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.

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

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

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.