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Perioperative Factors Associated With Chronic Central Pain After the Resection of Intramedullary Spinal Cord Tumor

Onishi-Kato, Yuki MD*; Nakamura, Masaya MD, PhD; Iwanami, Akio MD, PhD; Kato, Masayoshi MD, PhD; Suzuki, Takeshi MD, PhD*; Kosugi, Shizuko MD, PhD*; Katori, Nobuyuki MD, PhD*; Hashiguchi, Saori MD, PhD*; Tsuzaki, Koichi MD, PhD*; Takeda, Junzo MD, PhD§; Morisaki, Hiroshi MD, PhD*

The Clinical Journal of Pain: July 2017 - Volume 33 - Issue 7 - p 640–646
doi: 10.1097/AJP.0000000000000438
Original Articles

Objective: Some patients experience severe chronic pain after intramedullary spinal cord tumor (IMSCT) resection, but the underlying mechanisms have yet to be fully elucidated. We aimed to investigate perioperative factors associated with chronic pain after IMSCT resection.

Materials and Methods: We analyzed data from a postal survey and the medical records of patients who had undergone IMSCT resection in our institution between 2000 and 2008. Chronic pain was assessed using the Neuropathic Pain Symptom Inventory score, and its associations with factors related to tumor pathology, patient demographics, neurological findings, surgery, anesthesia, and perioperative management were determined.

Results: Seventy-eight consecutive patients (55 men and 23 women; age 17 to 79 y) were included in the statistical analysis of the present study. In univariate analyses, sex, body mass index, preoperative tumor-related pain, preoperative nonsteroidal anti-inflammatory drugs, intraoperative hypotension, postoperative corticosteroids, and decrease in Japanese Orthopaedic Association (JOA) scores were found to be associated with postsurgical chronic central pain. Logistic regression analysis identified 3 significant factors: a decline in JOA scores compared with preoperative values (odds ratio [OR], 3.33; 95% confidence interval [CI], 1.18-9.42; P=0.023), intraoperative hypotension (OR, 3.01; 95% CI, 1.02-8.97; P=0.047), and postoperative corticosteroids (OR, 3.21; 95% CI, 1.02-10.09; P=0.046).

Discussion: Decline in JOA score, intraoperative hypotension, and postoperative corticosteroids are independently associated with postsurgical chronic central pain. Intraoperative hypotension and the use of postoperative corticosteroids can be avoided or modified during perioperative management. As results from animal studies have indicated that the administration of corticosteroids may intensify chronic pain, further studies in larger cohorts are required to definitively determine the effect of corticosteroids on postsurgical central pain.

Departments of *Anesthesiology

Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku

Department of Cardiovascular Medicine, the University of Tokyo, Bunkyo-ku

§National Hospital Organization Tokyo Medical Center, Meguro-ku, Tokyo, Japan

Present address: Yuki Onishi-Kato, MD, Tokyo Adventist Hospital, Suginami-ku, Tokyo 167-8507, Japan.

Supported by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare (grant number H23-Itami-Shitei-006). The authors declare no conflict of interest.

Reprints: Yuki Onishi-Kato, MD, Tokyo Adventist Hospital, 3-17-3, Amanuma, Suginami-ku, Tokyo 167-8507, Japan (e-mail:

Received March 16, 2016

Received in revised form November 9, 2016

Accepted September 6, 2016

Neuropathic pain originating from the spinal cord is often intractable and affects more than 40% of patients with spinal cord lesions, including those with spinal cord injury (SCI)1 and multiple sclerosis.2 Intractable pain often reduces patients' quality of life (QOL) to a greater degree than functional disabilities resulting from neurological deficits.3 The mechanisms underlying neuropathic pain originating from the spinal cord are not fully understood due to its complex and heterogeneous nature and the rarity of the causative primary diseases. Animal studies have identified various mechanisms underlying pain sensation3 including damage to the specific regions,4 reorganization,5 ascending cortical activation,6 and gliopathy.7 In clinical practice, however, the identification of patients likely to develop chronic central pain remains challenging. Chronic postsurgical pain after intramedullary spinal cord tumor (IMSCT) resection is a known form of central pain that may affect patients with little preoperative pain initially and can be difficult to alleviate once established. Nakamura et al8 reported for the first time that the severity of this particular pain reduced QOL in more than half of the studied patients. Moreover, the association between neurological outcomes and pain severity varies according to tumor pathology and location. We previously demonstrated a weak negative correlation between postoperative Japanese Orthopaedic Association (JOA) scores and Neuropathic Pain Symptom Inventory (NPSI) scores in patients with thoracic tumors but not in those with cervical tumors.8 In the present study, we used the same surgical model to examine perioperative associated factors for postsurgical chronic central pain after IMSCT resection. We therefore sought to identify factors associated with the chronic postsurgical pain after IMSCT resection using NPSI scores that may inform the development of preventative strategies.

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Study Design

The Institutional Review Board of Keio University School of Medicine approved the present study. We obtained signed consent forms from all participants. To obtain detailed information regarding chronic pain, a questionnaire was sent to 105 consecutive patients who had undergone surgical resections of IMSCT at the Department of Orthopaedic Surgery at our institution between January 1, 2000 and December 31, 2008.8 The questionnaire consisted of the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and NPSI.

We conducted a companion study that used identical NPSI scores and the medical records of 83 adult patients, excluding 2 infants, out of 85 responders to the questionnaire (Fig. 1). We examined perioperative factors associated with chronic postsurgical pain, several of which were not evaluated in the companion study.8



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Outcomes and Associated Factors

Postsurgical chronic central pain was defined as an NPSI score >10, according to the companion study.8 The NPSI score consists of 10 questions that assess 10 different types of neuropathic pain or dysesthesia using a 0 to 10 point numerical rating scale per item categorized into 5 subgroups. In both of our studies, we adopted values ranging from 0 to 50 after calculating the sum of means of each of the 5 subgroups; NPSI scores were identical in the 2 studies. Patients were sufficiently familiar with the numerical rating scale to answer the questionnaires. Medical charts at the clinic of our institution recorded by orthopedic surgeons were reviewed to obtain details of chronic pain. We further examined the distribution of postsurgical pain from medical charts classified into the following 4 groups: “at-level,” “below-level,” “both,” and “above,” according to the positional relation to tumor level. Perioperative factors were also examined and divided into the following 3 groups: demographic data, tumor-related factors, and perioperative factors. Demographic data included age, sex, and body mass index (BMI). Tumor-related factors included tumor pathology, tumor level, longitudinal length within the spinal cord, and presence of preoperative tumor-related pain. Perioperative factors included duration of surgery, methods of anesthesia, intraoperative hypotension, abnormalities in intraoperative somatosensory-evoked potentials (SEPs) and motor-evoked potentials (MEPs), perioperative administration of corticosteroids, hyperosmolar solution Glyceol (consisting of 10% glycerol and 5% fructose in saline), nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. We used JOA scores for myelopathy (Appendix, Supplemental Digital Content 1, to evaluate overall neurological function due to its universal use. The manual muscle test was used to evaluate motor function.

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Determination of Associated Factors

The presence of preoperative tumor-related pain was determined from medical charts on admission. Intraoperative hypotension was defined as a mean blood pressure ≤80% of preoperative mean values for a minimum of 15 consecutive minutes during surgery. We assessed intraoperative blood pressure using an arterial line. Anesthesia methods, the types and dosage of opioids administered during surgery, and the types and approximate administration time of perioperative medication were examined.

Change in perioperative neurological status was assessed using JOA score, which was calculated according to neurological findings including motor, sensory, and bladder functions. We examined JOA scores obtained before surgery and at the time of discharge as preoperative and postoperative values, respectively, as these were available for all patients. Motor function was recorded more frequently according to patient condition. Patients were divided into 2 groups according to the presence or absence of a decline in JOA score compared with preoperative values.

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Statistical Analysis

When appropriate, continuous variables were compared using the Student t test or the Mann-Whitney test and categorical variables using the χ2 or the Fisher exact test. The dependent variable in the multivariate analysis was the presence or absence of chronic pain, as determined by an NPSI score >10. Adding to the traditional risk factors for postsurgical pain including age and sex, all variables with a cutoff point of P<0.1 were included into multivariate logistic regression analysis with backward selection method.

All statistical analyses were performed using the software SPSS version 23.0 (IBM Corp., New York, NY), and P-values of <0.05 were considered statistically significant.

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Seventy-eight patients were included in the final statistical analysis after the exclusion of 5 patients due to the absence of dysesthesia and pain. Interval between surgery and survey ranged from 11 to 109 months. At the time of the survey, 7 patients were prescribed adjuvant analgesics with or without opioids. The characteristics of the study population (N=78) demonstrated a male preponderance (55 men and 23 women), with a median overall age of 49 years (range, 17 to 79 y; Table 1). The maximum value of NPSI score was 40.0, with a median of 11.5. Dysesthesia, described as “tingling,” was usually strong regardless of the chronic central pain distribution shown in Figure 2. NPSI scores in patients with pain at both levels were greater than in those with pain either “at-level” or “below-level” (Fig. 2). Pathology was unrelated to chronic postsurgical central pain severity except in cases of schwannoma, lipoma, and fibroma, which were present in only a small number of study participants. Patients with any of these 3 tumor types reported mild pain at the time of survey.





The types and dosage of intraoperative opioid administration varied greatly (Table 2), with remifentanil administered at a maintenance infusion rate of 0.1 to 0.5 mcg/kg/h during total intravenous anesthesia.



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Univariate Analysis

Age, anesthesia method, duration of surgery, and analgesics other than NSAIDs and hyperosmolar solutions were not associated with chronic postsurgical pain.

Univariate analysis identified the following 7 factors as associated with the severity of chronic postsurgical pain (Table 3): sex, BMI, preoperative tumor-related pain, preoperative NSAID use, intraoperative hypotension, postoperative corticosteroids, and deterioration of JOA score.



The duration of preoperative tumor-related pain ranged from 10 to 108 months, with a median of 36 months. In all, 29 of 50 patients with preoperative tumor-related pain and 6 of 33 patients without received preoperative NSAIDs.

Of 78, 32 patients belonged to the hypotensive group. The duration of defined hypotension ranged from 15 to 315 minutes, with a median of 65 minutes. Intraoperative hypotension was usually maintained for a certain period with deep anesthesia or antihypertensive drugs rather than the use of vasopressors or blood transfusions, except in three patients. Twenty-three of 32 patients in the intraoperative hypotension group were administered antihypertensive drugs (including calcium channel blockers, beta-blockers, prostaglandin E1, nitroglycerin, and dexmedetomidine) to reduce bleeding from the surgical area. Intraoperative hypotension was not related to postoperative JOA score deterioration (P=0.418), nor to the longitudinal length of tumor (P=0.892).

Corticosteroids were administered for a maximum duration of 9 days, with maximum cumulative doses of 2500 mg for methylprednisolone, 12 mg for dexamethasone, and 2400 mg for cortisol. The median NPSI scores in the groups with and without postoperative corticosteroids were 18.7 and 9.5, respectively, and a statistically significant difference was observed (P=0.007).

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Multivariate Analysis

Seven associated factors obtained from univariate analysis and a traditional risk factor for chronic postsurgical pain9 were included in the multivariate logistic regression analysis: sex, BMI, preoperative NSAID use, preoperative tumor-related pain, intraoperative hypotension, postoperative corticosteroids, and decline in JOA score, in addition to age. Three independent associated factors were identified by logistic regression analysis (Table 4), without interaction between postoperative corticosteroid administration and decline in JOA score.



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We examined perioperative associated factors for chronic central pain after intramedullary spinal cord tumor resection as postsurgical pain is so severe as to reduce postoperative QOL in a proportion of patients8 even with little preoperative pain. We identified decline in JOA score, postoperative corticosteroid administration, and intraoperative hypotension as independent predictors of postsurgical pain.

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Decline in JOA Score

A decline in JOA score compared with preoperative values was associated with chronic postsurgical pain. These results are consistent with the findings reported in a previous study of 3 patients with cordotomy at upper level of thoracic spine due to malignant astrocytoma.8 NPSI scores of those 3 patients were found to vary greatly (from 2.5 to 31.5). Patients with severe paralysis before surgery are reportedly less likely to develop postsurgical pain compared with patients demonstrating postoperative exacerbation of paralysis. Further studies are required to determine whether this finding is associated with the previous demonstration that the coexistence of tissue damage and hemotoxin results in pain.10

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Postoperative Corticosteroids

Postoperative corticosteroids use was associated with an increased risk of chronic central pain. This result was contrary to our initial expectations as corticosteroids are occasionally administered to alleviate pain, including acute lumbago from disk herniation and postsurgical pain.11 Thus, we excluded factors with multicollinearity and ascertained that interaction with JOA score a surrogate indicator of tissue injury—was not observed in multivariate analysis. There was no statistical difference between the groups with and without postoperative corticosteroids use regarding 7 factors in univariate analysis as well as age, a traditional risk factor (Table 5).



The predominant reason for postoperative corticosteroids administration was deterioration of neurological findings according to MEP/SEP scores, JOA scores, or manual muscle test. Nonetheless, indications for the administration in our cohort included upper airway edema, supplementation for autoimmune disease, respiratory failure, and coadministration of local anesthetic for trigger point injections, which is occasionally adopted in Japan.

Although this unexpected result must be interpreted with care, corticosteroids should be used cautiously as they may worsen clinical neurological outcomes.12 In animal studies, both the pain-alleviating13 and pain-precipitating effects14 of corticosteroids are reportedly attributable to mechanisms underlying anti-inflammatory and proinflammatory effects on the central nervous system.

The ability of corticosteroids to suppress or augment inflammation depends on the site of action (peripheral tissue or central nervous system), dose, timing, duration of exposure, and the type of glucocorticoid.12 We speculate that the site of action in the present study of spine surgery differed from that in earlier studies,11 which is particularly relevant as low-dose synthetic corticosteroids are unable to cross the blood-brain barrier under normal conditions. The administered dose in the present cohort was apparently higher than that typically administered to alleviate postsurgical pain.11 In addition to the dosage, the rate of administration may be associated with chronic pain. A total amount of 2500 mg methylprednisolone, which was the largest amount in our cohort, was administered to 2 patients for paralysis and for muscle weakness—to 1 with NPSI score of 7, continuously over 26 hours; to the other with NPSI score of 22.7, divided into 3 doses administered once per day, respectively. Timing of administration may also be a related factor. We examined the influence of interval between the end of surgery and first postoperative corticosteroids in 18 patients with both postoperative corticosteroid use and decline in JOA score. Higher NPSI score were observed in patients with an interval >12 hours (P=0.037) when the administration of corticosteroids immediately after surgery was considered to be intraoperative administration.

The results of the present study indicate postoperative corticosteroids are associated with chronic central pain after intramedullary spinal cord tumor resection. Accordingly, the effects of postoperative corticosteroids after resection of intramedullary spinal cord tumors should be monitored closely and warrant further study.

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Intraoperative Hypotension

Intraoperative hypotension was associated with chronic postsurgical pain. It was not related to postoperative JOA score deterioration, a surrogate indicator of nerve injury, or to the longitudinal length of tumor, an indicator of extension of tumor in the spinal cord.

Spinal cord blood flow is typically autoregulated in a manner similar to cerebral blood flow15; however, mild hypotension as low as 80% of the preoperative baseline values may result in ischemia.16,17 Although the autoregulation appears to be compromised dependently on the types of anesthetics,18,19 there was no significant difference in the NPSI scores between 2 groups with and without nitrous oxide among patients with intraoperative hypotension (P=0.526). Laminectomy itself has also been reported to precipitate hypoperfusion,20 with one case report describing moderate systemic hypotension during a surgical procedure near the spinal cord leading to hypoperfusion.21 Hypoperfusion, not accompanied with nerve injury detected with the JOA score, may be associated with postsurgical chronic central pain in our study.

In patients who have suffered stroke, glial cells induce secondary inflammation.22 In animal studies, even transient ischemia has been shown to be responsible for remarkable accumulation23 and activation of microglia.24

In addition to deliberate hypotension to reduce intraoperative bleeding, deep anesthesia is required to avoid movement during microscopic surgery without resorting to muscle relaxants, thereby allowing the monitoring of neurological function with MEP. We also demonstrated the importance of maintaining blood pressure at a higher level to reduce the possibility of chronic central pain, while deliberate hypotension is well-known to be contraindicated in patients likely to be vulnerable to ischemia.25

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Preoperative Pain

Preoperative pain was not significantly associated with chronic postsurgical pain in multivariate analysis (P=0.082). A distinct feature in our cohort was that preoperative tumor-related pain signified direct stimulation or damage to the sensory system, which is believed to cause central sensitization. There was a trend toward an association between this factor and increased risk of chronic postsurgical pain.

Despite long postoperative intervals, factors related to the acute phase of spinal cord surgery were found to be associated with chronic postsurgical central pain. We speculate that certain processes may occur during the acute phase that trigger either the first step of a chain reaction or a long-lasting event.

In the present study, well-known risk factors for postsurgical pain, such as age and sex, were not found to be associated with chronic central pain.

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The small sample size of the present study may affect the ability to detect significant findings. The present study was retrospectively conducted and we did not assess the severity of pain immediately after surgery, psychosocial factors, or persistent inflammatory processes. Expansion in the horizontal plane was not examined as tumors expanded intricately in 3 dimensions to a maximum length of 8 vertebral bodies. Further studies are required to assess the validity of the present findings in larger prospective cohorts.

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The results of the present study demonstrate the factors related to the acute phase of intramedullary tumor resection are associated with the subsequent chronic central pain. Specifically, we identified decline in JOA score, postoperative corticosteroids, and intraoperative hypotension as associated with chronic postsurgical central pain. We believe that the present findings will facilitate the development of measures to prevent and alleviate chronic central pain following intramedullary tumor resection.

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The present study was carried out as a 2010 multidisciplinary research project for measures to help the handicapped patients (survey study of chronic musculoskeletal pain). The authors thank Naoko Kuzumaki, PhD, Doctor of Pharmacy, Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, for providing comments on the manuscript and Aya Shigeta, Clinical Engineering Technologist, Medical Engineering Center, Keio University Hospital, for her assistance in collecting and interpreting MEP/SEP data.

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postsurgical pain; central pain; intramedullary spinal cord tumor; perioperative associated factors; corticosteroids

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