An Early Phase 1 interventional study of Lidocaine and Ketamine Infusion and Active Placebo (Midazolam) Infusion in Opioid-Refractory Chronic Cancer-Related Pain, sponsored by National and Kapodistrian University of Athens. Recruiting at 1 site in Greece. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-07-07.
Sponsored by National and Kapodistrian University of Athens · Early Phase 1, Interventional, and Treatment
This is a randomized, double-blinded, placebo-controlled, cross-over trial examining the effect of a series of two weekly intravenous infusions of lidocaine 4 mg/kg and ketamine 0.2 mg/kg in patients with moderate to severe opioid-refractory chronic cancer-related pain. The aim of this study is to investigate whether the lidocaine - ketamine (LK) regimen provides better analgesia that an active placebo of midazolam 0.02 mg/kg, in this population.
Background
Opioids are the mainstay of treatment for chronic cancer-related pain, but their use is associated with multiple adverse effects, tolerance requiring progressively higher doses, and, in rare cases, opioid-induced hyperalgesia. Standard adjuvant analgesics (antiepileptics and antidepressants) may provide modest benefit. However, despite maximally tolerated therapy, many patients continue to experience refractory pain.
Lidocaine and low-dose ketamine may be beneficial in these difficult-to-treat pain scenarios due to their favorable safety profile and mechanisms of action. The main limitation of these drugs is their short duration of action; however, mechanisms involving central plasticity and reversal of opioid tolerance and opioid-induced hyperalgesia may explain the longer analgesic effects observed in some studies.
Study Design
This is a randomized, double-blind, active placebo-controlled, cross-over trial evaluating the efficacy of two weekly lidocaine-ketamine (LK) infusions compared to active placebo in patients with opioid-refractory chronic cancer-related pain.
The investigators will assess:
Pain intensity and physical functioning using the Brief Pain Inventory (BPI) Emotional functioning using the Beck Depression Inventory (BDI) Patient-reported overall improvement using the Patient Global Impression of Change (PGIC) scale Total opioid consumption expressed as oral morphine equivalents (MME) Neuropathic pain effects in patients with confirmed neuropathic components using the Neuropathic Pain Symptom Inventory (NPSI)
Adult patients presenting to the pain clinic of Attikon University General Hospital with a diagnosis of chronic cancer-related pain according to the International Association for the Study of Pain definition will be screened for eligibility. Participants will be adult patients with chronic cancer-related pain who continue to experience moderate to severe pain despite stable, optimized analgesic therapy. Eligible patients will be on a stable opioid regimen of at least 60 mg oral morphine equivalents per day for at least one week, with stable adjuvant analgesics in those with a neuropathic pain component. A minimum life expectancy of three months and the ability to provide informed consent will be required. Patients with significant hepatic or renal dysfunction, uncontrolled psychiatric or neurological illness, pregnancy, or contraindications to lidocaine, ketamine, or midazolam will be excluded. The presence of a neuropathic pain component will be assessed clinically and with validated instruments to allow exploratory subgroup analyses of treatment effects on neuropathic pain.
Randomization and Blinding Patients will be randomized using a computer-generated sequence in blocks of four.
Allocation will be concealed in sequentially numbered sealed envelopes. Infusions will be prepared by anesthesiology staff not involved in the trial, using identical, unmarked transparent syringes to maintain blinding.
Both patients and assessors (including companions or clinic staff assisting with questionnaires) will be blinded to treatment.
Intervention
Active intervention (LK infusion):
Lidocaine 4 mg/kg + ketamine 0.2 mg/kg, administered over 45 minutes using an electronic infusion pump Dosing based on actual body weight; for BMI >30, ideal body weight will be used
Active placebo: Midazolam 0.02 mg/kg IV over 45 minutes, selected to mimic sedative effects without analgesic activity
Procedure:
Pre-infusion: patients complete questionnaires and undergo brief clinical assessment IV cannula insertion and standard monitoring (pulse oximeter, ECG, non-invasive BP) Infusion over 45 minutes, followed by 1-hour post-infusion observation Two infusions will be administered 7 days apart After a 14-day washout, patients cross over to the alternate intervention
Rescue Analgesia
All patients will have access to rescue analgesics (e.g., oral oxycodone), converted to oral morphine equivalents for measurement and comparison.
Safety Monitoring Hepatic function: SGOT/SGPT monitored during the study Renal function: Creatinine and GFR monitored
Protocol adjustments:
If SGOT/SGPT above ULN => Extend infusion to 60 min; If SGOT/SGPT >3x ULN => Reduce lidocaine dose to 2 mg/kg; If. SGOT/SGPT >5x ULN, Child B/C liver disease, or GFR \<30ml/min => Discontinue participation
Common side effects:
Lidocaine: lightheadedness, somnolence, peri-oral paresthesia, nausea, headache, dysarthria, dry mouth, metallic taste Ketamine: nausea, vomiting, psychotomimetic effects, headache, fatigue, sedation
Outcome Measures
Primary Outcome:
Change in BPI question 3 (pain intensity) from baseline to end of treatment.
Secondary Outcomes:
Physical functioning (BPI) Emotional functioning (BDI) Patient Global Impression of Change (PGIC) Opioid consumption (MME) Neuropathic pain (NPSI)
Statistical analysis will be performed using the SPSS software package (IBM SPSS Statistics, Chicago, IL, USA) and R Project. The Shapiro-Wilk test will be applied to assess the normality of data distribution, and the level of statistical significance will be set at 5% (p \< 0.05). Continuous variables with a normal distribution will be expressed as mean ± standard deviation (mean ± SD), whereas those not following the normal distribution will be presented as median and interquartile range (IQR). Categorical variables will be presented as absolute and relative frequencies (percentages).
Comparisons between the two treatment conditions in the crossover design will be performed using the paired Student's t-test or the Wilcoxon signed-ranks test, depending on the normality of the data distribution. To explore potential correlations among study parameters, Pearson's correlation coefficient (r) or other appropriate correlation coefficients will be calculated. If required by the study findings, additional analyses-such as multivariable logistic regression to identify independent determinants of observed changes, or mixed-effects model analyses-will be conducted.
Sample size calculation was performed using the Hedwig tool provided online by Massachusetts General Hospital Biostatistics Center. A sample of 20 patients has 80% statistical power for a level of significance of a=0.05 to detect a clinically significant change of 2 points in question 3 of the Brief Pain Inventory - Short Form from baseline to end of treatment assessment, given an SD of 3 based on data from studies assessing this particular outcome. Based on that, at least 20 patients need to be enrolled. We aim to enroll 24 patients.
Common side effects associated with lidocaine infusion include lightheadedness, somnolence, peri-oral paresthesia, nausea, headache, dysarthria, dry mouth, metallic taste. Common side effects associated with ketamine infusion include nausea, vomiting, psychotomimetic effects, headache, fatigue, sedation. No serious adverse events have been reported with these drugs at the dosages used in this RCT. Any adverse events will be reported, along with any action taken.
310 studies on the registry are indexed under Cancer Pain; 73 are open to participants now.
This study's planned enrollment of 24 is below the median of 62 across 235 interventional studies indexed under Cancer Pain.
Browse Cancer Pain studies →National and Kapodistrian University of Athens is the lead sponsor of 176 studies on the registry; 54 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
NYHA class (heart failure)
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Life expectancy
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Drug: Lidocaine and Ketamine Infusion
Drug: Active Placebo (Midazolam) Infusion
Drug pages: Lidocaine · Ketamine
Participants receive two intravenous infusions, 7 days apart, containing lidocaine 4 mg/kg and ketamine 0.2 mg/kg (using actual body weight, or ideal body weight if BMI \>30). The drugs are combined in a single, clear solution and administered via an electronic pump in an outpatient setting.
Participants receive two intravenous infusions, 7 days apart, containing midazolam 0.02mg/kg (using actual body weight, or ideal body weight if BMI \>30). The drugs are combined in a single, clear solution and administered via an electronic pump in an outpatient setting.
Change from Baseline in the Worst Pain During the Last 24 Hours on an 11-Point, 0 to 10, Numerical Rating Scale
Question 3 of the Brief Pain Inventory - Short Form, where 0 is equivalent to no pain and 10 indicates the worst possible pain.
Time frame: Baseline (immediately before the first LK or placebo infusion) and one week after the second infusion.
Changes in the Score of Pain Intensity of the Brief Pain Inventory - Short Form
Assesses changes in patient-reported pain severity, including worst, least, average pain over the past 24 hours, and current pain ("pain right now").
Time frame: Baseline (before the first LK or placebo infusion), before the second infusion (LK or placebo), and, one week after the second infusion (LK or placebo).
Change in the Proportion of Patients Achieving 2-Point Reduction on Worst and Least Pain of the Brief Pain Inventory - Short Form
Evaluates the proportion of patients achieving a clinically significant improvement, defined as a ≥2-point reduction in worst and least pain on the Brief Pain Inventory.
Time frame: Baseline (before the first LK or placebo infusion), before the second infusion (LK or placebo), and, one week after the second infusion (LK or placebo).
Change in the Score of the Interference Scale of the Brief Pain Inventory - Short Form
Measures changes in the degree to which pain interferes with daily functioning, mood, sleep, work, and social activities.
Time frame: Baseline (before the first LK or placebo infusion), before the second infusion (LK or placebo), and, one week after the second infusion (LK or placebo).
Change in total Oral Morphine Equivalents Consumption of the Previous Week
Assesses changes in total opioid use by calculating the weekly oral morphine equivalent dose consumed by each participant.
Time frame: Baseline (before the first LK or placebo infusion), before the second infusion (LK or placebo), and, one week after the second infusion (LK or placebo).
Immediate Analgesic Effect of the Infusion (LK or placebo)
Evaluated using question 6 of the Brief Pain Inventory - Short Form (pain right now)
Time frame: Before the infusion and one hour after infusion termination.
Change in the Score of the Beck Depression Inventory
Measures changes in depressive symptom severity associated with treatment over the course of the study. Beck Depression inventory is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression. Scores range from 0 to 63, where higher score indicates more depressive symptoms.
Time frame: Baseline (immediately before the first LK or placebo infusion) and one week after the second infusion.
Rating of Overall Improvement Using Patient Global Impression of Change Scale
Assesses the patient's overall perceived improvement in pain and function following the treatment. PGIC is a 7 point scale depicting a patient's rating of overall improvement. Patients rate their change as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse."
Time frame: one week after the second (LK or placebo) infusion
Plan to share: Yes
Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report
Time frame: They will be available from the end of the recording of the response of the last patient and for 5 years thereafter.
Access criteria: Researchers that would have come in contact with our team firstly and that shall be able to prove that they will use the data solely for research purposes and not for commercial use.
Data sharing details ↗ · attikonhospital.gov.gr
Started Mar 2026 (actual). Primary completion is estimated for Aug 2027, 17 months after the start.
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Studies of the drugs tested here: Lidocaine · Ketamine
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