Chronic Postsurgical Neuropathic Pain Research Articles

Efficacy and safety of perioperative ketamine for the prevention of chronic postsurgical pain: A meta-analysis.

Assessment of the efficacy and safety of perioperative intravenous ketamine in reducing incidence and severity of chronic postsurgical pain. A systematic review and meta-analysis of randomized controlled trials (RCTs). The following data sources were systematically searched: MEDLINE, CENTRAL, and EMBASE (till 02/2021). Adult patients undergoing any surgery. Perioperative use of intravenous ketamine as an additive analgesic drug compared to placebo, no active control treatment, and other additive drugs. Primary outcomes were number of patients with chronic postsurgical pain after 6 months and ketamine related adverse effects. Secondary outcomes were chronic postsurgical pain incidence after 3 and 12 months, chronic postsurgical neuropathic pain incidence, chronic postsurgical moderate to severe pain incidence, intensity of chronic postsurgical pain at rest, and during movement, oral morphine consumption after 3, 6, and 12 months and incidence of opioid-related adverse effects. Thirty-six RCTs were included with a total of 3572 patients. Ketamine compared to placebo may result in no difference in the number of patients with chronic postsurgical pain after 6 months (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.71-1.05; I2 = 34%; 16 studies; low-certainty evidence). Ketamine may reduce the incidence of chronic postsurgical neuropathic pain after 3 months in comparison to placebo (RR 0.78, 95% CI 0.62-0.99, I2 = 31%, seven trials, low-certainty evidence). Ketamine compared to placebo may increase the risk for postoperative nystagmus (RR 9.04, 95% CI 1.15-70.90, I2 30%, two trials, low-certainty evidence) and postoperative visual disturbances (RR 2.29, 95% CI 1.05-4.99, I2 10%, seven trials, low-certainty evidence). There is low-certainty evidence that perioperative ketamine has no effect on chronic postsurgical pain in adult patients. Low-certainty evidence suggests that ketamine compared to placebo may reduce incidence of chronic postsurgical neuropathic pain after 3 months. Questions like ideal dosing, treatment duration and more patient-related outcome measures remain unanswered, which warrants further studies. Prospero CRD42021223625, 07.01.2021.

Capsaicin 8% Patch and Chronic Postsurgical Neuropathic Pain

(1) Background: Surgery is a frequent cause of persistent pain, defined chronic post-surgical pain (CPSP). The capsaicin 8% patch (Qutenza®) is approved for the treatment of postherpetic neuralgia (PHN) and for diabetic peripheral neuropathy (DPN) of the feet. We propose a review of the literature on use of the capsaicin 8% patch to treat neuropathic pain associated with surgery; (2) Methods: We identified the articles by searching electronic databases using a combination of such terms as “capsaicin 8% patch”, “Qutenza®”, and “chronic postsurgical pain”; (3) Results: We identified 14 selected studies reporting on a total of 632 CPSP cases treated with capsaicin 8% patch. Treatment with the capsaicin 8% patch significantly reduced the average pain intensity. Only 5 studies reported adverse events (AEs) after the patch application. The most common AEs were erythema, burning sensation and pain; (4) Conclusions: Our review indicate that capsaicin 8% patch treatment for CPSP is effective, safe and well tolerated, but randomized controlled trials on efficacy, safety and tolerability should be conducted.

High-frequency (10kHz) spinal cord stimulation for the treatment of focal, chronic postsurgical neuropathic pain: results from aprospective study in Belgium.

Aim: Chronic postsurgical pain (CPSP) is a common complication of surgery. This study was conducted to evaluate the efficacy and safety of paresthesia-free, 10-kHz spinal cord stimulation (SCS) as a treatment for CPSP. Patients & methods: Subjects in this prospective, single-arm study had an average pain intensity of ≥5cm on a 10-cm visual analog scale. The subjects who had pain relief of ≥50% (response) with temporary trial stimulation were permanently implanted with 10-kHz SCS and assessed for 1year. Results: At 12months, 94% of subjects were responders to 10-kHz SCS, and 88% had pain remission (visual analogscale ≤2.5cm). Conclusion: The pain relief was durable in CPSP subjects and the safety profile of 10-kHz SCS was as expected. Clinical Trial registration number: VT005076953 (Privacy Commission of Belgium).

A preliminary prospective observational study of the effectiveness of high-concentration capsaicin cutaneous patch in the management of chronic post-surgical neuropathic pain.

Chronic post-surgical neuropathic pain is difficult to treat. Topically applied analgesics provide an alternative to systemic therapy in localised neuropathic pain syndromes. The aim of this study was to prospectively assess whether 8% capsaicin is effective in surgically induced neuropathic pain. Patients were screened for neuropathic pain using DN4 questionnaire. Validated questionnaires were completed at baseline and at 6 and 12weeks (BPI, HADS, PGIC), and the affected area was mapped. The study received ethical approval from the local research ethics committee. There were 12 participants. The most common operation was open thoracotomy (n = 8). There was a significant improvement in pain-interference from baseline to 12weeks (p = .018). There were no significant changes in pain intensity or in the HADS. Repeat patches were performed for 4 participants on a second occasion (33%) and for 3 participants a third time (25%). There was a significant reduction in the surface area of the painful region on second (p = .04) and third applications (p = .023). At 12weeks, 17% rated their symptoms very much better, 8% were much better, and 33% were minimally better, while 42% rated their symptoms no better. This prospective study provides preliminary evidence for an improvement in patient outcomes with 8% capsaicin in surgically induced neuropathic pain. Improvements were noted in pain interference, and significant reductions in the painful surface area were noted for those who underwent subsequent treatments. Findings should be replicated in a randomised control trial to establish causation.

Static mechanical allodynia in post-surgical neuropathic pain after breast cancer treatments

Objectives Static mechanical allodynia (SMA), i.e., pain caused by normally non-painful static pressure, is a prevalent manifestation of neuropathic pain (NP). Although SMA may significantly affect the patient's daily life, it is less well studied in the clinical context. We aimed to characterize SMA in women with chronic post-surgical NP (CPSNP) after breast cancer surgery. Our objective was to improve understanding of the clinical picture of this prevalent pain condition. This is a substudy of a previously published larger cohort of patients with intercostobrachial nerve injury after breast cancer surgery (Mustonen et al. Pain. 2019;160:246-56). Methods We studied SMA in 132 patients with CPSNP after breast cancer surgery. The presence, location, and intensity of SMA were assessed at clinical sensory examination. The patients gave self-reports of pain with the Brief Pain Inventory (BPI). We studied the association of SMA to type of surgery, oncological treatments, BMI, other pains, and psychological factors. General pain sensitivity was assessed by the cold pressor test. Results SMA was prevalent (84%) in this cohort whereas other forms of allodynia were scarce (6%). Moderate-to-severe SMA was frequently observed even in patients who reported mild pain in BPI. Breast and the side of chest were the most common locations of SMA. SMA was associated with breast surgery type, but not with psychological factors. Severe SMA, but not self-reported pain, was associated with lower cold pain tolerance. Conclusions SMA is prevalent in post-surgical NP after breast cancer surgery and it may represent a distinct NP phenotype. High intensities of SMA may signal the presence of central sensitization. Implications SMA should be considered when examining and treating patients with post-surgical NP after breast cancer surgery.

Sensory profiles in women with neuropathic pain after breast cancer surgery

PurposeWe performed a detailed analysis of sensory function in patients with chronic post-surgical neuropathic pain (NP) after breast cancer treatments by quantitative sensory testing (QST) with DFNS (German Research Network on Neuropathic Pain) protocol and bed side examination (BE). The nature of sensory changes in peripheral NP may reflect distinct pathophysiological backgrounds that can guide the treatment choices. NP with sensory gain (i.e., hyperesthesia, hyperalgesia, allodynia) has been shown to respond to Na+-channel blockers (e.g., oxcarbazepine).Methods104 patients with at least “probable” NP in the surgical area were included. All patients had been treated for breast cancer 4–9 years ago and the handling of the intercostobrachial nerve (ICBN) was verified by the surgeon. QST was conducted at the site of NP in the surgical or nearby area and the corresponding contralateral area. BE covered the upper body and sensory abnormalities were marked on body maps and digitalized for area calculation. The outcomes of BE and QST were compared to assess the value of QST in the sensory examination of this patient group.ResultsLoss of function in both small and large fibers was a prominent feature in QST in the area of post-surgical NP. QST profiles did not differ between spared and resected ICBN. In BE, hypoesthesia on multiple modalities was highly prevalent. The presence of sensory gain in BE was associated with more intense pain.ConclusionsExtensive sensory loss is characteristic for chronic post-surgical NP several years after treatment for breast cancer. These patients are unlikely to respond to Na+-channel blockers.

Neuropathic pain after thoracotomy: Tracking signs and symptoms before and at monthly intervals following surgery.

As the development of neuropathic symptoms contributes to pain severity and chronification after surgery, their early prediction is important to allow targeted treatment. We longitudinally investigated trajectories of signs and symptoms in patients undergoing thoracotomy and assessed whether and at which time they were related to the development of neuropathic pain symptoms 6months after surgery. Presurgical and 6 monthly postsurgical assessments included questionnaires for mental and physical well-being (e.g., depression/anxiety, pain catastrophizing, sleep quality, neuropathic pain symptoms), and quantitative sensory testing (QST). QST trajectories indicated nerve impairment of the surgery site with predominant loss of function. Signs of recovery towards the end of the assessment period were observed for some tests. Unsupervised cluster analysis with NPSI scores 6months after surgery as clustering variable identified one group with no/low levels of neuropathic symptoms and one with moderate levels. The two groups differed w.r.t. several signs and symptoms already at early time points. Notably, neuropathic pain anywhere in the body differed already preoperatively and sleep impairment differentiated the two groups at all time points. Regression analysis revealed three factors that seemed particularly suited to predicted 6months NPSI scores, namely preoperative neuropathic pain symptoms, with contributions from sleep impairment 1month after surgery and the presence of dynamic mechanical allodynia 3months after surgery. Clinical routine should focus on the individual's physiological state, including pre-existing neuropathic pain and sleep quality to identify patients early who might be at risk to develop chronic post-surgical neuropathic pain. Development of neuropathies contributes to pain severity and pain chronification after surgery. Here we demonstrate trajectories of quantitative sensory tests (assessed at monthly intervals for 6 months after surgery) that reveal accurate time courses of gain/loss of nerve function following thoracotomy. Independent of the degree of neuropathic signs after surgery, the main predictors for post-surgical neuropathic pain are self-reported neuropathic pain before surgery and sleep quality shortly after surgery.

Infiltracija hirurške rane hronični neuropatski bol kao posledica epiziotomije - postporođajni hronični neuropatski bol

Introduction: Chronic postsurgical pain has an estimated mean incidence of 30% and varies according to the type of surgery and patient characteristics. The pain can be severe and result in clinically relevant functional impairment reported by 5-10% of patients. Epidemiological surveys have shown that many patients with neuropathic pain do not receive appropriate treatment. Bio-psycho-social model of chronic pain is highly expressive in neuropathic pain management and requires the adjustment of the therapeutic approach. Case Report: A 37-year-old female complained of numbness, burning, and discomfort of the perineum. In 2016, after the vaginal baby delivery followed by episiotomy, she experienced discomfort and variety of painful sensations in the episiotomy incision region. A year later, after a hemorrhoid surgery followed by episiotomy scar reconstruction symptoms intensified with a strong influence on the patient's psychosocial condition. Consultation of obstetrician, psychiatrist and neurologist took part. Nevertheless, after two years had passed without significant clinical improvement, the patient was referred to a pain specialist. The pain specialist noticed inconsistency in the current treatment and the pain assessment was done only by one specialist. Testing revealed severe symptoms of hyperalgesia and allodynia, impaired psychosocial functioning related to chronic postsurgical pain. Pregabalin and duloxetine were introduced into the therapy and significantly improved pain relief and psychosocial functioning. Conclusion: Chronic postsurgical neuropathic pain is a complex syndrome which is not necessarily related to extensive surgical stimulus. The multidisciplinary therapy approach is crucial. Health providers who understand bio-psycho-social origin of chronic pain should be members of a multidisciplinary team.

Management of neuropathic pain induced by surgery: Review of the literature by a group of experts specialized in pain management, anesthesia and surgery.

Chronic postsurgical neuropathic pain (CPSNP) is frequent. While prevalence varies considerably according to type of operation and means of evaluation, it can reach 37% following breast surgery. Identification of risk factors related to the procedure and to the patient and taking into account the development of new, minimally invasive surgical techniques is increasingly nerve-sparing and reduces the likelihood of injury. CPSNP diagnosis in daily practice is facilitated by simple and quickly usable tools such as the NP4 4-question test. Management is based on pharmacological (analgesics, antiepileptics, antidepressants, local anesthetics) and non-pharmacological (kinesitherapy, neurostimulation, psychotherapy) approaches. In light of the present review of the literature, the authors, who constitute an expert group specialized in pain management, anesthesia and surgery, express their support for topical treatments (lidocaine, capsaicin) in treatment of localized postsurgical neuropathic pain in adults.

Evaluating the efficacy of cannabidiol to manage surgically induced neuropathic pain in a preclinical rat model: Are T cells a sexually dimorphic target?

ABSTRACTBackground: Considering the poorly understood etiology and complex symptoms of chronic neuropathic pain (NP), the lack of effective treatments, and sex-dependent differences in the neuroimmune system as well as in antinociceptive responses to existing pharmacological agents, the potential to therapeutically target the endocannabinoid system as a means of treating this type of intractable pain is clinically relevant and timely. Chronic NP may involve the utilization of distinct immune cell populations in males and females that differentially affect supraspinal and spinal neuromodulation. It is therefore important to investigate the effects of cannabidiol (CBD) on chronic NP-induced nociceptive responses in both sexes.Aims: Evaluating whether the expression of markers associated with CD4+ T cells are affected by CBD in a sexually dimorphic manner will provide key insights into the contribution of these adaptive immune cells to the onset and progression of NP.Methods: Future research will be directed toward examining the potential sex-dependent effects of this nonpsychotropic cannabinoid relative to vehicle in a preclinical model of chronic postsurgical NP. Specifically, (1) differences in nociceptive behavior, (2) chronic changes in neural firing patterns, and (3) up- or downregulation of markers associated with CD4+ T cells in relevant tissues will be evaluated to better understand CBD-mediated neuroimmune modulatory effects in males and females.Conclusions: Chronic postsurgical pain is a growing clinical problem. Current treatment strategies rely on opioid-based therapeutics, which affect patient quality of life and are associated with addiction and withdrawal. Treatment of nerve injuries with CBD could provide an effective alternative to manage NP. Understanding its mechanisms of action will provide important insights into the sex-dependent application of this nonpsychoactive cannabinoid, setting the groundwork for large-scale Canadian clinical trials in women and men presenting with chronic pain.

Lidocaine medicated plaster, an additional potential treatment option for localized post-surgical neuropathic pain: efficacy and safety results of a randomized, placebo-controlled trial

Objective: To assess the efficacy and safety of lidocaine 700 mg medicated plaster (lidocaine plaster) compared to placebo in patients with moderate to severe chronic post-surgical neuropathic pain (PSNP).Methods: Patients (n = 363) with a diagnosis of PSNP for a minimum of 3 months to 36 months were randomized (1:1) to lidocaine plaster or placebo for a 12 week double-blind treatment period. Randomization was stratified as “plaster-only” (no concomitant medication for PSNP) or as “add-on” (stable systemic medication for PSNP). The primary efficacy endpoint was the change from baseline in 24 hour average pain intensity at Week 12, assessed by 11 point numerical rating scale (NRS). The trial was registered in ClinicalTrials.gov (NCT01752322) and EudraCT (2012-000347-28).Results: Treatment with lidocaine or placebo plaster led to a clinically relevant reduction in average pain intensity. Pain reduction (least squares mean [LS mean] standard error [SE], [95% confidence interval, CI]) with lidocaine plaster (−1.70 [0.16], [−2.03, −1.38]) was numerically higher than with placebo (−1.47 [0.16], [−1.78, −1.15]) but the difference was not statistically significant (−0.23 [0.23], [−0.69, 0.22]). Pre-specified exploratory subgroup analyses showed the largest differentiation between lidocaine and placebo in patients without concomitant pain medication, and in patients with more than 1 year between surgery and enrollment. Many secondary outcomes showed a numerically larger improvement in favor of lidocaine. The most commonly reported adverse events were administration site reactions linked to topical administration.Conclusions: A clinically relevant pain reduction was observed with lidocaine plaster in patients with PSNP. The safety and tolerability profile is consistent with current knowledge.Trial registration: ClinicalTrials.gov identifier: NCT01752322.

What makes surgical nerve injury painful? A 4-year to 9-year follow-up of patients with intercostobrachial nerve resection in women treated for breast cancer.

Nerve injury during breast cancer surgery can cause neuropathic pain (NP). It is not known why some, but not all, patients develop chronic postsurgical neuropathic pain (CPSNP) after the same nerve injury. In this study, we examined 251 breast cancer survivors with surgeon-verified intercostobrachial nerve resection to identify factors that associate with CPSNP. The patients were recruited from a previous study of 1000 women treated for breast cancer in 2006 to 2010. This enabled us to analyze preoperative factors that associate with future CPSNP. The patients were re-examined in 2014 to 2016 to diagnose CPSNP using the revised NP diagnostic criteria. Preoperative assessments were pain in the area to be operated on, any chronic pain condition, depressive symptoms, anxiety, sleep, and experimental cold pain sensitivity using the cold pressor test (CPT). Follow-up assessments were CPT, psychological factors, sleep, any chronic pain, and basic laboratory tests. One hundred thirty-seven (55%) patients with intercostobrachial nerve resection fulfilled CPSNP diagnostic criteria after 4 to 9 years. Of them, 30 patients (22%) had moderate to severe pain in self-reports and 86 (63%) presented moderate to severe evoked pain at examination. Preoperative pain in the surgical area, other chronic pains, and breast-conserving surgery were associated with future CPSNP. Other chronic pains, increased psychological burden, and insomnia, both before surgery and at the follow-up, were associated with CPSNP. Preoperative CPT did not associate with future CPSNP. Patients with established CPSNP showed increased pain sensitivity in CPT and higher levels of inflammatory markers, suggesting that central sensitization and inflammation may associate with the maintenance of CPSNP.

Perioperative pregabalin administration does not prevent chronic postoperative pain: systematic review with a meta-analysis of randomized trials.

The efficacy of perioperative pregabalin treatment for preventing chronic pain remains a matter of debate. We searched the MEDLINE, EMBASE, LILACS, Cochrane, and Clinical Trial Register databases, and other sources, for randomized controlled trials comparing the effects of pregabalin and placebo. The primary outcome was the incidence of chronic postsurgical pain (CPSP) at 3 months. The secondary endpoints were CPSP at 3, 6, and 12 months and the incidence of chronic postsurgical neuropathic pain at the same time points. A random-effect meta-analysis was performed on the combined data. Evidence quality was rated by the GRADE method. We included 18 studies (2485 patients) in the meta-analysis. Overall, 60% of the trials reporting the primary outcome at 3 months were unpublished; the unpublished trials corresponded to 1492/1884 (79%) of the patients included in these studies. No difference in CPSP incidence between pregabalin and placebo was found at any time point; the risk ratio was 0.87 (0.66, 1.14), I = 57% at 3 months. The evidence was considered to be of moderate quality. Subgroup analysis by publication status, daily dose, type of administration, and type of surgery did not highlight any differences between subgroups. Insufficient data concerning the incidence of chronic postsurgical neuropathic pain were available for any firm recommendation to be made. Pooled data from published and unpublished studies provide no support for the efficacy of pregabalin for preventing CPSP.

Clinical, histological, and biochemical predictors of postsurgical neuropathic pain.

Surgical nerve injury sometimes leads to chronic postsurgical neuropathic pain (CPSNP). The risk factors for this condition are not well understood. We prospectively assessed 46 patients scheduled for iliac crest bone harvest, 2 days (D2) and 3 months (M3) after surgery, to determine the time course of nerve fiber degeneration and expression of the TNF-α and NGF genes in skin punch biopsies. Mechanical and thermal detection and pain thresholds were evaluated at D2 and M3, by quantitative sensory testing. Skin punch biopsies were also obtained from the thighs ipsilateral and contralateral to iliac crest bone harvest. Intraepidermal nerve fiber density (IENFD) and cutaneous TNF-α and NGF gene expression were analyzed. Forty-five volunteers matched for age, sex, skin color were examined as controls. Chronic postsurgical neuropathic pain was defined as pain in an area of hypesthesia with a positive Douleur Neuropathique 4 questionnaire score. Overall, 73% (N = 32) of patients developed hypesthesia and 40% (N = 13) of these patients had developed CPSNP at M3. Quantitative sensory testing results, IENFD, and skin TNF-α and NGF gene expression at D2 and M3 did not differ between patients with and without CPSNP. However, in patients with CPSNP, burning, compression, and pain provoked by brushing were correlated with IENFD at M3, suggesting a possible association between partial nerve lesions and more intense CPSNP, than with total nerve lesion. Furthermore, preoperative pain and opioid use were higher in patients who developed CPSNP than in those without CPSNP. These findings suggest that the predictors of CPSNP development are clinical rather than histological or biochemical.

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Directed neurectomy for treatment of chronic postsurgical neuropathic pain

BackgroundChronic neurogenic pain after surgery, especially inguinal herniorrhaphy, remains a major cause of morbidity. The traditional treatment of postinguinal herniorrhaphy neurogenic pain has included triple neurectomy with the removal of any mesh. This report describes a directed, minimally invasive surgical neurectomy that provided pain relief in 28 patients with minimal morbidity. MethodsAfter temporary but successful proximal peripheral nerve blockade, the nerve was blocked in the operating room using a small amount of blue dye mixed with the local anesthetic. After confirming pain relief with the dye-anesthetic mixture, the patient was then sedated, and all blue-stained tissue was excised through a small incision, avoiding both the previous surgical scar and mesh. ResultsAll but 1 of the 28 patients had complete relief for a minimum of 12 months when discharged from follow-up. ConclusionsThis simple directed neurectomy method typically provides long-term relief for patients suffering from chronic postsurgical neurogenic pain.

Risk factors predictive of chronic postsurgical neuropathic pain: The value of the iliac crest bone harvest model

Nerve lesions and secondary hyperalgesia may both be present after surgery, and their relative contributions to chronic postsurgical neuropathic pain (CPSNP) remain unclear. This prospective study explored the roles of these factors in the development of CPSNP after iliac crest bone harvest. CPSNP was defined as pain in the area of hypoesthesia, with a positive Douleur neuropathique 4 questionnaire (DN4) score 3months after iliac crest bone harvest. The location, intensity, and neuropathic characteristics of pain were evaluated in 82 patients who were followed for 6months. Neuropathic characteristics were assessed by clinical examination and DN4 questionnaire. The area of secondary hyperalgesia was evaluated 48h and 1month after surgery. The area of mechanical hypoesthesia, detection, and mechanical pain threshold were evaluated at 48h and at 1 and 3months. Nineteen patients (23%) had CPSNP at 3months. The patients who developed CPSNP had a larger area of secondary hyperalgesia at 48h (88cm2 vs 33cm2; P=.001), higher pain intensity (numerical rating scale 6.7 vs 4.7; P=.02), and higher neuropathic characteristics score on the DN4 questionnaire (4.3 vs 2.3; P=.001). However, neither the area nor the severity of hypoesthesia differed significantly between patients with and without CPSNP. Two independent, additive predictors of CPSNP were identified: area of secondary hyperalgesia (odds ratio 1.02; P=.004) and DN4 score (odds ratio 1.94; P=.001). These findings suggest that both nerve lesions and central sensitization are involved in CPSNP development and could be seen as early warning signs.

Perisurgical amitriptyline produces a preventive effect on afferent hypersensitivity following spared nerve injury

Following surgery, nerve injury can lead to persistent neuropathic pain. Pre-emptive and preventive analgesic treatments in the perioperative period aim to minimize nerve injury-induced pain. Here we demonstrate that a perioperative regimen of amitriptyline (10 mg/kg i.p. 30 min before and immediately after surgery, followed by oral amitriptyline 15–18 mg/kg/day in the drinking water for 7 days post-surgery) prevents hypersensitivity to a chemogenic stimulus (αβ-MeATP, a ligand for P2X3 receptors, together with noradrenaline or NA) in the spared nerve injury (SNI) model in rats. It also prevents hyposensitivity to capsaicin and NA. However, amitriptyline treatment had no effect on the development of mechanical allodynia. We investigated the role of NA mechanisms in the action of amitriptyline by using the neurotoxin 6-hydroxydopamine (6-OHDA) and by examining desipramine. Intrathecal treatment with 6-OHDA on the day of surgery reversed the preventive effect of amitriptyline on hypersensitivity to αβ-MeATP/NA, and desipramine exhibited a similar effect to amitriptyline. We also examined the effect of antibodies to the nerve growth factors glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), given intrathecally three times (days 0, 3 and 7) on the action of amitriptyline and observed that the interruption of GDNF and BDNF signaling impaired the prevention of hypersensitivity to αβ-MeATP/NA. This study indicates that tricyclic antidepressants given in the perioperative period may be useful in preventing nerve injury-induced sensory changes that contribute to the development of chronic post-surgical neuropathic pain.