Chronic postsurgical pain in children and young adults with cancer and choice of regional anesthesia for amputation and limb‐sparing surgery

Abstract Background Patients undergoing limb amputation (LA) or limb‐sparing (LS) for lower extremity oncologic diagnoses are at similar risk for chronic postsurgical pain of neuropathic nature (CPSP/NP). Regional anesthesia (RA) techniques are pre‐emptive measures to prevent the occurrence of the CPS/NP. However, recommendations for epidural (EP) versus peripheral nerve blocks (PNBs) lack in pediatric literature. Aims This study investigates the incidence and duration of CPSP/NP and describes NP‐directed regimens. Methods and Results Data on demographics, use of EP or PNB, duration of CPSP/NP, and NP‐directed medication were retrospectively collected for LA and LS between 2009 and 2019. Mixed effects logistic regression was used to compare the odds of CPSP/NP between EP and PNB. Cox PH model with adjustment for clustering due to multiple surgeries on patients was used to quantify rate of pain relief between surgery groups (LA vs. LS) and RA groups (EP vs. PNB). The incidence of CPSP/NP was 36 (23.8%) after 165 surgeries (150 patients). The odds of CPSP/NP after PNB were 2.5 times those of CPSP/NP after EP (p = .11). The rate of pain relief at any instant after the EP was 1.2 times that after PNB (p = .3). The rate of pain relief for LS with EP was 1.9 times that of pain relief for LA with EP, a statistically significant difference (p = .03). Gabapentin was used (94.5%), with addition of amitriptyline (24.2%) and both amitriptyline and methadone (12.7%). Conclusion The LS with the EP group had a significantly higher rate of relief of CPSP/NP than LA with EP. Odds of CPSP/NP after PNB were 2.5 times those of CPSP after EP.

surgical records, and nursing intraoperative records were compared to ensure data accuracy.
Data on pain outcomes were collected from pain service notes and included the following: (1) duration (days) of postsurgical pain that met characteristics of NP, (2) duration (days) of therapy for each line of NP-targeted medication, and (3) initial and maximum dose (mg/kg/ day). Descriptors used to characterize NP included tingling, burning, shooting, "pins and needles," and phantom limb pain (PLP). The NPdirected medications included gabapentinoids (gabapentin, pregabalin), tricyclic antidepressants (amitriptyline), and methadone. The NP treatment follows an institutional algorithm that escalates medications in successive "layers" of gabapentinoids, tricyclic antidepressants, and methadone, based on tolerance and analgesic efficacy. Pain was considered resolved if all NP medications were weaned without recurrence of NP symptoms. Patients were considered lost to follow up due to transfer of care to another institution, death before complete resolution of the pain, or weaning off NP-targeting medications, or due to missing documentation to support the resolution of NP. The pain outcomes were compared between groups treated with EP and PNB.
If a patient underwent a subsequent surgery while ongoing treatment for postsurgical NP (e.g., LA/disarticulation after an initial LS while having ongoing postsurgical NP), pain outcomes were attributed to the subsequent surgery. Patients with CPSP/NP were defined as being treated postoperatively with NP-targeted lines of medications for longer than 90 days.

| Statistical analysis
Descriptive statistics were reported as frequency (percent) and mean (SD). Duration of CPSP/NP was calculated as the time from surgery to complete resolution of NP and absence of NP-directed medications.
The rate of pain relief at any instance was compared between EP or PNB groups and between surgery (LA or LS) and treatment (EP or PNB) combination groups, using the Cox PH model with adjustment for clustering due to multiple surgeries on patients. CPSP/NP was defined as postsurgical pain of duration more than 90 days, and mixed effects logistic regression was used to compare the odds of CPSP/NP between RA groups. All the analyses were performed in R (version: 3.6.2). All p < .05 were considered significant.
One hundred thirty-seven (91.3%) patients underwent one, 11 (7.3%) underwent two, and two (1.3%) underwent three surgeries (i.e., LS followed by LA and disarticulation 3.2 | Incidence, probability, and duration of CPSP/NP The calculation of incidence of CPSP/NP was based on 151 surgeries with evaluable data. Data from mixed-effects logistic regression analysis were excluded for 14 surgeries, after which patients were lost to follow up before 90 days (therefore not meeting the chronic pain criterion). Thirty-six (23.8%) surgeries resulted in CPSP/NP. No difference was found in odds of CPSP/NP between EP and PNB (p = .11).
Odds of having CPSP/NP after PNB were 2.5 (0.8-7.9) times the odds after EP. No difference was found in pain relief between EP and PNB groups (p = .3). Rate of pain relief at any instance in the EP group was 1.2 times that of the PNB group. There was a difference in the rate of pain relief between LS with EP and LA with EP (p = .03); rate of pain relief in LS with EP was 1.9 times that in LA with EP. Among all 165 surgeries, mean (SD) number of days patients had postsurgical pain/NP were 60.8 (61.1) overall, 66.6 (60.7) in PNB group, and 54.7 (62.1) in EP group (Table 3).

| NP-specific medications-Type, duration, and dose
Data for all 165 surgeries were used in analysis of medications.
Patients received gabapentin in 156 (94.5%) surgeries (Table 4). Mean (SD) initial dosage (mg/kg/day) for gabapentin was 16 (6.7) in the PNB group, and 18.3 (11.7) in the EP group (Table 6). Mean  Although the role of EP in postoperative pain relief is well established, effectiveness of PLP prevention is inconsistently reported. 18,19 Preoperative epidural blockade 18 h before amputation did not prevent PLP during the first year postoperatively. 20 Conversely, others showed reduced incidence of PLP after amputation with epidural analgesia. [21][22][23] Epidural analgesia for 48 h preoperatively was associated with decreased PLP at 6 months. 24 Preemptive epidural analgesia 72 h preoperatively and 72 h postoperatively reduced the incidence of PLP during the first year compared to treatment with opioids and NSAIDs. 25 Overall, studies found that preoperative EP analgesia had a beneficial impact on acute and chronic pain, although the statistical impact is inconclusive for EP as a PLP preventative therapy. 18,23 In adults undergoing lower extremity LA, preemptive use of continuous PNB lowered the postoperative incidence of pulmonary complications, acute postoperative pain scores, and opioid use when compared to general anesthesia. 26  Literature lacks conclusions about whether RA could decrease the incidence of CPSP in LA. 37 A review of orthopedic oncologic surgeries indicated that whereas RA may be effective postoperatively, pain management requires multimodal approaches. 12 The RA techniques within multimodal plans contribute to reducing severe immediate postoperative pain, a consistent risk factor for CPSP. 18,19,35,36,38 Optimized analgesia in the acute phase after LA is theorized to help prevent chronic pain. In surgeries for patients with high risk of chronic pain development (LA, breast cancer surgery, thoracotomies, Cesarean sections), RA initiation is recommended prior to incision and continued 24-72 h as preventative strategy for postoperative pain and CPSP. 37 Cochrane reviews support RA as reducing CPSP after breast cancer surgery, thoracotomies, and Cesarean sections; however, this conclusion was not extended to LA due to variable timing of RA administration and heterogenous study designs. [39][40][41] A review of 39 randomized controlled trials found the strongest evidence for use of EP for thoracotomies and paravertebral blocks for breast surgery. 39 Adjuvants like ketamine in combination with perioperative neural blockades warrant further investigation in CPSP prevention. 5 Overall, the current literature comparing RA modalities is limited to specific types of surgery for adults. It is important to note the paucity of data in pediatric patients: although RA in children is safe and effective for postoperative pain, little is known about its role in longterm pain outcomes. 11 When characterizing the NP-targeted medications dosing, we found that a higher percentage of patients received gabapentin, pregabalin, amitriptyline, and methadone in the EP than the PNB group, and greater dosages were used. Our approach to NP treatment is based on a clinical algorithm, including anticonvulsants (gabapentin and pregabalin), tricyclic antidepressants (TCA; amitriptyline), and methadone added in a stepwise manner. One in three patients can be expected to require an escalation of the regimen, with addition of amitriptyline and/or methadone to gabapentinoids. 1