phone and by a tracking 
notebook, the last phone call held at 7 days of infusion. 
  
Description of study stop, rules or criteria of exclusion for subjects. 
All serious adverse events, defined by: ketamine or its excipients, shock, pushed 
hypersensitivity reaction hypertensive greater than 180/110 defined as hypertensive 
emergency according to the HAS, a depression respiratory causing a desaturation < 92% in 
air, a marked psychodysleptique reaction causing a major stir, that can be linked to the 
administration of the product will immediately stop the infusion, supported by a doctor 
specializing in Anaesthesia-resuscitation and the statement from pharmacovigilance and the 
ANSM. 
Each observation will include a reporting of serious adverse events card. 
The patient will be analysed in the study for intention to treat analysis, the last pain expressed 
will be chosen as main analysis on which the study will be judged. 
Per-protocol analysis will also take place, excluding patients who have not benefited from the 
full dose of ketamine. 
Any withdrawal of consent before the infusion will result in the exclusion of the subject of the 
study. 
Withdrawal of consent after the end of the infusion, will lead to the choice of the subject, an 
analysis by intention to treat if the patient accepts the conservation of already saved data or 
also if it wishes the ouster of the subject of the study so that the deletion of all the data related 
to the patient, in agreement with the notion of free consent informed, revocable at any time. 
  
The study will end permanently after the 48th patient tracking. 
Is 7 days after the inclusion and treatment of the 48th patient (see calculation of the number of 
subjects needed here below) 

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Safety assessment and management of serious events 
  
 The investigator has the responsibility to report every adverse events. 
Definitions 
Adverse event : any harmful event occurring in a person who lends itself to 
biomedical research, that this event is related to research or the product on which 
this research is defined as adverse event 
Side effect: all adverse event due to research. 
We class them in subclasses: 
-Serious expected adverse effect: already mentioned in the summary of the 
characteristics of the product for drugs with permission of placing on the market as 
is the case in our study. This definition also applies to the test drug when 
administered to a population off-label of the AMM. 
-Unexpected serious adverse: if its nature, severity or evolution differ from those 
described in the most recent version of the brochure for investigators or the 
summary of the characteristics of the drug. 
Serious adverse event : any event or adverse reaction which results in death, is 
endangering the life of the person who lends itself to research, requires 
hospitalization or prolongation of hospitalization, causes an inability or a 
significant or long-lasting, handicap or well translates an anomaly or a congenital 
defect. 
The expression "which endangers the life of the person" is reserved for an immediate 
existential threat, at the time of the adverse event regardless of the consequences of 
a corrective or palliative therapy. 
Deaths , whatever their cause, including when they correspond to a progression of 
the disease being treated, are considered serious events. 
Other events do not meet the above qualifications, may be considered to be "potentially 
serious", including certain biological abnormalities. The medical judgment of the investigator 

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or the sponsor may lead to the declaration of such events in the same way that the events 
"serious." 
All new interesting research (or the product used) and may adversely affect the safety of the 
people who lend themselves to research will be of appropriate urgent safety and information 
without delay by the promoter from the competent authority and the patients committee 
protection.  
Serious adverse event reporting: 
The investigator has the obligation to report within 24 hours to the promoter all serious 
adverse events occurred in all patients included in the study: 
-       during the active study, 
-       in the weeks after the discontinuation of treatment 
-       within the established time of follow-up of tolerance without treatment, 
before (phase out wash or withdrawal) or after the active phase. 
-       After the trial, regardless of the deadline, as no other cause than the research 
cannot reasonably be offending, 
on a form 'Serious adverse event' where will be indicated the date of onset, intensity, the 
relationship with the treatment (or search), and monitoring. The narrative report should be 
completed and forwarded to the proponent as soon as new relevant information. Depending 
on the nature and the severity of the event, copies of anonymised medical records of the 
patient can be joined, as well as the results of laboratory tests. 
When a serious adverse event persists at the end of the study, the investigator will follow the 
patient until the event is considered to be resolved. 
According to the Decree of application No. 2006 - 477 of 26/04/2006 amending the chapter I 
of title II of book 1 St of the first part of the French code of public health on biomedical 
research, all suspicions of unexpected serious adverse will be a statement of the proponent 
ANSM, the CPP and the EMA (via the Eudravigilance basis) for research on a drug, as soon 
as it is known, and at the latest: 
-       7 days after the death or life-threatening event 
-       15 days after the onset of the unexpected event for any other SAES. 

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The proponent will decide on the significance of the serious adverse events that he says and 
what he doing, particularly with regard to the conduct of research. 
The proponent will also adjudicate accountability of the adverse event a test together with the 
Regional Center of Pharmacovigilance. 
The unexpected character will be established by the sponsor from the RCP. 
The proponent will keep detailed records of all adverse events which are reported to him by 
the investigators. 
Once a year or on request, the proponent will forward to the ANSM and CPP an annual safety 
report taking into account all of the available security information. 
The proponent will also to the investigators of the study any information that may affect the 
safety of the people. 
Oversight Committee 
Given that the active principle assessed as part of this clinical trial is a product that is on the 
market for several decades and that it is used at the recommended dosages, there we not seem 
justified to set up an Oversight Committee. 
Judgment of learning 
The end of the test corresponds to the date of the last visit of the last person in the trial. When 
a serious adverse event persists at the end of the study, the investigator will follow the patient 
until the event is considered to be resolved. 
A temporary stoppage of the study will be considered when new fact (as defined above) in 
order to give himself time to reassess the balance of benefits and risks of research jointly with 
ANSM . 
 
Ratings criteria 
Main evaluation criterion 
Decrease (more than 30%) the intensity of neuropathic pain evaluated at the moment on a 
numeric scale of 10 points between H0 and H4.   
  
Secondary evaluation criteria 

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Score of NPSI on H0, J1, J4, J7 
Under the NPSI score; H0, J1, J4, J7 
Score of depression HADS or Hamilton J0, J7 
Pain timeline between J0 and J7. 
Painful surface evaluated on mapping H0, J1, J4, J7 
Decrease in scores between baseline and H4. 
Side effects of the drugs evaluated H0 and H4 of the end of the infusion then in J1. 
Auto assessment of relief of pain and mood improvement at 7 days after infusion. 
Blood assays pre administration of Ketamine then H4 after end of Directors of: serotonin (5-
HT), kynurenine (KYN), indoleamine 2, 3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), 
kynurenic acid (KA) and quinolinic acid (QA), as well as 3 proinflammatoires cytokines it-
1β, IL-6, and TNF - α   
  
Patient selection, exclusion and data collected. 
The criteria for inclusion: 
-       SCI with central neuropathic pain with or without bed sores. 
-       Adults speaking and understanding the French 
-       With chronic neuropathic pain, according to the IASP definition 
-       Painful intensity > or = 6 / 10 during the week prior to the inclusion 
-       Spinal cord injury a few either the origin (traumatic, degenerative, tumor, 
post operative), responsible for paraplegia in a chronic state. 
-       Able to give their informed consent after a clear, fair and appropriate 
information 
-       Having given their agreement by a written consent signature. 
 
No inclusion criteria: 
-       Patients with a hypersensitivity to ketamine or one of its excipients. 
-       Another Interventional trial participation, or participation in another trial 
interrupted for less than 3 months. 

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-       Patient unable to give their consent 
-       Pregnancy or lactation underway 
-       Refusal of consent signature 
-       Cardiovascular diseases particularly associated with rhythm disorders and 
severe heart failure, coronary, discovered by examination, ECG or biological 
assessment or known. 
-       HTA unstabilized > 180/100 mmHg 
-       Severe hepato cellular and / or renal failure. 
-       For the group without sores, lack of ongoing inflammatory pathology noted 
by the interrogation (fever, sepsis, urinary tract infection) 
Exclusion criteria: 
As defined above, any adverse product will lead to the immediate cessation of the infusion 
however the patient will be analysed in the study for an intention to treat analysis. If it refuses 
the analysis or withdraws consent at any time of the study patients will be excluded from the 
study in accordance with best practices. 
After the duration of 7 days of participation and follow-up, the patient will be released the 
study as planned in the Protocol (end of final follow-up). 
Data collected on patients: 
These data will include: full name, Date of birth, the patient's Age, height, weight, BMI, sex, 
usual treatments, Presence of allergy, medical conditions, age of evolution of chronic pain, 
spinal cord injury, the more important pain in the week prior to the inclusion. Score NPSI, 
HADS Score, painful Surface evaluated on mapping, Patient having already benefited from 
infusion of ketamine before, history of use of other non-drug therapies for treatment of 
chronic pain. 
The data collected during the study will be for 7 days with the periods already mentioned: 
Score of NPSI on H0, J1, J4, J7, NPSI underscore; H0, J1, J4, J7, Score of depression HADS  
J0, J7 (for all elements in H1 and H4 previous evaluation by the clinician investigator, J1 J4 
J7 by a self-report filled at home or by telephone call) 

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Painful surface evaluated on H0, J1, J4, J7 (H1 and H4 by the clinician investigator, J1 J4 J7 
by the patient at home on a sheet displaying the human body). 
Regarding the lost to follow-up and missing data, the most pejorative result already gathered 
about each score will be taken as a reference to complete missing data, for analysis by 
intention to treat. 
Two blood samples will be carried out on each patient. The first will arrive in SSPI before 
infusion of ketamine. The following sample will be 4 hours after the end of the infusion or 6 
hours after the start of the infusion in outpatient service. Sampling and dosing methodology is 
explained below. 
In addition 24 samples will be collected without ketamine infusion (12 patients with bedsores 
and 12 without), to assess the effect of inflammation on kynurenine pathway.  
Methodology of dosage 
Blood samples will be collected after 48 h of a diet serotonin (avoid bananas in particular) and 
tryptophan (chocolate to be avoided) in Vacutainer 7 mL containing EDTA tubes. 
After gentle inversions of the tubes (agitation brutal would cause damaging platelet activation 
with the determination of serotonin, almost exclusively contained in platelets) total 500 µL of 
blood are immediately frozen (-20 ° C or - 80) (° C). The rest of each sample is centrifuged at 
4 ° C and 2500 g for 15 minutes and the resulting plasma is aliquote under 500 µL and frozen 
at-80 ° C until analysis. Blood serotonin and tryptophan plasma will be measured by 
HPLC(31). Kynurenic acid and kynurenine will be also measured by HPLC 
according to Fujigaki, Swartz and al and al respectively(32.33). For his part, 
quinolinique acid will be measured by LC - MS(34). The kynurenine/tryptophan 
ratio will be conventionally used as index of activity IDO1. 
Cytokines il1beta, IL6 and TNFalpha will be measured by electrochimiluminescence on a 
multiplex platform (35) . 
  
  
  
  
  
  
  
Drugs allowed or stopped during and before the test 
  

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Our population being affected by chronic pain, many treatments to target pain are generally 
used. The usual treatment of patients will be continued before, during and at the end of the 
study. 
Painkillers of tier 1, 2 or 3. Anti epileptic on pain neuropathic, antidepressants (SSRIS, 
MAOIS, tricyclics...). None of these drugs will prohibit participation in the study however we 
will proceed with a compendium of the various treatments by patients. 
  
Ketamine can potentiate the neuromuscular blocking atracurium and the tubocurarine 
including respiratory depression with apnea. The concomitant administration of ketamine 
with halogenated anesthetic agents may extend the elimination half-life of ketamine and delay 
the recovery phase. Our patients are not surgical patients, none will have received this type of 
product before the infusion. 
Co-administration of theophylline may lower the convulsive threshold. No administration of 
Theophylline is scheduled. 
Only bananas and chocolate will be an eviction during the 48 hours preceding blood sampling 
in order not to distort the dosages of serotonin and tryptophan. 
  
Procedures to assess compliance of subjects to treatment 
The infusion being in post operative monitoring room for a period of two hours. Compliance 
assessment can be done without bias. 
In the follow-up phone calls and self-report at home will be considered follow-up. Missing 
data management has already been clarified above. 
  
Assessment of treatment effectiveness 
The effectiveness of the treatment will be judged on a reduction of more than 30% of the 
intensity of neuropathic pain evaluated at the moment on a numeric scale of 10 points 
between H0 (before infusion) and H4 (after the end of the infusion). This criterion will be 
assessed by one of the investigators of the study. 
  
Assessment of the safety of the treatment 
Infusion being made in recovery room, the usual follow-up of a patient in recovery room will 
be arranged: decision-making of the constants every 15 minutes including the oxygen 
saturation, blood pressure, heart rate, awareness of Glasgow score, the respiratory rate. 
Supervision of one hour after the end of the infusion will be implemented. 
The release of recovery room will be one hour after the end of the infusion and with the usual 
criteria of output with Aldrete score. 
Any adverse event during infusion will be reported to a doctor Anaesthesiologist resuscitator 
and will be declared. 

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If an adverse event occurs a period of hospitalization is equal to 5 times the half-life (3 hours 
about ketamine), more than 15 hours will be organized until total elimination of the product. 
  
Sample size and statistical analysis 
After data from a study underway by our team (study LIKE), the standard deviation of instant 
pain score is of 1.4 on the same model. We considered that an improvement of 30% in the 
score of the intensity is relief significant clinic. Based on these figures and assuming a risk α 
= 0.05 and a risk β = 0.90, and using a one-sided Student's T test for a comparison of the 2 to 
2 groups the minimum calculated sample size is 12 patients analyzed per group (for a total of 
48 patients). 
After checking the normality of distributions, comparison of continuous variables (Score, 
NPSI, pain, depression and biology Score) between the two groups will be analyzed with the 
Student's T test, variables with a no normal distribution will be analyzed with the non-
parametric Mann-Whitney U test. p < 0.05 was considered statistically significant p-values. R 
and SPSS software will be used for the production of statistics. 
As part of a master of Pharmacology 2 to be made for may 2018, an interim analysis will be 
carried out by end April 2018, that this will have the same criteria as the final analysis. A 
security assessment will be also carried out at this time and an assessment of the derivatives to 
the Protocol. 
Both analyses above cited will be intention to treat, all randomized subjects will be 
included. Management of the lost will be extrapolating value worst case being investigated for 
missing data. Patients withdrawing consent during the study without desiring the removal of 
their data will be analyzed. If an application for withdrawal with withdrawal of the data then 
patients won’t be analyzed. 
  
Access to the sources and documents related to the research. 
Protection of research participants will be an anonymisation of the data recording in secure 
files. A declaration to the CNIL has been registered for this search No. 2122369 v 0 as of 
November 21, 2017. 
  
Access to the source file, anonymised data collection will be left in an audit requested on the 
study. 
  
 
Quality control and Assurance 
  

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For our study insurance civil liability promoter of Interventional research under article L 
1121-1 of the Code of public health is subscribed to hospital society of mutual assurances 
with the number of contract No. 124.626. 
To ensure quality control satisfactory we will put in place standardized operating procedures 
(POS) with standardized patients support instructions given to investigators of the study. 
Each patient will have a specification of anonymized observation which will include all 
identified information, the collection different scores used in the study as well as a record of 
serious adverse event reporting. These notebooks of observation will be kept throughout the 
study and one year after the end (last patient included either 7 days after the end of the 
48th patient inclusion). 
  
  
Direct benefit: 
  
Patients will be able to benefit from treatment with ketamine and the support and follow-up 
pain specialist for their refractory neuropathic pain.  
If patients included in this study have a real clinical benefit, this treatment may be proposed 
outside the clinical trial. Then, they will be given priority in the queue. 
For society this study will allow progress in the potential effectiveness of ketamine on chronic 
pain, hypothesis put forward in cancer pain and other chronic pain but for which we still lack 
of data sufficient to prove its benefit. It will also standardize administration protocols and 
avoid prolonged high doses of ketamine over several weeks that is responsible of serious 
adverse (36) . 
In addition it will better understand the mechanism of action of the product on this type of 
pain. 
  
Risks incurred and constraints: 
  
Ketamine at a dose of 1 mg / kg is well tolerated in the clinic and in the various studies 
around ketamine. 
The contraindications of ketamine are allergy, severe hypertension, severe heart failure: 
patients excluded from our study. 
In the conditions of the study, dosage and duration of infusion, the risk of adverse effect is 
minimal. 
  
  
The constraints for our patients will include: 
  

V1.2 12/30/2017 
Learn about 48 h of infusion a diet serotonin (avoid the bananas in particular) and tryptophan 
(chocolate to be avoided). 
Come to the appointment for the administration of infusion. 
Inform the doctor of the research of the use of any medication, as well as of any event 
occurring during the search. 
An accompanying person for the return home for patients on an outpatient basis. 
Do not take part in another Interventional trial for the duration of the study. 
Being affiliated to a social security scheme or equivalent. 
  
Agenda forecast 
  
      May - June 2017: finalization writing project, application to tender 
      September 2017-December 2017: registration of the candidate in MASTER 
2, and theoretical courses in parallel, finalisation of the project and 
administrative procedures (Committee of protection of individuals, filing 
ANSM, CNIL) 
      January 2018 - may 2018: Inclusion of patients and first report on the 
effectiveness on the first patients included with interim analysis end of April 
/ beginning of may 2018. 
      End of year 2018: writing article and dissemination of results at the Congress 
of pain, anesthesia 
      Early 2019: Finalization of article and submission to a journal international 
  
Expected end-of-project results: 
Publication of the results in an international journal of high level with oral communication 
and as a poster in the Congress of anaesthesia, pain and neuroscience. The expected clinical 
benefits may be a more targeted ketamine use. . This is a preliminary work which would open 
other opportunities of work, including the controlled randomised studies evaluating different 
doses and administration of ketamine in this target population. 
  
 
 
Feasability elements 

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Patient recruitment will be made easier because our research takes place within the 
Department of functional rehabilitation of the Raymond Poincaré hospital in Garches, 
following one of the largest cohorts of SCI patients in France. A quick calculation on the 
number of patients hospitalized and monitored for spinal cord injury, allows us to glimpse a 
potential 90 patients on the 6 month meets our criteria for inclusion. We aim included 48 
patients. The feasibility level organizational is real with the participation of the team 
pain, formed of two anaesthetists accustomed to the administration of ketamine and versed in 
clinical research. 
  
 
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