Previous studies have shown that the anterior cingulate cortex is involved in the regulation of pain and its associated negative emotions, that pyramidal neurons are highly excitable in chronic neuropathic pain conditions, and that silencing of pyramidal neurons can eliminate pain. The aim of this study was to evaluate the safety, tolerability, and efficacy of intracranial injection of GA (containing the hM4Di gene) in the anterior cingulate cortex in combination with oral clozapine for the treatment of refractory neuropathic pain.
Regularised treatment with conventional medical therapy (including, but not limited to, medication, physiotherapy, cognitive therapy, nerve blocks and other non-invasive or minimally invasive treatments) for at least 3 months with no symptomatic relief or emergence of tolerance, as assessed by the investigator
Pharmacological treatment means a full course of treatment with at least two first-line medications, as assessed by the investigator
Mean visual analogue scale (VAS) value ≥4 cm and/or mean numerical rating scale (NRS) value ≥4 points within one week of baseline at enrolment
Subjects who have had a stable analgesic regimen for at least 30 days prior to the intensity of pain described in Inclusion Criterion 2 and agree not to arbitrarily change the type and dose of medication that they are currently taking until the end of the period of assessment of the effectiveness of this trial, as assessed by the investigator
suffering from severe cardiopulmonary disease such as unstable angina, myocardial infarction, severe arrhythmia, recurrent asthma attacks, etc;
white blood cell count <3.5 x 109/L and neutrophil count <1.0 x 109/L
Platelet (PLT) <75 x 109/L
Coagulation: prothrombin time and activated partial thromboplastin time >1.5 x ULN
Single group
GA+clozapine
GeneticPatients were first given intracranial injections of GA and observed for 14-28 days, followed by a dose-climbing trial of clozapine medication, and finally, after the investigators had determined an effective dose of clozapine, the patients were given a fixed dose of clozapine orally for three months.
Incidence and severity of adverse events (AE)/serious adverse events (SAE) as assessed by CTCAE v5.0
Patient-Reported Adverse Events, Abnormalities on Physical Examination, and Abnormalities in Laboratory Tests
effectiveness: the degree of pain improvement was assessed by visual analogue scale (VAS).
The degree of pain improvement was assessed by visual analogue scale (VAS). VAS Score: i.e. Pain Scale Rating, which assesses the severity of pain using visual analogue methods. The scale uses a 10cm long straight line with '0' cm and '10' cm at each end, with 0 indicating no pain and 10 indicating unbearable severe pain.
effectiveness: the pain improvement was assessed by Brief pain inventory (BPI) scale.
the pain improvement was assessed by Brief pain inventory (BPI) scale. BPI: Evaluates pain severity and functional interference. Part 1 (Severity): Current pain, average pain (24h), worst pain (24h), least pain (24h), pain relief from treatments. Part 2 (Interference): Impact on general activity, mood, walking ability, work, relationships, sleep, and enjoyment of life.
effectiveness: the degree of sleep quality improvement was assessed by Insomnia Severity Index (ISI).
The degree of sleep quality improvement was assessed by Insomnia Severity Index (ISI). ISI scale: 7 entries, each rated 0-4. The total score ranges from 0-28, and the higher the score the greater the severity of insomnia.
effectiveness: the sleep quality improvement was assessed by Daily Sleep Interference Scale (DSIS).
the sleep quality improvement was assessed by Daily Sleep Interference Scale (DSIS). DSIS: An 11-point Likert scale ranging from 0 ("Pain did not interfere with sleep") to 10 ("Pain completely interfered with sleep" \[inability to sleep due to pain\]). Subjects will recall sleep interference over the preceding 24 hours each morning and record scores.
fMRI: Neuronal activation in ACC brain regions and connectivity of ACC brain regions with other brain regions
fMRI: is a radiation-free, non-invasive functional imaging technique that detects the level of neuronal activation in brain tissue by probing blood oxygen saturation and water levels in brain tissue. In this programme, local brain activity (activation of neurons in brain regions) and brain integration (functional connectivity between brain regions) are assessed, especially in the ACC brain region.
Drug Dose Reduction
After the patient is treated with GA intracranial injections combined with oral clozapine and the pain symptoms improve, the previous analgesic medication of patients may be considered to be gradually tapered off
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