Lidocaine and Ketamine Levels in Plasma After Simultaneous Lidocaine/Ketamine Infusions. An Observational Assessment of Therapy Effects and Side-effects.
Conditions: Chronic Pain
Sponsor: University Hospital, Basel, Switzerland

 
LiKe-Level-Trial 
 
Version 1.1, 02.05.2023 
 
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Lidocaine and ketamine levels in plasma after simultaneous lidocaine/ketamine 
2 
infusions. An observational assessment of therapy effects and side-effects.  
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Research legislation: 
 Ordinance on human research with the exception of Clinical trials 
7 
(HRO). 
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Type of Research Project: 
Research project involving human subjects  
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Risk Categorisation:  
Category A 
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Sponsor Investigator:  
Wilhelm Ruppen, Prof. 
17 
 
Head of the Pain Unit 
18 
  
Department of Anaesthesiology 
19 
                                  
University Hospital of Basel (USB) 
20 
                                   
Spitalstrasse 21 
21 
                                      
CH - 4031 Basel 
22 
                                         
Phone: +41 61 328 64 96 
23 
                                   
Fax: +41 61 265 57 20 
24 
                                   
E-mail: wilhelm.ruppen@usb.ch 
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Project Leader and PI:  
Tobias Schneider, MD 
29 
                                          
Senior Physician 
30 
                                 
Department of Anaesthesiology 
31 
                           
University Hospital of Basel (USB) 
32 
                              
Spitalstrasse 21 
33 
                           
CH - 4031 Basel 
34 
                                
Phone: +41 61 328 65 43  
35 
                               
Fax: +41 61 265 57 20 
36 
                              
E-mail: tobias.schneider@usb.ch  
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PROTOCOL SIGNATURE FORM    
39 
 
40 
 
41 
Study Title 
Lidocaine and ketamine levels in plasma after simultaneous 
lidocaine/ketamine infusions. An observational assessment of 
therapy effects and side-effects.   
 
42 
The project leader has approved the protocol version [1.1 (dated 02.05.2023)] and confirms 
43 
hereby to conduct the project according to the protocol, the Swiss legal requirements, current 
44 
version of the World Medical Association Declaration of Helsinki and the principles and 
45 
procedures for integrity in scientific research involving human beings.  
46 
 
47 
Sponsor Investigator: 
48 
 
49 
Name: Wilhelm Ruppen, Prof. 
50 
Date: 
 _________________________ 
Signature:  ___________________________  
51 
 
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Project Leader and Principal Investigator: 
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Name: Tobias Schneider, MD 
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Date: 
 _________________________ 
Signature:  ___________________________  
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Co-Investigators: 
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Name: Flavia Flepp, pract. med. 
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Date: 
 _________________________ 
Signature:  ___________________________  
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Name: Matthijs de Leeuw, pract. med.  
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Date: 
 _________________________ 
Signature:  ___________________________  
67 
 
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Name: Regula Steiner, Dr. sc. nat. 
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Date: 
 _________________________ 
Signature:  ___________________________  
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72 
5.5.2023
08.05.2023
8th of May 2023
08.05.2023
08.05.2023

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TABLE OF CONTENTS 
73 
TABLE OF CONTENTS 
3 
74 
GLOSSARY OF ABBREVATIONS 
4 
75 
STUDY SYNOPSIS 
5 
76 
1 BACKGROUND AND PROJECT RATIONALE 
11 
77 
2 PROJECT OBJECTIVES AND DESIGN 
12 
78 
2.1 Hypothesis and primary objective 
12 
79 
2.1.2 
Secondary objectives 
12 
80 
2.2 Primary and secondary endpoints 
12 
81 
2.3 Project design 
13 
82 
3 PROJECT POPULATION AND STUDY PROCEDURES 
13 
83 
3.1 Project population, inclusion and exclusion criteria 
13 
84 
3.2 Recruitment, screening and informed consent procedure 
14 
85 
3.3 Study procedures 
14 
86 
3.3.1 Investigated variables 
15 
87 
3.3.2 Standard Procedure of lidocaine-ketamine infusions at the Pain Unit of 
88 
USB 
16 
89 
3.3.3 Laboratory Analysis 
16 
90 
3.4 Withdrawal and discontinuation 
16 
91 
4 STATISTICS AND METHODOLOGY 
17 
92 
4.1. Statistical analysis plan 
17 
93 
4.2. Handling of missing data 
17 
94 
5 REGULATORY ASPECTS AND SAFETY 
18 
95 
5.1 Local regulations / Declaration of Helsinki 
18 
96 
5.2 Notification of safety and protective measures (HRA Art. 15, HRO Art. 20) 
18 
97 
5.3 Serious events (HRO Art. 21) 
18 
98 
5.4 Amendments 
18 
99 
5.5 End of project 
18 
100 
5.6 Insurance 
18 
101 
6 FURTHER ASPECTS 
18 
102 
6.1 Overall ethical considerations 
18 
103 
6.2 Risk-Benefit Assessment 
19 
104 
7 QUALITY CONTROL AND DATA PROTECTION 
19 
105 
7.1 Quality measures 
19 
106 
7.2 Data recording and source data 
19 
107 
7.3 Confidentiality and coding 
19 
108 
7.4 Retention and destruction of project data and biological material 
20 
109 
8 FUNDING / PUBLICATION / DECLARATION OF INTEREST 
20 
110 
9 REFERENCES 
20 
111 
Appendix 1: Schedule of assessments 
1 
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113 
 
 
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GLOSSARY OF ABBREVATIONS 
115 
 
116 
AE        
Adverse Event 
117 
BASEC 
Business Administration System for Ethical Committees 
118 
BDI-II       
Beck Depression Inventory - 2 
119 
CRF 
Case report form 
120 
FOPH 
Federal Office of Public Health 
121 
HRA 
Human Research Act 
122 
HRO        
Ordinance on Human 
123 
NRS       
Numeric rating scale  
124 
PI            
Principal Investigator  
125 
SAE        
Serious Adverse Event 
126 
SF-MPQ    Short form – McGill Pain Questionnaire  
127 
USB        
University Hospital Basel 
128 
USZ       
University Hospital Zurich  
129 
 
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 STUDY SYNOPSIS 
132 
Sponsor / Sponsor-
Investigator 
Wilhelm Ruppen, Prof. 
Head of the Pain Unit 
Department of Anaesthesiology 
University Hospital of Basel (USB) 
Spitalstrasse 21 
CH - 4031 Basel 
Phone: +41 61 328 64 96 
Fax: +41 61 265 57 20 
E-mail: wilhelm.ruppen@usb.ch 
Study Title: 
Lidocaine 
and 
ketamine 
levels 
in 
plasma 
after 
simultaneous 
lidocaine/ketamine infusions. An observational assessment of therapy 
effects and side-effects. 
Short Title / Study ID: 
LiKe-Level-Trial 
Protocol Version and 
Date: 
Version 1.1 (dated 02/05/2023) 
Trial registration: 
The study will be registered at clinicaltrials.gov and the Swiss National 
clinical trial portal (SNCTP) upon ethical approval. 
Study  category and 
Rationale  
Category A: Participants in this study will be exposed to minimal additional 
risks. 
Background  
and 
Rationale:  
Around 20% of the European population suffers from chronic pain. In 
addition to the huge emotional and physical burden of chronic pain, the 
financial impact on society is also enormous, currently estimated at more 
than €200 billion each year in Europe and $150 billion each year in the 
USA. [1] However, there are many different treatment strategies for 
chronic pain, suggesting difficulties in effectively treating these patients. 
[2] In addition, a substantial number of patients do not respond to first-line 
treatment. [5] Medications that are frequently prescribed for pain (e.g., 
NSAIDs, acetaminophen, metamizole, opioids, antidepressants and 
antiepileptics) often have limiting side effects. [6] Opioids have the 
additional problem that they have a high potential for abuse and addiction. 
[7, 8] One possible treatment strategy, especially for therapy-resistant 
pain, is intravenous infusions with certain pharmacological agents, such 
as lidocaine and ketamine. [9] Studies have shown that treatments with 
lidocaine and ketamine have an immediate effect on the one hand, and 
can also result in longer-lasting pain relief on the other. [10-13] Lidocaine-
ketamine infusions (every 4-6 weeks) have been performed at the 
University Hospital Basel (USB) for almost 20 years. In our pain unit, we 
combine the positive properties of lidocaine and ketamine by 
administering infusions of the two agents simultaneously. Internationally, 
however, safety concerns have been raised following some case studies 
reported serious side effects [17-19] and the death of a young mother 
reported in the British media after lidocaine infusion [20]. Therefore, in 
2021, an international expert consensus was conducted on the efficacy 
and safety of intravenous lidocaine for postoperative pain. [21] The 
elaborated statement includes recommendations for the safe use of 
lidocaine infusions in the perioperative setting, such as: 
 
- A loading dose of no more than 1.5mg/kg lidocaine given as an 
intravenous infusion over 10 minutes is recommended 
- After the initial loading dose, an intravenous infusion of 1.5mg/kg/h 
lidocaine is recommended 
- No more than 120mg/h of lidocaine should be infused intravenously 
 

Version 1.1, 02.05.2023 
 
 
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The dosage regimens proposed in this recommendation are clearly 
exceeded by the standard regime at our pain unit (i.e. 4mg/kg lidocaine 
over 30 minutes). For note the new consensus statement addresses 
perioperative use of lidocaine in acute postoperative pain, and our 
treatment regime is based on previous studies investigating chronic pain. 
[9, 22] In addition, during a previous retrospective study at our Pain Unit, 
no serious adverse events were registered during 2995 infusions 
performed, rendering it a safe procedure. [23] Nevertheless, Foo, 
Macfarlane et al. defined a toxic lidocaine concentration in plasma as 
>5µg/ml. In order to assess whether this concentration is exceeded at the 
USB, the aim of this pilot project is to measure the lidocaine plasma level 
in a limited number of patients to generate explorative data on inter- and 
intrapersonal stability and safety of drug plasma levels. Beyond safety 
issues, we are interested in dosing and effects of our treatments. In the 
literature, there is evidence that higher doses of ketamine are associated 
with greater and longer pain relief, which is also consistent with the data 
from our retrospective study. [23, 24] As a standard regime of our infusion 
therapies, we increase the ketamine dose from 0.15mg/kg at the first 
infusion to 0.25mg/kg at the second infusion and 0.5mg/kg at the third 
infusion. Therefore, another aim of this study is to investigate whether 
higher plasma levels of ketamine can be correlated with a better analgesic 
effect. 
Objective(s): 
The primary objective of this study is to measure the concentration of 
lidocaine in the plasma of patients at the USB after an intravenous infusion 
with 4mg/kg lidocaine over 30 minutes. 
We hypothesize that lidocaine concentrations in plasma of patients at the 
USB are inter- and intrapersonal stable and do not exceed 5µg/ml by the 
end of the applied infusions. 
The secondary objectives of this study include the prospective side effects 
assessment of lidocaine and ketamine as well as the measurement of 
plasma levels of ketamine. Further, to correlate the plasma levels with the 
analgesic efficacy and change in possible depressive symptoms, due to 
the infusions. 
Outcome(s): 
The primary endpoint of our study is the concentration of lidocaine in the 
plasma of patients who received an intravenous infusion with 4mg/kg 
lidocaine and 0.15 – 0.5mg/kg ketamine over 30 minutes at the time 
directly after the infusion.  
 
The secondary endpoints of our study are the recorded side-effects typical 
for lidocaine and ketamine reported by questionnaires and patient 
monitoring. A further endpoint of interest is the concentration of ketamine 
in the plasma of patients directly after the infusion. Development of pain 
and mood as assessed by the Short form - McGill Pain Questionnaire (SF-
MPQ) and Beck Depression Questionnaire II (BDI-II), respectively. 
Study design: 
This study is designed as monocentric observational study at the 
University Hospital Basel. 

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Inclusion / Exclusion 
criteria: 
Inclusion Criteria: 
- Patient is a new recipient of lidocaine-ketamine infusions 
- Patient is 18 years of age or older 
- Patient is able to provide Informed Consent 
 
Exclusion Criteria: 
- Contraindication to blood sampling (on arm not used for infusion) 
- Insufficient knowledge of German language 
- Inability to give consent 
- Patient is under 18 years of age 
- Contraindication to treatment with lidocaine and/or ketamine  
Measurements and 
procedures: 
Standard procedure of lidocaine/ketamine infusions at USB 
 
Patients with therapy refractory chronic pain are scheduled for Infusion 
therapies on a four-week interval basis, by their treating pain physician. 
Before each infusion, a brief medical history interview takes place, during 
which compliance with the fasting time (6 hours for solid food, 2 hours for 
clear liquids) in particular is queried. Subsequently, installation of 
monitoring (10-minute blood pressure measurement, continuous 5-lead 
ECG, and continuous SPO2 measurement) and placement of venous 
access. Lidocaine and ketamine are infused over a 30-minute period 
(detailed dosing schedules are provided in the protocol). After infusion, 
patients are monitored for at least another half hour, discharged in 
company, and instructed not to operate heavy machinery or motor 
vehicles for at least 24 hours. Over the first three infusions the Ketamine 
dose is adjusted up to 0.5mg/kg/bw, the Lidocaine dose is stable at 
4mg/kg/bw during the infusions. Beyond the third infusion dose 
adjustments are only made if needed (c.f. side-effects)  
 
Study procedures  
 
Recruitment and consent to participate in the study will take place in the 
consultation prior to the first infusion. (c.f. 3.2) During the infusion, the 
patients' vital signs will be monitored as usual (10-minute blood pressure 
measurement, continuous SPO2 and 5-lead ECG are recorded, c.f. 3.3.2). 
As a part of this study, at the end of the first, second and third infusion, 
side effects will be screened using customized questionnaires. (c.f. eCRF 
forms document). In addition, blood will be collected during each of the 
first three infusion appointments. The blood collection itself will take place 
within 3 minutes after termination of the infusion, as we assume the 
highest plasma levels at that point in time. [25, 26] For blood collection we 
will use a Butterfly cannula (BBraun Venofix® Safety 23G, PZN 08839883, 
B. Braun Melsungen AG) which will be inserted on the "non-infusion arm" 
and two green 7.5ml Lithium-Heparin monovettes (S-Monovette® Lithium-
Heparin, liquid, preparation: lithium heparin, liquid, 7.5 ml, membrane 
screw cap, closure green, color code ISO, (LxØ) without closure: 92 x 
15 mm, with paper label, label/printing: green Sarstedt AG & Co. KG, 
Nümbrecht).  
Patients will complete the Short form - McGill Pain Questionnaire (with 
additional recording of pain on the numeric rating scale (NRS) from 0 (no 
pain at all) to 10 (worst pain imaginable)) and Beck Depression 
Questionnaire directly prior to the first three infusions. The SF – MPQ is a 
validated instrument for measures of clinical pain that capture its sensory, 
affective and other qualitative components. [27] The BDI-II provides a 
validated psychological test procedure that assesses the severity of 

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depressive symptoms in adolescents 13 years of age and older and adults. 
[28] 
In addition, these questionnaires will also be completed at the time points 
7 days after, and 14 days after the first, second and third Infusion. The 
participants will receive a link by e-mail so that they can fill in the 
questionnaires online. According to the license agreement, the BDI-II will 
be filled out in paper form and the results will be subsequently transferred 
to REDCap. If desired by the participant, these questionnaires can also be 
completed during a telephone survey conducted by the study staff. The 
surveys will be conducted with REDCap. After the third infusion, this online 
questioning will take place additionallyafter 28 days (c.f. Appendix 1). After 
this questioning, the study ends for the participants. 
Investigated variables  
 
Demographic  
 
Variable: Age  
Categories: Age at beginning of therapy (recorded in years)  
 
Variable: Gender  
Categories: female / male / diverse 
 
Variable: Nationality  
Categories: Recorded as free text  
 
Variable: Diagnosis that led to the indication for lidocaine/ketamine 
infusion 
Categories: Main pain-related diagnosis coded with ICD11, free text  
Variable: Dosage 
Categories: Weight (recorded in kg) / Height (recorded in cm) / Dosage 
of lidocaine (recorded in mg) / Dosage of ketamine (recorded in mg) 
Effects and Side effects 
Variable: Depressive Symptoms  
Categories: Recorded by BDI-II at the beginning of the infusion, 7 days 
after and 14 days after 
Variable: Pain  
Categories: Recorded by SF-MPQ-2 at the beginning of the infusion, 7 
days after and 14 days after, and by NRS (Number from 0 to 10) at the 
beginning of the infusion, 7 days after and 14 days after 
Variable: Vital sings 
Categories: blood pressure (recorded in mmHg) / heart rate (recorded in 
bpm) / saturation of oxygen under infusion (recorded as percentage) / 
Respiratory rate (recorded in breaths per minute), recorded at the start of 
the infusion and subsequently during a period of 60 minutes 
Variable: ECG  
Categories: Heart rate (recorded in bpm), regular sinus rhythm (recorded 
as yes or no), PQ interval (recorded in ms), QRS-complex (recorded in 
ms), ST segment (recorded as conspicuous/inconspicuous), T wave 
(recorded as conspicuous/inconspicuous), QTc (recorded in ms), 
Extrasystolies (recorded as number), other anomalies (recorded as free 
text) at start of infusion and at the end of infusion (minute 30) 
Variable: Side effects at end of infusion (patient recorded) 

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Categories: Injection site pain, dysphoria, euphoria, nervousness, 
anxiety, dyspnea, nausea, hypersalivation, nightmares, hallucinations, 
visual disturbances, tinnitus, hyperacusis, paresthesias, numbness, 
dizziness (recorded as present/absent). 
Variable: Side effects at end of infusion (patient observation by 
physician, monitoring) 
Categories: Exanthema, redness injection site, vomiting, tremor, 
dysarthria, nystagmus, convulsions, dissociation, disorientation, 
restlessness, agitation (recorded as present/absent)  
 
Variable: Medication plasma levels 
Categories: Lidocaine and ketamine plasma levels are recorded 
specified in mg/l al the end of infusions 
Laboratory Analysis  
Samples were analyzed on a Thermo Scientific™ Orbitrap Exploris™ 240 
Mass Spectrometer coupled to reversed phase liquid chromatography with 
an LLOQ of 0.1 μmol/L for lidocaine and 0.1 mg/L for ketamine. The 
methods were fully validated according to EMA guideline.   
Number of 
Participants with 
Rationale: 
A total of max. 15 patients (10 + Drop-out of 50%) will be included. 
Study Duration: 
In total, we expect a study duration of 7 months. Study duration for each 
individual participant will be 12 weeks. 
Study Schedule: 
First-Participant-In: 06/2023 
Last-Participant-Out: 12/2023 
Principal Investigator 
and Project Leader: 
Wilhelm Ruppen, Prof. 
Leiter der Schmerzklinik  
Klinik für Anästhesiologie  
Universitätsspital Basel (USB) 
Spitalstrasse 21 
CH - 4031 Basel 
Telefon: +41 61 328 64 96 
Fax: +41 61 265 57 20 
E-mail: wilhelm.ruppen@usb.ch 
 
Tobias Schneider, MD  
Senior Physician  
Department of Anaesthesiology  
University Hospital of Basel (USB)  
Spitalstrasse 21  
CH - 4031 Basel  
Phone: +41 61 328 65 43  
Fax: +41 61 265 57 20  
E-mail: tobias.schneider@usb.ch    

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Co-Investigator(s): 
Flavia Flepp, pract. med.  
Doctoral candidate  
Department of Anaesthesiology  
University Hospital of Basel (USB)  
Spitalstrasse 21  
CH - 4031 Basel  
Phone: +41 61 556 55 73  
Fax: +41 61 265 57 20  
E-mail: flaviabarla.flepp@usb.ch  
 
Matthijs de Leeuw, pract. med.  
Doctoral candidate  
Department of Anaesthesiology  
University Hospital of Basel (USB)  
Spitalstrasse 21  
CH - 4031 Basel  
Phone: +41 61 328 59 14  
Fax: +41 61 265 57 20  
E-mail: matthijsjan.deleeuw@usb.ch   
 
Regula Steiner, Dr. sc. nat. 
Head of Laboratory for Therapeutic Drug Monitoring and Toxicology 
Institute for Clinical Chemistry 
University Hospital of Zurich (USZ)  
OPS D29 
Rämistrasse 100 
CH - 8091 Zurich  
Phone: +41 43 253 06 09 
E-mail: regula.steiner@usz.ch  
Study Centre(s): 
University Hospital of Basel (USB)  
Spitalstrasse 21  
CH - 4031 Basel  
Statistical 
Considerations: 
Patients characteristics regarding to age, gender, pharmacological 
treatment, medical diagnosis will be analyzed exploratively/ descriptively. 
 
Primary outcome: 
The primary outcome (Lidocaine plasma level) of our study is explorative 
and not comparative, therefore, no H0 or H1 are formulated no power 
analysis is performed and only descriptive/ explorative statistics are 
reported.   
We plan to include 10 patients with complete data sets, meaning, full data 
of three infusions with stable dose of lidocaine (4mg/kg/BW) and 
escalating dose of ketamine (0.15 – 0.5mg/kg/BW). This corresponds to 
thirty measures of lidocaine plasma concentrations at a dose of 
4mg/kg/BW). Patients without full data sets will be replaced but data from 
patients with preliminary study termination will be reported in the final 
protocol. 
 
Secondary outcomes:  
1. Ketamine plasma levels are assessed according to lidocaine levels.  
 
2. H0: dose escalation of ketamine has no effect on pain (outcome 
measure: SF-MPQ-2) and mood (outcome measure: BDI-II. H1: we 
hypothesize that ketamine dose has an effect on both outcome measures.  
For repeated measurements, an ANOVA will be separately calculated for 
outcome measures of pain and mood as dependent variable. This analysis 
will be performed separately for intermediate (one and two weeks) and 

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long term effects (four weeks). For comparative outcomes a level of 
significance of 0.05 will be used. In case of multiple testing a correction 
factor (in case of ANOVA: Bonferroni) for multiple testing is applied. 
 
3. Side effects during treatment will be primary analyzed descriptively. 
 
4. Multiple exploratory linear regressions will be calculated to evaluate the 
impact of dose and plasma levels of lidocaine and ketamine on pain and 
mood as well as occurrence of side-effects. 
 
SPSS Version 25 will be used for data analyzation and graph pad PRISM 
Version 9 for data visualization. The investigators, Flavia Flepp and Tobias 
Schneider, will perform all analysis steps. If needed, statistical guidance 
will be applied by statisticians of the Clinical Trial Unit (CTU) of the USB. 
Handling of missing data: 
Dropouts will be replaced. We do not plan data imputation. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as 
far as applicable) as well as all national legal and regulatory 
requirements. 
 
133 
 
134 
1 
BACKGROUND AND PROJECT RATIONALE  
135 
Around 20% of the European population suffers from chronic pain. In addition to the huge 
136 
emotional and physical burden of chronic pain the financial impact on society is also enormous, 
137 
currently estimated at more than €200 billion each year in Europe and $150 billion each year in 
138 
the USA. [1] Moreover, chronic pain is the most common cause of long-term disability in middle-
139 
aged people. [2] Chronic pain is complex and the pathomechanisms behind it are still not fully 
140 
understood. Nevertheless, it is increasingly regarded not only as a symptom, but as a disease in 
141 
its own right. This is also visible in the fact that chronic pain can be coded independently for the 
142 
first time in ICD 11. [3] In recent years, clinical research has shown that chronic pain can occur 
143 
independently of disease or tissue damage due to increased sensitization of the central or 
144 
peripheral nervous system. If chronic pain is inadequately treated, it leads to multidimensional 
145 
adverse effects: Impairments in daily activities and work ability, general health, and social life. [4] 
146 
However, there are many different treatment strategies for chronic pain, suggesting difficulties in 
147 
effectively treating these patients. [2] In addition, a substantial number of patients do not respond 
148 
to first-line treatment. [5] Medications that are frequently prescribed for pain (e.g., NSAIDs, 
149 
acetaminophen, metamizole, opioids, antidepressants and antiepileptics) often have limiting side 
150 
effects. [6] Opioids have the additional problem that they have a high potential for abuse and 
151 
addiction. [7, 8]  
152 
One possible treatment strategy, especially for therapy-resistant pain, is intravenous infusions 
153 
with certain pharmacological agents, such as lidocaine and ketamine [9] Studies have shown that 
154 
treatments with lidocaine and ketamine have an immediate effect on the one hand, and can also 
155 
result in longer-lasting pain relief on the other. [10-13] Ketamine is also interesting for pain therapy 
156 
due to its antidepressant effect [14, 15]  since chronic pain is often accompanied by depressive 
157 
symptoms. [16] 
158 
Lidocaine-ketamine infusions (every 4-6 weeks) have been performed at the University Hospital 
159 
Basel (USB) for almost 20 years. In our pain unit, we combine the positive properties of lidocaine 
160 
and ketamine by administering infusions of the two agents simultaneously. This allows us to 
161 
achieve good clinical results in patients who are non-responders to first- or second-line therapy. 
162 

Version 1.1, 02.05.2023 
 
 
12/24 
Internationally, however, safety concerns have been raised following some case studies reported 
163 
serious side effects [17-19] and the death of a young mother reported in the British media after 
164 
lidocaine infusion. [20] Therefore, in 2021, an international expert consensus was conducted on 
165 
the efficacy and safety of intravenous lidocaine for postoperative pain. [21] The elaborated 
166 
statement includes recommendations for the safe use of lidocaine infusions in the perioperative 
167 
setting, such as: 
168 
 
169 
- A loading dose of no more than 1.5mg/kg lidocaine given as an intravenous infusion over 10 
170 
minutes is recommended 
171 
- After the initial loading dose, an intravenous infusion of 1.5mg/kg/h lidocaine is recommended 
172 
- No more than 120mg/h of lidocaine should be infused intravenously 
173 
- For the dose calculation, the ideal body weight should be used 
174 
 
175 
The dosage regimens proposed in this recommendation are clearly exceeded by the standard 
176 
regime at our pain unit (i.e. 4mg/kg lidocaine over 30 minutes). For note the new consensus 
177 
statement addresses perioperative use of lidocaine in acute postoperative pain, and our treatment 
178 
regime is based on previous studies investigating chronic pain. [9, 22] In addition, during a 
179 
previous retrospective study at our Pain Unit, no serious adverse events were registered during 
180 
2995 infusions performed, rendering it a safe procedure. [23] Nevertheless, Foo, Macfarlane et 
181 
al. defined a toxic lidocaine concentration in plasma as >5µg/ml. In order to assess whether this 
182 
concentration is exceeded at the USB, the aim of this pilot project is to measure the lidocaine 
183 
plasma level in a limited number of patients to generate explorative data on inter- and 
184 
intrapersonal stability and safety of drug plasma levels.  
185 
Beyond safety issues, we are interested in dosing and effects of our treatments. In the literature, 
186 
there is evidence that higher doses of ketamine are associated with greater and longer pain relief, 
187 
which is also consistent with the data from our retrospective study. [23, 24] As a standard regime 
188 
of our infusion therapies, we increase the ketamine dose from 0.15mg/kg at the first infusion to 
189 
0.25mg/kg at the second infusion and 0.5mg/kg at the third infusion. In cases where patients 
190 
already experiencing sufficient analgesic effect and/or improvement in quality of life after the 1st 
191 
or 2nd infusion or if side effects are not tolerated, no further increase of ketamine dosage is made. 
192 
Therefore, another aim of this study is to investigate whether higher plasma levels of ketamine 
193 
can be correlated with a better analgesic effect. 
194 
 
195 
2 
PROJECT OBJECTIVES AND DESIGN  
196 
2.1 Hypothesis and primary objective  
197 
The primary objective of this study is to measure the concentration of lidocaine in the plasma of 
198 
patients at the USB after an intravenous infusion with 4mg/kg lidocaine over 30 minutes. 
199 
We hypothesize that lidocaine concentrations in plasma of patients at the USB are inter- and 
200 
intrapersonal stable and do not exceed 5µg/ml by the end of the applied infusions. 
201 
 
202 
2.1.2 
Secondary objectives  
203 
The secondary objectives of this study include the prospective side effects assessment of 
204 
lidocaine and ketamine as well as the measurement of plasma levels of ketamine. Further, to 
205 
correlate the plasma levels with the analgesic efficacy and change in possible depressive 
206 
symptoms, due to the infusions. 
207 
2.2 Primary and secondary endpoints 
208 

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The primary endpoint of our study is the concentration of lidocaine in the plasma of patients who 
209 
received an intravenous infusion with 4mg/kg lidocaine and 0.15 – 0.5mg/kg ketamine over 30 
210 
minutes at the time directly after the infusion.  
211 
 
212 
The secondary endpoints of our study are the recorded side-effects typical for lidocaine and 
213 
ketamine reported by questionnaires and patient monitoring. A further endpoint of interest is the 
214 
concentration of ketamine in the plasma of patients directly after the infusion. Development of 
215 
pain and mood as assessed by the Short form - McGill Pain Questionnaire (SF-MPQ) and Beck 
216 
Depression Questionnaire II (BDI-II), respectively. 
217 
2.3 Project design  
218 
This study is designed as monocentric observational pilot-study at the USB. 
219 
 
220 
 
221 
 
222 
3 
PROJECT POPULATION AND STUDY PROCEDURES 
223 
3.1 Project population, inclusion and exclusion criteria  
224 
 
225 
For our pilot project on drug plasma levels in an ambulatory infusion regime, a total of max. 15 
226 
patients (10 + Drop-out of 50%) newly receiving lidocaine-ketamine infusions at the USB will be 
227 
randomly selected. To minimize selection bias (including only responders, or patients with less 
228 
side-effects) and because we increase the ketamine dosage normally during the first 3 infusions, 
229 
we will only include patients who are new to lidocaine/ketamine infusions. 
230 
 
231 
Inclusion Criteria: 
232 
- Patient is a new recipient of lidocaine-ketamine infusions 
233 

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- Patient is 18 years of age or older 
234 
- Patient is able to provide Informed Consent 
235 
 
236 
Exclusion Criteria: 
237 
- Contraindication to blood sampling (on arm not used for infusion) 
238 
- Insufficient knowledge of German language 
239 
- Inability to give consent 
240 
- Patient is under 18 years of age 
241 
- Contraindication to treatment with lidocaine and/or ketamine  
242 
 
243 
3.2 Recruitment, screening and informed consent procedure 
244 
All patients who are newly assigned to lidocaine-ketamine infusions at the USB and who meet 
245 
the inclusion criteria will be asked to take part in the study by their treating physician. 
246 
If the patients are willing to participate, they will be informed in verbal and written form by one of 
247 
the investigators about the study and the blood collection. 
248 
All study participants will receive an informed consent form describing the study and providing 
249 
sufficient information to allow participants to make an informed decision about their participation 
250 
in the study. Sufficient time (at least 24 hours) will be given to the potential participants to make 
251 
a decision about participation. 
252 
Formal informed consent will be obtained from a participant using the approved consent form 
253 
before the participant undergoes any of the study procedures. 
254 
The consent form will be signed and dated by the investigator or his/her designee concurrently 
255 
with the participant's signature. A copy of the signed consent form will be given to the study 
256 
participant. The informed consent form will be retained as part of the study records. 
257 
The patients themselves have no direct advantage from participating in the study. The risk 
258 
resulting from an additional venepuncture is to be considered minimal. The typical risks of 
259 
inserting an indwelling venous cannula are already part of the infusion information. However, 
260 
patients are explicitly informed that taking part in the study includes three additional venous 
261 
punctures. 
262 
3.3 Study procedures 
263 
Recruitment and consent to participate in the study will take place in the consultation prior to the 
264 
first infusion. (c.f. 3.2) During the infusion, the patients' vital signs will be monitored as usual (10-
265 
minute blood pressure measurement, continuous SPO2 and 5-lead ECG are recorded, c.f. 3.3.2).  
266 
As a part of this study, at the end of the first, second and third infusion, side effects will be 
267 
screened using customized questionnaires (c.f. eCRF forms document). In addition, blood will be 
268 
collected during each of the first three infusion appointments. The blood collection itself will take 
269 
place within 3 minutes after termination of the infusion, as we assume the highest plasma levels 
270 
at that point in time. [25, 26] For blood collection we will use a Butterfly cannula (BBraun Venofix® 
271 
Safety 23G, PZN 08839883, B. Braun Melsungen AG) which will be inserted on the "non-infusion 
272 
arm" and two green 7.5ml Lithium-Heparin monovettes (S-Monovette® Lithium-Heparin  liquid, 
273 
preparation: lithium heparin, liquid, 7.5 ml, membrane screw cap, closure green, color code ISO, 
274 
(LxØ) without closure: 92 x 15 mm, with paper label, label/printing: green Sarstedt AG & Co. KG, 
275 
Nümbrecht). 
276 
Patients will complete the Short form - McGill Pain Questionnaire (with additional recording of 
277 
pain on the numeric rating scale (NRS) from 0 (no pain at all) to 10 (worst pain imaginable)) and 
278 
Beck Depression Questionnaire directly prior to the first three infusions. The SF – MPQ is a 
279 
validated instrument for measures of clinical pain that capture its sensory, affective and other 
280 

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qualitative components. [27] The BDI-II provides a validated psychological test procedure that 
281 
assesses the severity of depressive symptoms in adolescents 13 years of age and older and 
282 
adults. [28] 
283 
In addition, these questionnaires will also be completed at the time points 7 days after, and 14 
284 
days after the first, second and third Infusion. The participants will receive a link by e-mail so that 
285 
they can fill in the questionnaires online. According to the license agreement, the BDI-II will be 
286 
filled out in paper form and the results will be subsequently transferred to REDCap. If desired by 
287 
the participant, these questionnaires can also be completed during a telephone survey conducted 
288 
by the study staff. The surveys will be conducted with REDCap. After the third infusion, this online 
289 
questioning will take place additionally after 28 days (c.f. Appendix 1). After this questioning, the 
290 
study ends for the participants. 
291 
 
292 
3.3.1 Investigated variables  
293 
 
294 
Demographic  
295 
 
296 
Variable: Age  
297 
Categories: Age at beginning of therapy (recorded in years)  
298 
 
299 
Variable: Gender  
300 
Categories: female / male / diverse 
301 
 
302 
Variable: Nationality  
303 
Categories: Recorded as free text  
304 
 
305 
Variable: Diagnosis that led to the indication for lidocaine/ketamine infusion 
306 
Categories: Main pain-related diagnosis coded with ICD11, free text  
307 
Variable: Dosage 
308 
Categories: Weight (recorded in kg) / Height (recorded in cm) / Dosage of lidocaine (recorded in 
309 
mg) / Dosage of ketamine (recorded in mg) 
310 
Effects and Side effects 
311 
Variable: Depressive Symptoms  
312 
Categories: Recorded by BDI-II at the beginning of the infusion, 7 days after and 14 days after 
313 
Variable: Pain  
314 
Categories: Recorded by SF-MPQ-2 at the beginning of the infusion, 7 days after and 14 days 
315 
after, and by NRS (Number from 0 to 10) at the beginning of the infusion, 7 days after and 14 
316 
days after 
317 
Variable: Vital sings 
318 
Categories: blood pressure (recorded in mmHg) / heart rate (recorded in bpm) / saturation of 
319 
oxygen under infusion (recorded as percentage) / Respiratory rate (recorded in breaths per 
320 
minute), recorded at the start of the infusion and subsequently during a period of 60 minutes 
321 
Variable: ECG  
322 
Categories: Heart rate (recorded in bpm), regular sinus rhythm (recorded as yes or no), PQ 
323 
interval (recorded in ms), QRS-complex (recorded in ms), ST segment (recorded as 
324 
conspicuous/inconspicuous), T wave (recorded as conspicuous/inconspicuous), QTc (recorded 
325 
in ms), Extrasystolies (recorded as number), other anomalies (recorded as free text) at start of 
326 
infusion and at the end of infusion (minute 30) 
327 

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Variable: Side effects at end of infusion (patient recorded) 
328 
Categories: Injection site pain, dysphoria, euphoria, nervousness, anxiety, dyspnea, nausea, 
329 
hypersalivation, nightmares, hallucinations, visual disturbances, tinnitus, hyperacusis, 
330 
paresthesias, numbness, dizziness (recorded as present/absent). 
331 
Variable: Side effects at end of infusion (patient observation by physician, monitoring) 
332 
Categories: Exanthema, redness injection site, vomiting, tremor, dysarthria, nystagmus, 
333 
convulsions, dissociation, disorientation, restlessness, agitation (recorded as present/absent)  
334 
 
335 
Variable: Medication plasma levels 
336 
Categories: Lidocaine and ketamine plasma levels are recorded specified in mg/l al the end of 
337 
infusions 
338 
3.3.2 Standard Procedure of lidocaine-ketamine infusions at the Pain Unit of USB 
339 
 
340 
During a short medical history interview Patients are briefly asked about their current pain 
341 
situation before each infusion. For safety reasons, additional questions are asked about weight 
342 
changes, compliance with fasting (= no solid food for 6 hours, no drinks for 2 hours) and allergies.  
343 
Monitoring is then installed (10-minute blood pressure measurement, continuous SPO2 and 5-
344 
lead ECG are recorded) and venous access is established. Lidocaine and ketamine are infused 
345 
over a period of 30 minutes. The dosage of lidocaine is 4mg/kg is maintained throughout the 
346 
infusions, and the dosage of ketamine is increased within the first three infusions from 0.15mg/kg 
347 
at the first, to 0.25mg/kg at the second and 0.5mg/kg at the third infusion. In case patients already 
348 
experiencing sufficient analgesic effect and/or improvement in quality of life after the 1st or 2nd 
349 
infusion or if side effects do not allow a further dose increase, no further step up of ketamine 
350 
dosage is made. We define a sufficient effect as a significant pain reduction (more than 50%) for 
351 
at least 2 weeks and/or better quality of life with improved functionality during at least 2 weeks. 
352 
After the infusion, patients are monitored for at least another half hour, are discharged in company 
353 
and are instructed to not run heavy machines and motor vehicles for at least 24 hours. 
354 
 
355 
3.3.3 Laboratory Analysis  
356 
Plasma concentrations of lidocaine and ketamine are determined at the Institute of clinical 
357 
chemistry at University Hospital Zurich under ISO/IEC 17025:2017 accreditation. 
358 
The Plasma lidocaine and ketamine concentrations are measured using liquid chromatography 
359 
coupled to high-resolution accurate mass-spectrometry (LC-MS).  
360 
For lidocaine measurement, 100uL of plasma samples are precipitated with 100uL acetonitrile 
361 
(containing internal standard) and centrifuged. Supernatant is diluted with 5mM ammonium format 
362 
buffer pH 3 for analysis.  
363 
For ketamine measurement, 1 mL of plasma samples are diluted with 0.5mL H2O and 0.5 mL 
364 
ethanol (containing internal standard) extracted using e 150 µl 1 M NaOH in H2O and 5 ml n-
365 
Hexan/Dichlormethan (4+1, v+v). Supernatant was separated and dried down under steam of N2. 
366 
For measurement, samples are reconstituted with acetonitrile and 10 mM ammonium acetate 
367 
buffer.  
368 
Samples were analyzed on a Thermo Scientific™ Orbitrap Exploris™ 240 Mass Spectrometer 
369 
coupled to reversed phase liquid chromatography with an LLOQ of 0.1 μmol/L for lidocaine and 
370 
0.1 mg/L for ketamine. The methods were fully validated according to EMA guideline.  
371 
Both methods were fully validated according to EMA guideline.  
372 
 
373 
3.4 Withdrawal and discontinuation 
374 
Patients may withdraw from the study at any time and for any reason (stating reason is not 
375 

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required). No further data will be collected after withdrawal. Unless otherwise requested, the data 
376 
collected up to that point will still be evaluated in encrypted form and anonymized after the 
377 
evaluation. 
378 
The following reasons result in withdrawal: 
379 
 
SAE  
380 
 
AE challenging the health of the subject if continuing the study 
381 
 
382 
Drop-outs will be replaced by new patients and will be reported in the final publication. 
383 
 
384 
4 
STATISTICS AND METHODOLOGY 
385 
4.1. Statistical analysis plan 
386 
Patients characteristics regarding to age, gender, pharmacological treatment, medical 
387 
diagnosis will be analyzed exploratively/ descriptively. 
388 
 
389 
Primary outcome: 
390 
The primary outcome (Lidocaine plasma level) of our study is explorative and not comparative, 
391 
therefore no H0 or H1 are formulated no power analysis is performed and only descriptive/ 
392 
explorative statistics are reported.   
393 
We plan to include 10 patients with complete data sets, meaning, full data of three infusions with 
394 
stable dose of lidocaine (4mg/kg/BW) and escalating dose of ketamine (0.15 – 0.5mg/kg/BW). 
395 
This corresponds to thirty measures of lidocaine plasma concentrations at a dose of 4mg/kg/BW). 
396 
Patients without full data sets will be replaced but data from patients with preliminary study 
397 
termination will be reported in the final protocol. 
398 
 
399 
Secondary outcomes:  
400 
1. Ketamine plasma levels are assessed according to lidocaine levels.  
401 
 
402 
2. H0: dose escalation of ketamine has no effect on pain (outcome measure: SF-MPQ-2) and 
403 
mood (outcome measure: BDI-II. H1: we hypothesize that ketamine dose has an effect on both 
404 
outcome measures. For repeated measurements, an ANOVA will be separately calculated for 
405 
outcome measures of pain and mood as dependent variable. This analysis will be performed 
406 
separately for intermediate (one and two weeks) and long term effects (four weeks). For 
407 
comparative outcomes a level of significance of 0.05 will be used. In case of multiple testing, a 
408 
correction factor (in case of ANOVA: Bonferroni) for multiple testing is applied. 
409 
 
410 
3. Side effects during treatment will be primary analyzed descriptively. 
411 
 
412 
4. Multiple exploratory linear regressions will be calculated to evaluate the impact of dose and 
413 
plasma levels of lidocaine and ketamine on pain and mood as well as occurrence of side-effects. 
414 
 
415 
SPSS Version 25 will be used for data analyzation and graph pad PRISM Version 9 for data 
416 
visualization. The investigators, Flavia Flepp and Tobias Schneider, will perform all analysis 
417 
steps. If needed, statistical guidance will be applied by statisticians of the Clinical Trial Unit (CTU) 
418 
of the USB. 
419 
4.2. Handling of missing data  
420 

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Dropouts will be replaced (c.f. 3.4). We do not plan data imputation.  
421 
5 
REGULATORY ASPECTS AND SAFETY 
422 
5.1 Local regulations / Declaration of Helsinki 
423 
This research project will be conducted in accordance with the protocol, the Declaration of 
424 
Helsinki [3], the principles of Good Clinical Practice, the Human Research Act (HRA) and the 
425 
Human Research Ordinance (HRO) [1] as well as other locally relevant regulations. The project 
426 
leader acknowledges his responsibilities as both the project leader and the Sponsor. 
427 
5.2 Notification of safety and protective measures (HRA Art. 15, HRO Art. 20) 
428 
If, during the research project, circumstances arise which could jeopardise the safety or health of 
429 
the participants or lead to a disproportionate relationship between the risks and burdens and the 
430 
benefits, all the measures required to ensure protection are to be taken without delay. 
431 
The project leader is promptly notified (within 24 hours) if immediate safety and protective 
432 
measures have to be taken during the conduct of the research project. The Ethics Committee will 
433 
be notified via BASEC of these measures and of the circumstances necessitating them within 7 
434 
days. 
435 
5.3 Serious events (HRO Art. 21) 
436 
If a serious event occurs, the research project will be interrupted and the Ethics Committee 
437 
notified on the circumstances via BASEC within 7 days according to HRO Art. 211. 
438 
5.4 Amendments 
439 
Substantial changes to the project set-up, the protocol and relevant project documents will be 
440 
submitted to the Ethics Committee for approval according to HRO Art. 18 before implementation.  
441 
5.5 End of project 
442 
Upon project completion or discontinuation, the Ethics Committee is notified within 90 days. All 
443 
biological materials and health-related data are anonymized upon termination of data analysis. 
444 
5.6 Insurance 
445 
In the event of project-related damage or injuries, the Sponsor will be liable, except for damages 
446 
that are only slight and temporary; and for which the extent of the damage is no greater than 
447 
could be expected according to the current state of scientific knowledge (Art. 12 HRO).  
448 
6 
FURTHER ASPECTS 
449 
6.1 Overall ethical considerations 
450 
Overall, this project is in accordance with the regulatory requirements of the HFG and the HFV. 
451 
An approval of the local ethic committee is mandatory to conduct this project. The minimal 
452 
                                                        
 
1 A serious event is defined as any adverse event where it cannot be excluded, that the event is attributable to the 
sampling of biological material or the collection of health-related personal data, and which: 
a. requires inpatient treatment not envisaged in the protocol or extends a current hospital stay; 
b. results in permanent or significant incapacity or disability; or 
c. is life-threatening or results in death. 

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additional risks of an additional venous cannulation for the single patient is outweighed by far due 
453 
to the additional knowledge we generate about the safety profile and dose adjustments for 
454 
patients receiving future infusion treatments. As this is an observational study and the blood 
455 
sample analysis only evaluates the drug plasma levels, we do not expect incidental findings due 
456 
to study procedures. Especially the screening for depression is a standard procedure at the pain 
457 
clinics, suspicion of depression would be communicated to the patient independently of study 
458 
participation. This is also the case for incidental findings during the hemodynamic monitoring 
459 
during the infusion therapies. 
460 
6.2 Risk-Benefit Assessment  
461 
Venous catherization brings the risk of bleeding, bruises, swellings with it, as well as the small 
462 
chance of infection.  
463 
In summary, this study will not provide any direct benefit beyond the expected relief by the infusion 
464 
therapy on pain, to the participating patients, but it may provide valuable insights as a basis from 
465 
which we can optimize and adopt our infusion regimes up on plasma levels of lidocaine and 
466 
ketamine correlated with effects and side-effects. Participants will be exposed to minimal 
467 
additional risks due to the venous cannulation. 
468 
7 
QUALITY CONTROL AND DATA PROTECTION 
469 
7.1 Quality measures  
470 
The study will be conducted by a small team of the Pain Unit of the USB. All team members will 
471 
be trained on all important study related aspects. 
472 
For quality assurance the sponsor, the Ethics Committee or an independent trial monitor may visit 
473 
the research sites. Direct access to the source data and all study related files is granted on such 
474 
occasions. All involved parties keep the participant data strictly confidential.  
475 
 
476 
7.2 Data recording and source data 
477 
Study data will be recorded with electronic CRFs, using a database (RedCap, Research 
478 
Electronic Data Capture, Vanderbilt University, Tennessee, USA). For each enrolled study 
479 
participant CRFs will be maintained. Participants will not be identified in the CRF by name or 
480 
initials and birth date; instead the participant number will be used. The study staff and the PIs are 
481 
authorized for all CRFs.  
482 
Demographic data, visit dates, participation in study and Informed Consent Forms, randomization 
483 
number, SAEs, AEs and concomitant medication, results of relevant examinations and all CRFs 
484 
are considered the source documents in the study. 
485 
Paper source documents will be archived in folders at the study site with restricted access (Pain 
486 
Unit USB). 
487 
 
488 
7.3 Confidentiality and coding 
489 
Project data will be handled with uttermost discretion and is only accessible to authorized 
490 
personnel who require the data to fulfil their duties within the scope of the research project. On 
491 
the CRFs and other project specific documents, participants are only identified by a unique 
492 
participant number.  
493 
The data collection is based on electronic CRFs, other source documents will be on paper. Data 
494 
from paper forms will then be transferred to the source documentation in a secure database. Only 
495 
CIs and study team members will be authorized to coordinate CRF entries. Data entry of paper 
496 

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pencil documents will be checked double after entry into the eCRF. The electronic database is 
497 
based on the secure web application REDCap (Research Electronic Data Capture) and will be 
498 
operated with individual user log in, time stamp, and logging of changes with the name of the 
499 
respective study member. Only authorized personnel will be able to enter the system to view and 
500 
edit data.  
501 
Participants will not be identified in the CRF by name or initials and birth date. Only participant 
502 
identification codes will be used to track participants. The participant identification list will be 
503 
stored at the Pain Unit and will be only accessible for the investigators. The data will be locked 
504 
and therefore protected from unauthorized or accidental disclosure, alteration, deletion, copying 
505 
and theft. 
506 
 
507 
Biological material in this project is not identified by participant name but by a unique participant 
508 
number. Biological material is appropriately stored in a restricted area only accessible to 
509 
authorized personnel. The plasma samples analyzed by the laboratory of the USZ are coded with 
510 
a unique batch and no personal/ identifying data will be shared with the USZ. The identification 
511 
list is stored locked and protected from unauthorized access at the Pain Unit USB.   
512 
7.4 Retention and destruction of project data and biological material 
513 
All study data will be archived for a minimum of 10 years after study termination or premature 
514 
termination of the clinical trial. All data is archived in folders at the study site with restricted access 
515 
(Pain unit USB). 
516 
Upon conclusion, the database is secured and cannot be changed anymore. The Plasma samples 
517 
will be disposed by the laboratory of the USZ directly after analysis.  
518 
 
519 
8 FUNDING / PUBLICATION / DECLARATION OF INTEREST 
520 
The study is funded by the Clinic for Anesthesia, USB. There is no conflict of interest and the 
521 
financing party has no influence on the protocol, analysis or publication. We plan to publish the 
522 
results in a peer-reviewed scientific journal. Upon request, we will provide the full study protocol 
523 
and data (as required by some journals). The trial results might be presented at scientific 
524 
congresses. The main publication will be created by Flavia Flepp, Matthijs de Leeuw, Regula 
525 
Steiner, Tobias Schneider and Wilhelm Ruppen. No unpublished data may be transmitted to a 
526 
third party without prior written approval by sponsors and PIs. No publication or communication 
527 
involving the results of the study is authorized without prior written consent from the PIs. In view 
528 
of patent and confidentiality issues, however, the PIs must accept requirements on the timing of 
529 
early publication. No use of professional writers is intended. The PIs will have ultimate authority 
530 
over any of the activities. 
531 
9 
REFERENCES 
532 
1. 
van Hecke, O., N. Torrance, and B.H. Smith, Chronic pain epidemiology and its clinical 
533 
relevance. Br J Anaesth, 2013. 111(1): p. 13-8. 
534 
2. 
Scascighini, L., et al., Multidisciplinary treatment for chronic pain: a systematic review 
535 
of interventions and outcomes. Rheumatology (Oxford), 2008. 47(5): p. 670-8. 
536 
3. 
WHO. 
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15.03.]; 
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from: 
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http://id.who.int/icd/entity/1581976053  
538 
4. 
Clauw, D.J., et al., Reframing chronic pain as a disease, not a symptom: rationale and 
539 
implications for pain management. Postgrad Med, 2019. 131(3): p. 185-198. 
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5. 
Norbury, A. and B. Seymour, Response heterogeneity: Challenges for personalised 
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medicine and big data approaches in psychiatry and chronic pain. F1000Res, 2018. 7: 
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p. 55. 
543 
6. 
Coles, S., W. Dabbs, and S. Wild, Pharmacologic Management of Chronic Pain. Prim 
544 
Care, 2022. 49(3): p. 387-401. 
545 
7. 
Blondell, R.D., M. Azadfard, and A.M. Wisniewski, Pharmacologic therapy for acute 
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pain. Am Fam Physician, 2013. 87(11): p. 766-72. 
547 
8. 
Cohen, S.P., L. Vase, and W.M. Hooten, Chronic pain: an update on burden, best 
548 
practices, and new advances. Lancet, 2021. 397(10289): p. 2082-2097. 
549 
9. 
Kosharskyy, B., et al., Intravenous infusions in chronic pain management. Pain 
550 
Physician, 2013. 16(3): p. 231-49. 
551 
10. 
Niesters, M., C. Martini, and A. Dahan, Ketamine for chronic pain: risks and benefits. Br 
552 
J Clin Pharmacol, 2014. 77(2): p. 357-67. 
553 
11. 
Horvat, S., B. Staffhorst, and J.M.G. Cobben, Intravenous Lidocaine for Treatment of 
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Chronic Pain: A Retrospective Cohort Study. J Pain Res, 2022. 15: p. 3459-3467. 
555 
12. 
Tran, K. and S. McCormack, CADTH Rapid Response Reports, in Ketamine for Chronic 
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Non-Cancer Pain: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines. 
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2020, Canadian Agency for Drugs and Technologies in Health 
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Copyright © 2020 Canadian Agency for Drugs and Technologies in Health.: Ottawa (ON). 
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13. 
Tully, J., et al., Utilization of Intravenous Lidocaine Infusion for the Treatment of 
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Refractory Chronic Pain. Anesth Pain Med, 2020. 10(6): p. e112290. 
561 
14. 
Jelen, L.A. and J.M. Stone, Ketamine for depression. Int Rev Psychiatry, 2021. 33(3): p. 
562 
207-228. 
563 
15. 
McIntyre, R.S., et al., Synthesizing the Evidence for Ketamine and Esketamine in 
564 
Treatment-Resistant Depression: An International Expert Opinion on the Available 
565 
Evidence and Implementation. Am J Psychiatry, 2021. 178(5): p. 383-399. 
566 
16. 
Goesling, J., L.A. Lin, and D.J. Clauw, Psychiatry and Pain Management: at the 
567 
Intersection of Chronic Pain and Mental Health. Curr Psychiatry Rep, 2018. 20(2): p. 
568 
12. 
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17. 
Afacan, M.A., et al., Lidocaine-induced delirium: a case report. Am J Emerg Med, 2015. 
570 
33(4): p. 603.e1-2. 
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18. 
Daraz, Y.M. and O.H. Abdelghffar, Lidocaine Infusion: An Antiarrhythmic With 
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Neurologic Toxicities. Cureus, 2022. 14(3): p. e23310. 
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19. 
Digala, L.P. and S. Lucchese, IV Lidocaine Infusion Leading to the Toxic Levels in Serum 
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Causing Asystole - A Case Report. Headache, 2020. 60(1): p. 269-270. 
575 
20. 
Warburton, D. Mum dies after two heart attacks when hospital gave her unlicensed 
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drugs. The Mirror 2019; Available from: https://www.mirror.co.uk/news/uk-
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21. 
Foo, I., et al., The use of intravenous lidocaine for postoperative pain and recovery: 
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international consensus statement on efficacy and safety. Anaesthesia, 2021. 76(2): p. 
580 
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Tremont-Lukats, I.W., et al., Systemic administration of local anesthetics to relieve 
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neuropathic pain: a systematic review and meta-analysis. Anesth Analg, 2005. 101(6): 
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584 
23. 
Striebel, J., T. Schneider, and W. Ruppen, Simultaneous Application of Lidocaine and 
585 
Ketamine During an Ambulatory Infusion Therapy as a Treatment Option in Refractory 
586 
Chronic Pain Conditions – A retrospective analysis, in Pain Unit, Clinic for 
587 
Anaesthesiology University Hospital Basel. 2022. Unpublished data under review.  
588 

Version 1.1, 02.05.2023 
 
 
22/24 
24. 
Orhurhu, V., et al., Ketamine Infusions for Chronic Pain: A Systematic Review and Meta-
589 
analysis of Randomized Controlled Trials. Anesth Analg, 2019. 129(1): p. 241-254. 
590 
25. 
Berk, T. and S.D. Silberstein, The Use and Method of Action of Intravenous Lidocaine 
591 
and Its Metabolite in Headache Disorders. Headache, 2018. 58(5): p. 783-789. 
592 
26. 
Weinberg, L., et al., Pharmacokinetics and pharmacodynamics of lignocaine: A review. 
593 
World Journal of Anesthesiology, 2015. 4(2): p. 17-29. 
594 
27. 
Dworkin, R.H., et al., Development and initial validation of an expanded and revised 
595 
version of the Short-form McGill Pain Questionnaire (SF-MPQ-2). Pain, 2009. 144(1-2): 
596 
p. 35-42. 
597 
28. 
Beck, A.T., et al., Beck-Depressions-Inventar - Revision. - Deutsche Adaption.   © 2006 
598 
Harcourt Test Services GmbH, Frankfurt/M. 2. Auflage © 2009 Pearson Assessment 
599 
& Information GmbH, Frankfurt am Main. 
600 
 
601 

 
LiKe-Level-Trial 
 
Version 1.1, 02.05.2023 
 
 
Appendix 1: Schedule of assessments  
 
 
 
Time (days) 
>-1 
day 
0 
+7 
+14 
+28 
 
+35 
 
+42 
+56 
+63 
+70 
+84 
Visit 
Informati
on 
Infusion 
1  
Questionn
aires 
online 
Questionn
aires 
online 
Infusion 
2 
Questionn
aires 
online 
Questionn
aires 
online 
Infusion 
3 
Questionn
aires 
online 
Questionn
aires 
online  
Questionn
aires 
online 
oral and written 
Information 
+ 
 
 
 
 
 
 
 
 
 
 
Written consent 
+ 
 
 
 
 
 
 
 
 
 
 
check inclusion-/ 
exclusion criteria 
+ 
 
 
 
    
 
 
 
 
 
 
Medical history 
+ 
 
 
 
 
 
 
 
 
 
 
Participant 
Characteristics  
 
+ 
 
 
 
 
 
 
 
 
 
Questionnaires 
Side effects 
 
+ 
 
 
+ 
 
 
+ 
 
 
 
Blood Sampling 
 
+ 
 
 
+ 
 
 
+ 
 
 
 
Short form McGill 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Beck Depression 
 
   + 
    + 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 

 
LiKe-Level-Trial 
 
Version 1.1, 02.05.2023