The Role of Coadministration of Lidocaine and Ketamine in Opioid-Refractory Chronic Cancer-Related Pain.

February 18, 2026 updated by: Konstantinos Kalimeris, National and Kapodistrian University of Athens

The Role of Coadministration of Lidocaine and Ketamine in Opioid-Refractory Chronic Cancer-Related Pain: a Randomized, Double-Blinded, Placebo-Controlled, Cross-Over Trial.

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

24

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Konstantinos Kalimeris MD, PhD, Associate Professor of Anesthesiology, Associate Professor
  • Phone Number: +302105831997
  • Email: kkalimeris@med.uoa.gr

Study Contact Backup

Study Locations

  • Greece
    • Attica
      • Athens, Attica, Greece, 12461
        • University General Hospital of Athens "Attikon" - National and Kapodistrian University of Athens Medical School
        • Contact:
          • Konstantinos Kalimeris MD, PhD, Associate Professor of Anesthesiology
          • Phone Number: +302105831997
          • Email: kkalimeris@med.uoa.gr
        • Contact:
          • Erond Zeneli, MD
          • Phone Number: +306982094129
        • Principal Investigator:
          • Erond Zeneli, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age 18 years or more
  • Capacity to provide informed consent, ability to complete study assessments and comply with the study procedures
  • Meets the IASP definition for chronic cancer-related pain
  • Moderate or severe pain, defined as average pain of 4 or greater on an 11-point (0-10) NRS in the past 24h
  • Adequate trial of opioid medication, defined as a dose of at least 60 mg/day oral morphine equivalent or maximum tolerated dose, in the past 24h
  • For patients with neuropathic component to pain: adequate trial of at least one adjuvant analgesic, defined as a daily dose of at least Amitriptyline 37.5mg, Duloxetine 30mg, Gabapentin 900mg, Pregabalin 150mg, Venlafaxine 60mg or equivalent (26), or maximum tolerated dose in the past 24h

Exclusion Criteria:

  • Previous adverse reaction to ketamine, lidocaine or other amide-type local anesthetics, midazolam
  • Severe liver disease (Child Class B or C)
  • SGPT or SGOT >5 times the upper limit of normal
  • End stage kidney disease
  • Serious cardiac comorbidity (e.g. unstable angina, poorly controlled hypertension or tachycardia, high-risk coronary vascular disease, symptomatic heart failure with NYHA class III-IV, history of heart block, Wolf-Parkinson-White syndrome, Adams-Stokes syndrome)
  • Elevated intracranial or intraocular pressure
  • Pheochromocytoma or poorly controlled hyperthyroidism
  • History of psychosis, schizophrenia or substance abuse
  • Pregnant or breastfeeding
  • Porphyria
  • Life expectancy shorter than the duration of the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Lidocaine and Ketamine Infusion
Drug: Lidocaine and Ketamine Infusion
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.
Placebo Comparator: Active Placebo (Midazolam) Infusion
Drug: Active Placebo (Midazolam) Infusion
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from Baseline in the Worst Pain During the Last 24 Hours on an 11-Point, 0 to 10, Numerical Rating Scale
Time Frame: Baseline (immediately before the first LK or placebo infusion) and one week after the second infusion.
Question 3 of the Brief Pain Inventory - Short Form, where 0 is equivalent to no pain and 10 indicates the worst possible pain.
Baseline (immediately before the first LK or placebo infusion) and one week after the second infusion.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in the Score of Pain Intensity of the Brief Pain Inventory - Short Form
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).
Assesses changes in patient-reported pain severity, including worst, least, average pain over the past 24 hours, and current pain ("pain right now").
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
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).
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.
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
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).
Measures changes in the degree to which pain interferes with daily functioning, mood, sleep, work, and social activities.
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
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).
Assesses changes in total opioid use by calculating the weekly oral morphine equivalent dose consumed by each participant.
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)
Time Frame: Before the infusion and one hour after infusion termination.
Evaluated using question 6 of the Brief Pain Inventory - Short Form (pain right now)
Before the infusion and one hour after infusion termination.
Change in the Score of the Beck Depression Inventory
Time Frame: Baseline (immediately before the first LK or placebo infusion) and one week after the second infusion.
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.
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
Time Frame: one week after the second (LK or placebo) infusion
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."
one week after the second (LK or placebo) infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National and Kapodistrian University of Athens

Collaborators

Attikon Hospital

Investigators

  • Study Chair: Konstantinos Kalimeris, Assoc Prof of Anesthesiology, National and Kapodistrian University of Athens
  • Study Chair: Maria Riga, Assis Prof of Anesthesiology, National and Kapodistrian University of Athens
  • Study Chair: Ioannis Kotsantis, Assis Prof of Oncology, National and Kapodistrian University of Athens

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

March 1, 2026

Primary Completion (Estimated)

August 1, 2027

Study Completion (Estimated)

August 1, 2027

Study Registration Dates

First Submitted

February 6, 2026

First Submitted That Met QC Criteria

February 6, 2026

First Posted (Actual)

February 13, 2026

Study Record Updates

Last Update Posted (Actual)

February 20, 2026

Last Update Submitted That Met QC Criteria

February 18, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 801/30-12-2025

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Sharing Time Frame

They will be available from the end of the recording of the response of the last patient and for 5 years thereafter.

IPD Sharing 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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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