Neuralgia

All patients were consecutively recruited on the day before surgery. After written informed consent was obtained, baseline questionnaires were completed. Follow-ups after surgery for pain evaluation were performed on postoperative days (POD) 1, 3, 7, 14, 21, and 30 and monthly thereafter until pain resolution was reached or up to 6 months after surgery; the sessions were conducted by face-to-face interviews during the hospital stay or telephone interviews after discharge. Loss to follow-up was defined as the patient not being contacted during two consecutive follow-ups.
A standard perioperative pain management protocol was performed. Multimodal analgesia during surgery included the following: 1) corticosteroids, such as intravenous injection of methylprednisolone 40–80 mg before induction; 2) continuous infusion of dexmedetomidine at a rate of 0.4–0.6 μg/kg/h until incision closure; 3) short-acting opioids, including intermittent intravenous injection of sufentanil with a total dose of 0.5–1.0 μg/kg and continuous infusion of remifentanil 0.1–0.2 μg/kg/min until the end of surgery; and 4) flurbiprofen 100 mg or parecoxib 40 mg intravenously administered before the end of surgery when no contraindication presented. At the end of surgery, patient-controlled intravenous analgesia (PCIA) with sufentanil was provided to each patient for at least 72 hours. The PCIA device was initially set to deliver sufentanil at a rate of 2 μg/hour (solution 1 μg/ml) and a bolus of sufentanil 3 μg on request with a lockout time of 15 minutes. Background infusion was stopped if the worst pain score was <= 3 or opioid-related side effects (such as nausea and vomiting and dizziness) were reported during follow-ups. If severe opioid-related side effects persisted despite pharmacological treatment, PCIA was stopped at the request of the patient.
In wards, nonsteroidal anti-inflammatory drugs or COX-2 inhibitors were used as needed based on the surgeons’ preference. If patients reported pain with neuropathic characteristics, such as numbness and burning, gabapentin was added. Immediate-release oxycodone (5 mg) or tramadol (100 mg) was administered orally for rescue analgesia. Oral sustained-release oxycodone (5 mg every 12 hours) or a transdermal fentanyl patch (25 μg/hour for 72 hours) was provided for persistent severe pain after cessation of PCIA. Pain consultations were held when necessary.

Genetic analysis was completed in two parts. The first analysis was to identify variants of clinical relevance in known pain genes., grouping rare variants in genes for all neuropathic pain phenotypes considering both a targeted panel of pain genes and their promoters and all genes in the human genome that carried rare variants. Two ion channel variants were selected for electrophysiological analysis to investigate their functional impact (Supplementary Fig. 1).