Pre-emptive Topical Lidocaine 5% Plaster for Prevention of Post-Craniotomy Pain: A Protocol for a Multicentred, Randomized, Triple-Blind, Placebo-Controlled Clinical Trial
Post-craniotomy pain is a significant clinical challenge, with 48% to 69% of patients experiencing moderate to severe pain within the first 48 hours after surgery. Uncontrolled pain can lead to sympathetic activation, potentially elevating arterial and intracranial pressure, and increasing the risk of intracranial hemorrhage. Current post-operative analgesia primarily relies on opiates, which, while effective, are associated with increased incidences of post-operative nausea and vomiting. Non-steroidal anti-inflammatory drugs (NSAIDs) are less commonly used due to concerns about intracranial bleeding. Pre-operative incisional infiltration and scalp nerve block are alternative strategies, but there is limited evidence supporting their superiority. Consequently, there is a pressing need for effective, safe, simple, and non-invasive approaches to prevent or treat post-craniotomy pain.
Lidocaine 5% plaster (L5P) was initially approved for the treatment of neuropathic pain associated with postherpetic neuralgia. Its therapeutic effect is based on its topical action on impaired peripheral nerve endings. Transdermal lidocaine blocks voltage-gated sodium channels in unmyelinated C fibers and small myelinated A-delta fibers, thereby blocking the transduction of pain nociception. Recent studies have demonstrated that pre-emptive application of L5P is effective in preventing post-operative pain following percutaneous endoscopic lumbar discectomy and thoracotomy. For instance, Fiorelli et al. reported that pre-emptive L5P scalp analgesia significantly reduced post-thoracotomy pain intensity and total morphine consumption compared to placebo, with minimal systemic adverse events (AEs). Given these findings, pre-emptive scalp analgesia with L5P is considered a promising approach for alleviating post-craniotomy pain.
This article presents a protocol for a multicentred, prospective, randomized, placebo-controlled, triple-blind clinical trial designed to evaluate the efficacy and safety of pre-emptive L5P for the prevention of post-craniotomy pain. The study, named the EASY trial, is scheduled to be conducted at three large-scale medical institutions in China specializing in neurosurgery: Beijing Tiantan Hospital, Peking University Third Hospital, and Peking University International Hospital. The trial is estimated to start in June 2020 and last for approximately 24 months. The protocol has been approved by the local Institutional Review Board (No. KY2020-008-02) and registered at ClinicalTrials.gov (No. NCT 04169854). The study adheres to the Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) guidelines, and all participants will provide informed consent.
Eligibility criteria for the trial include patients aged 18 years or older, with an American Society of Anesthesiologists (ASA) status of I or II, who are scheduled for elective craniotomy. Exclusion criteria include allergy to lidocaine or the hydrogel plaster, chronic headache, craniofacial pain or neuralgia, Glasgow Coma Scale (GCS) less than 15, current or previous cardiovascular or cerebrovascular accident, expected delayed recovery or extubation, uncontrolled arrhythmia, history of intracranial operation, emergency or revision craniotomy, mental illness, psychiatric drug use or alcohol abuse, and inability to understand the use of a 100 mm visual analog scale (VAS) or patient-controlled analgesia (PCA).
Participants will be randomized into either the masked intervention group or the placebo control group at a 1:1 ratio using computer-generated randomization. Allocation concealment will be maintained using sealed opaque envelopes stored in a secure locker. The masked intervention group will receive masked lidocaine 5% white hydrogel plasters (10 cm x 14 cm, containing 700 mg of lidocaine), while the placebo control group will receive plain hydrogel plasters of the same size, appearance, and material but without lidocaine. Both the surgeon and the patients will be blinded to the allocation. Emergency unblinding will only occur if unexpected excessive AEs are associated with one of the interventions, such as uncontrollable pain or excessive withdrawals, with the final decision authorized by the principal investigator or the Data Monitoring Committee (DMC).
Surgeons will mark the planned incisions as soon as informed consent is obtained. For participants in the masked intervention group, the L5P will be applied to cover the marked incision and head-holder sites. The plaster may be cut to fit the incision shape if necessary. Similarly, participants in the placebo control group will have plain placebo plasters applied to cover the incision mark. The plasters will be applied for 12 hours at night (from 6:00 PM to 6:00 AM) and removed for 12 hours during the day (from 6:00 AM to 6:00 PM). All craniotomies will be performed in the morning within 3 hours after plaster removal.
General anesthesia will be induced with propofol (1.5–2.0 mg/kg) and sufentanil (10–15 mg), with neuromuscular blockade provided by intravenous cisatracurium (0.2 mg/kg) for tracheal intubation. Patients will be ventilated at 6 to 8 mL/kg tidal volume, with end-tidal carbon dioxide maintained within 28 to 35 mmHg. Mean arterial pressure and heart rate will be maintained within 30% of baseline values. Analgesic administration, extra neuromuscular blockers, and intra-operative vasoactive drugs will be used as needed. A loading dose of 0.1 mg/kg morphine will be administered for post-operative analgesia, with uncontrolled extreme post-operative pain treated with an intravenous rescue bolus of 2 mg of morphine.
The primary outcome of the study is pain intensity at 24 hours post-craniotomy, evaluated using a 100 mm VAS by two independent, well-trained researchers. Secondary outcomes include pain intensity at 1, 4, 6, 12, 48, and 72 hours post-craniotomy, time to first rescue analgesic administration, cumulative rescue analgesic consumption within 24, 48, and 72 hours, cumulative intra-operative analgesic consumption, skin reactions attributed to L5P application, and sleeping scores assessed using the Pittsburgh Sleep Quality Index self-rated questionnaire for the first three post-operative days.
Based on previous studies and clinical experience, a median 100 mm VAS score of 35 at 24 hours post-craniotomy is predicted for the placebo control group. A minimal improvement of 10 mm on the VAS is considered clinically significant. To detect this difference with a two-sided alpha of 0.05 and 85% power, 80 participants per group are required. Assuming a 10% drop-out rate, a total of 180 participants will be recruited.
Statistical analyses will be performed using SPSS software (version 25.0, IBM, Armonk, NY, USA), adhering to the intention-to-treat principle. The Kolmogorov-Smirnov test will assess normality, with continuous variables analyzed using Student’s t-test or the Mann-Whitney U test, and categorical variables compared using the Pearson Chi-square test or Fisher’s exact test. Subgroup analyses will explore potential differences in the primary outcome by operation type.
Data safety will be monitored by the DMC, with a clinical research associate ensuring adherence to the protocol and standard operating procedures. Any protocol changes will be approved by the local IRB and communicated to trial personnel. AEs or severe AEs will be reported to the DMC within 24 hours of occurrence.
The study acknowledges limitations, including potential confounding factors such as scalp thickness and incision shape. Scalp thickness, partially associated with body weight, may affect lidocaine permeation. Although body mass index will be considered in outcome interaction examination, confounding factors cannot be entirely avoided. Additionally, variations in incision shape may lead to unequal lidocaine distribution, potentially influencing the results.
In conclusion, the EASY trial aims to evaluate the efficacy and safety of pre-emptive L5P for preventing post-craniotomy pain. By addressing the limitations of current analgesic strategies and leveraging the potential benefits of L5P, this study seeks to provide a novel, non-invasive approach to post-craniotomy pain management.
doi.org/10.1097/CM9.0000000000001066
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