Progression of Neuropathic Pain after Acute Spinal Cord Injury: A Meta-Analysis and Framework for Clinical Trials

Abstract

The translation of therapeutic interventions to humans with spinal cord injury with the goal of promoting growth and repair in the central nervous system could, inadvertently, drive mechanisms associated with the development of neuropathic pain. A framework is needed to evaluate the probability that a therapeutic intervention for acute spinal cord injury modifies the progression of neuropathic pain. We analyzed a large, longitudinal dataset from the European Multi-Center Study about Spinal Cord Injury (EMSCI) and compared these observations with a previously published Swedish/Danish cohort. A meta-analysis was performed to produce aggregate estimates for the transition period between 1–6 months and the transition period between 1–12 months after injury. A secondary analysis used logistic regression to explore associations between the progression of neuropathic pain and demographics, pain characteristics, and injury characteristics. For overall neuropathic pain, 72% presenting with pain symptoms at one month reported persisting symptoms at six months, and 23% who did not have neuropathic pain at one month later had it develop. From 1–12 months, there was a similar likelihood of pain persisting (69%) and slightly higher rate of pain developing (36%). Characteristics that were significantly associated with the progression of pain included age and sensory and motor preservation. We provide historical benchmarks for estimating the progression of neuropathic pain during the first year after acute SCI. This information will be useful for comparison and evaluating safety during early phase acute spinal cord injury trials.

Introduction

Many therapeutic interventions have been explored in animal models with the goal of improving neurological outcomes after spinal cord injury.¹ A chief concern among those translated to humans^2
–4 is that promoting axonal growth and repair in the central nervous system could, inadvertently, drive pathophysiological mechanisms associated with the development of neuropathic pain.^2,5,6 This concern exists in early trials that lack a control group, or those that are underpowered to detect potentially detrimental secondary outcomes (e.g., cell based interventions).⁷ To this end, historical control data will serve an important role in establishing safety guidelines.

Of particular value is a clear understanding of the natural history of neuropathic pain progression after injury. This includes knowledge of the probability that individuals with neuropathic pain will have their pain resolve, as well as the probability that individuals without neuropathic pain will have symptoms develop. To date, two large studies have described prospectively the progression of neuropathic pain after acute traumatic spinal cord injury.^8,9 Because of variability in methodology and reporting, estimates to characterize the temporal changes of neuropathic pain are difficult to ascertain.

The goal of our study was to develop a framework to evaluate the probability that a therapeutic intervention for spinal cord injury modifies the progression of neuropathic pain in acute trials. In a two step process, data were analyzed from the European Multi-Center Study about Spinal Cord Injury (EMSCI) and meta-analyzed with outcomes from a previously published study.⁸ A secondary analysis explored the association of neuropathic pain progression with demographic, pain, and injury characteristics.

Methods

Study design, study cohorts, and inclusion criteria

Data from the EMSCI (https://www.emsci.org, ClinicalTrials.gov Identifier: NCT01571531) and a published observational cohort study performed in Denmark and Sweden⁸ were included in our analysis. The EMSCI has been approved at each site by local research ethics boards, and individuals consent to have their data entered into the EMSCI database. The EMSCI prospectively collects detailed neurological, neurophysiological, and functional outcomes from individuals with traumatic or ischemic spinal cord injuries during the first year after injury for research purposes. This includes sensory and motor scores according to the International Standards for the Neurological Classification of Spinal Cord Injury.¹⁰

Motor scores are calculated from select muscle groups, each muscle scored from 0–5 (0 = total paralysis, 5 = normal), for a maximum score of 25 for each extremity and a maximum total motor score of 100.¹⁰ Sensory scores are composed of light touch scores (sensation with a cotton wisp) and pinprick scores (sharp/dull discrimination with a safety pin) scored from 0–2 (0 = absent, 2 = normal). Select dermatomes are tested with comparison with the same sensation on the cheek, such that each sensory measure has a maximum total score of 112 points.¹⁰

These assessments are performed at fixed time points after injury: very acute (0–15 days), four weeks (16–40 days), 12 weeks (70–98 days), 24 weeks (150–186 days), and 48 weeks (≥300 days). Individuals were excluded if their spinal cord injury was caused by a non-traumatic event (excluding single event ischemia), if they had previous dementia/reduced learning capabilities, if they had peripheral nerve lesions above the level of injury, if they had a previous polyneuropathy, or if they had a severe craniocerebral injury.

Beginning in 2007 (and updated in 2011), a subset of EMSCI individuals completed an additional pain questionnaire.^11,12 Pain outcomes were ascertained by a trained interviewer. The questionnaire allowed up to three pain sites to be reported, with the categorization of musculoskeletal, visceral, or neuropathic pain. Each pain was characterized by the interviewer according to descriptors, location (i.e., relative to lesion level), alleviating and aggravating factors, frequency, and intensity (0–10 numeric rating scale). In agreement with the International Spinal Cord Injury Pain Classification,¹³ neuropathic pain status was determined according to its location (i.e., in an area of complete/partial sensory loss), key descriptors (e.g., hot-burning), lack of relationship with movement, and the presence of allodynia and paresthesia. Neuropathic pain was then classified further based on proximity to the level of injury (i.e., at-/below level).¹³

Three published studies have utilized the EMSCI pain questionnaire.^11,12,14 For our analysis, only individuals with a valid one-month examination for the American Spinal Injury Association Impairment Scale (AIS) grade (grade of A, B, C, or D) and level of injury (including upper cervical [C1–C4], lower cervical [C5–C8], thoracic [T1–T12], and lumbar [L1–L5]), and a complete pain questionnaire were included.

The Swedish/Danish cohort data have been published previously. The objectives of the prospective study were to identify pain phenotypes after traumatic spinal cord injury and determine whether sensory hypersensitivity predicted the development of neuropathic pain. The inclusion criteria and methods for this study, as well as the evaluation of pain, have been described previously.⁸

Primary analysis

The primary analysis addressed the progression of neuropathic pain by dichotomizing pain status (yes/no) at each time point. The inclusion of three time points (i.e., one, six, and 12 months, common to both EMSCI and the Swedish/Danish study) and two pain states (yes/no) resulted in two progression timelines for the progression of acute neuropathic pain: 1–6 months and 1–12 months. These frameworks were constructed for at-level, below-level, and overall (at-level and below-level) neuropathic pain. Meta-analyses were performed using logit transformations to fit random-effects logistic models (inverse variance methods, R function: rma.glmm). The pooled estimates were then calculated using the R package metaphor. All analyses were conducted using open access R Studio version 1.0.153.

Secondary analyses

Associations with developing and persistent pain

We explored the associations between demographics, pain characteristics, and injury characteristics with neuropathic pain using bivariable logistic regression in the EMSCI dataset only (previously performed in the Swedish/Danish cohort).⁸ To assess these associations, individuals were grouped into two categories: “developed pain” (i.e., no neuropathic pain present at one month, with symptoms occurring for the first time at six or 12 months) and six month “persistent pain” (neuropathic pain present at one month, with symptoms persisting into six months). The former definition required individuals with a valid pain examination at six or 12 months as the pooled outcome, because pain appearing at either time would be classified as “developing” later after injury.

The reference group was composed of those with no recorded neuropathic pain at one month or at the later time points. Six month persistent pain was defined as neuropathic pain at one month and at six months, with a reference group of those with neuropathic pain at one month and no neuropathic pain at six months (i.e., those who had pain that did not persist over time). The persistent pain was limited to pain persisting at six months, because extending this definition to 12 months decreased the numbers available for analysis.

Demographic variables included age at injury and sex. Injury characteristics were measured at one month post-injury and included level of injury, total motor score, total light touch score, and total pinprick score.¹⁰ We further examined sensory subscores, as described previously in a published study.¹⁵ This included at-level light touch and pinprick scores (sum of scores from three dermatomes of the neurological level of injury excluding injuries at L3/L4/L5) and low-level light touch and pinprick scores (sum of scores from dermatomes L3–L5). In addition, the difference between light touch and pinprick (light touch–pinprick scores) for total, at-level, and low-level scores were included.¹⁵

Pain characteristics included the presence of musculoskeletal pain and the presence of at-level neuropathic pain (for the evaluation of below-level pain progression) or below-level neuropathic pain (for the evaluation of at-level pain progression). In the six month persistent pain group, we additionally examined associations with one month pain severity.

Results

A total of 1,005 individuals completed the EMSCI pain questionnaire. After applying the exclusion criteria, 251 individuals were included in the 1–6 month analysis and 144 in the 1–12 month analysis from a total of eight participating centers. From the original 90 individuals in the published Swedish/Danish cohort,⁸ one individual with an AIS E injury was excluded. There were 77 who had a valid neuropathic pain status for 1–6 months, and 87 for 1–12 months after injury. The demographics for the EMSCI and Swedish/Danish cohorts are summarized in Table 1.

Table 1.

Demographics of the Cohorts at First Visit

	EMSCI cohorts		Swedish/Danish cohorts
	1–6 month (%)	1–12 month (%)	1–6 month (%)	1–12 month (%)
Total	251 (100)	144 (100)	77 (100)	87 (100)
Mean age (SD)	47.9 (18.5)	47.1 (19.0)	48.0 (15.5)	47.2 (16.1)
Sex
Males	208 (82.9)	127 (88.2)	68 (88.3)	77 (88.5)
Females	43 (17.1)	17 (11.8)	9 (11.7)	10 (11.5)
Level of Injury
Upper cervical	74 (29.5)	39 (27.1)	22 (28.6)	23 (26.4)
Lower cervical	55 (21.9)	27 (18.8)	22 (28.6)	26 (29.9)
Thoracic	97 (38.6)	54 (37.5)	25 (32.5)	28 (32.2)
Lumbar	25 (10.0)	24 (16.7)	8 (10.4)	10 (11.5)
AIS
A	107 (42.6)	51 (35.4)	31 (40.3)	37 (42.5)
B	26 (10.4)	11 (7.6)	8 (10.4)	8 (9.2)
C	43 (17.1)	18 (12.5)	19 (24.7)	19 (21.8)
D	75 (29.9)	64 (44.4)	19 (24.7)	23 (26.4)

EMSCI, European Multi-Center Study about Spinal Cord Injury; SD, standard deviation; AIS, American Spinal Injury Association Impairment Scale.

Progression

The combined EMSCI and Swedish/Danish aggregate estimates from the meta-analysis for the progression of overall neuropathic pain are shown in Figure 1. The estimates for overall, at-level, and below-level neuropathic pain are summarized (from 1–6 months and 1–12 months) and reported in Tables 2 and 3, respectively. The respective estimates from each of the EMSCI versus the Swedish/Danish cohort are available for comparison in Supplementary Table e-1; see online supplementary material at http://www.liebertpub.com. These aggregate estimates highlight the number of incident cases—that is, the number of new cases that develop within the first year after injury, in addition to the rates of neuropathic pain relief or persistence, given the initial pain state and timeline of a cohort.

FIG. 1.

The longitudinal progression of overall neuropathic pain. Estimates are pooled from the European Multi-Center Study about Spinal Cord Injury and the Swedish/Danish study and are evaluated from (A) 1–6 months, and (B) 1–12 months.

Table 2.

The Aggregate Estimates of Overall, At-Level, and Below-Level Neuropathic Pain from One to Six and One to 12 Months after Spinal Cord Injury

Neuropathic pain	Neuropathic pain at one month	N	Neuropathic pain at six months	% (95% CI)
Estimates from one to six months
Overall
	Yes	89	Yes	72% (62, 80)
			No	28% (20, 38)
	No	239	Yes	23% (14, 37)
			No	77% (63, 86)
At-level
	Yes	60	Yes	67% (54, 77)
			No	33% (23, 46)
	No	268	Yes	14% (7, 25)
			No	86% (75, 93)
Below-level
	Yes	44	Yes	55% (40, 68)
			No	45% (32, 60)
	No	284	Yes	14% (11, 19)
			No	86% (81, 89)
Estimates from 1 to 12 months
Overall
	Yes	66	Yes	69% (53, 81)
			No	31% (19, 47)
	No	165	Yes	36% (23, 52)
			No	64% (48, 77)
At-level
	Yes	45	Yes	47% (33, 61)
			No	53% (39, 67)
	No	186	Yes	19% (13, 26)
			No	81% (74, 87)
Below-level
	Yes	29	Yes	52% (34, 69)
			No	48% (31, 66)
	No	202	Yes	23% (17, 29)
			No	77% (71, 83)

CI, confidence interval.

Table 3.

Results of the Logistic Regression Models for At-Level Neuropathic Pain

Outcome (yes/no)	Characteristic	Odds ratio (95% CI)	p
Developed at-level neuropathic pain
N = 107 (35 with pain)	Age at injury	1.03 (1.00–1.05)	0.02^*
	Sex
	Female	Ref	-
	Male	0.65 (0.22–1.94)	0.42
	Level of injury
	Upper cervical	Ref	-
	Lower cervical	0.93 (0.27–3.13)	0.90
	Thoracic	0.66 (0.24–1.79)	0.41
	Lumbar	0.31 (0.06–1.24)	0.12
	Below-level neuropathic pain	1.66 (0.50–5.20)	0.39
	Musculoskeletal pain	1.00 (0.45–2.26)	1.00
	Motor score	0.99 (0.98–1.01)	0.50
	Light touch	1.00 (0.98–1.01)	0.79
	Pinprick	0.99 (0.98–1.00)	0.19
	Light touch–pinprick	1.04 (1.01–1.08)	0.03^*
	Low-level light touch	1.00 (0.91, 1.09)	0.98
	Low-level pinprick	0.96 (0.87, 1.06)	0.45
	Low-level light touch–pinprick	1.15 (0.95, 1.40)	0.14
N = 106 (34 with pain)	At-level light touch	1.00 (0.85, 1.18)	0.95
	At-level pinprick	0.95 (0.82, 1.11)	0.54
	At-level light touch–pinprick	1.12 (0.88, 1.43)	0.38
Six month persistent at-level neuropathic pain
N = 41 (26 with pain)	Age at injury	0.93 (0.87–0.97)	0.008^*
	Sex
	Female	Ref	-
	Male	2.00 (0.40-10.01)	0.39
	Level of injury^**
	Upper cervical	Ref	-
	Lower cervical	-	-
	Thoracic	-	-
	Lumbar	-	-
	Pain severity	1.10 (0.73–1.73)	0.66
	Below-level neuropathic pain	2.36 (0.62–10.32)	0.22
	Musculoskeletal pain	0.61 (0.16–2.23)	0.45
	Motor score	1.00 (0.97–1.03)	0.91
	Light touch	1.01 (0.98–1.03)	0.69
	Pinprick	1.01 (0.98–1.03)	0.59
	Light touch–pinprick	0.99 (0.95–1.03)	0.64
	Low-level light touch	1.08 (0.94, 1.27)	0.30
	Low-level pinprick	1.18 (0.99, 1.47)	0.09
	Low-level light touch–pinprick	0.89 (0.69, 1.13)	0.33
	At-level light touch	1.37 (1.05, 1.91)	0.04^*
	At-level pinprick	1.42 (1.11, 1.94)	0.01^*
	At-level light touch–pinprick	0.85 (0.63, 1.13)	0.27

CI, confidence interval.

Level of injury could not be included because of insufficient numbers.

The rates of neuropathic pain persistence and development were quite similar between the two cohorts, with significant differences only occurring in the proportions of developing pain from 1–6 months for at-level and overall neuropathic pain (a higher proportion was reported in the Swedish/Danish cohort (Supplementary Table e-1; see online supplementary material at http://www.liebertpub.com).

From 1–6 months, the aggregate estimates indicate that at-level pain was more likely to persist than below-level (67% vs. 55%) and was equally likely to develop (14% vs. 14%) (Table 2). From 1–12 months post-injury, at-level and below-level neuropathic pain had similar rates of persistence (47% and 52%, respectfully) and development (19% and 23%, respectfully) (Table 2). Higher rates of pain persistence and development were found for overall neuropathic pain from 1–6 months (72% and 23%, respectively), and 1–12 months (69% and 36%, respectively) (Supplementary Table e-2; see online supplementary material at http://www.liebertpub.com).

Associations with neuropathic pain in the EMSCI

The bivariable logistical regression analysis revealed that the odds of developing at-level neuropathic pain (i.e., first appeared at six or 12 months) was significantly increased in older individuals and those with a greater total light touch and pinprick score difference (Fig. 2, Table 3). The odds of below-level neuropathic pain symptoms developing were similarly increased in older individuals, as well with greater motor scores (i.e., less severe injuries), and greater low-level light touch and at-level light touch scores (Table 4). Overall neuropathic pain developing was only associated significantly with increased age (Supplementary Table e-2; see online supplementary material at http://www.liebertpub.com).

FIG. 2.

The differences for developing neuropathic pain in the European Multi-Center Study about Spinal Cord Injury cohort. (A) For age at injury, there was a significant difference between groups for at-level neuropathic pain (p = 0.02) and below-level neuropathic pain (p = 0.005). (B) For light touch pinprick difference, there was a significant difference between groups for at-level neuropathic pain (p = 0.03) and not for below-level neuropathic pain (p = 0.14).

Table 4.

Results of the Logistic Regression Models for Below-Level Neuropathic Pain

Outcome (yes/no)	Characteristic	Odds ratio (95% CI)	p
Developed below-level neuropathic pain
N = 112 (45 with pain)	Age at injury	1.03 (1.01–1.06)	0.005^*
	Sex
	Female	Ref	–
	Male	0.44 (0.12–1.47)	0.18
	Level of injury
	Upper cervical	Ref	–
	Lower cervical	0.89 (0.29–2.66)	0.83
	Thoracic	0.52 (0.20–1.31)	0.17
	Lumbar	0.67 (0.17–2.46)	0.55
	At-level neuropathic pain	2.45 (0.86–7.30)	0.10
	Musculoskeletal pain	1.41 (0.66–3.03)	0.37
	Motor score	1.02 (1.00, 1.04)	0.03^*
	Light touch	1.01 (1.00, 1.02)	0.18
	Pinprick	1.00 (0.99, 1.02)	0.60
	Light touch–pinprick	1.02 (0.99–1.05)	0.14
	Low-level light touch	1.10 (1.01, 1.19)	0.03^*
	Low-level pinprick low	1.07 (0.98, 1.16)	0.12
	Low-level light touch–pinprick	1.13 (0.95, 1.35)	0.19
N = 111 (44 with pain)	At-level light touch	1.25 (1.05, 1.52)	0.02^*
	At-level pinprick	1.09 (0.08, 1.11)	0.27
	At-level light touch–pinprick	1.20 (0.97, 1.50)	0.10
Six month persistent below-level neuropathic pain
N = 36 (19 with pain)	Age at injury	0.98 (0.94–1.01)	0.21
	Sex
	Female	Ref	–
	Male	2.22 (0.45–12.63)	0.33
	Level of injury
	Upper cervical	Ref	–
	Lower cervical	3.75 (0.35–53.50)	0.29
	Thoracic	3.93 (0.65–33.21)	0.16
	Lumbar	2.50 (0.26–29.56)	0.43
	Pain severity	1.11 (0.75–1.70)	0.60
	At-level neuropathic pain	3.30 (0.86–14.13)	0.09
	Musculoskeletal pain	1.01 (0.27–3.81)	0.99
	Motor score	0.98 (0.94–1.01)	0.20
	Light touch	0.97 (0.94–1.00)	0.09
	Pinprick	0.98 (0.95–1.01)	0.21
	Light touch–pinprick	0.98 (0.93–1.03)	0.54
	Low-level light touch low	0.90 (0.75, 1.08)	0.27
	Low-level pinprick low	0.92 (0.74, 1.13)	0.44
	Low-level light touch–pinprick
	At-level light touch	1.06 (0.82, 1.39)	0.63
	At-level pinprick	0.96 (0.76, 1.19)	0.69
	At-level light touch– pinprick	1.31 (0.90, 2.09)	0.19

CI, confidence interval.

indicates p < 0.05.

In contrast to developed pain, the odds of six month persistent at-level neuropathic pain (i.e., present at one and six months) were associated with younger age at injury and higher at-level light touch and pinprick scores (Table 3). Persistent below-level neuropathic pain was not associated significantly with any of the available characteristics (Table 4). Persistent overall neuropathic pain demonstrated similar trends to at-level pain and was associated significantly with younger age and greater at-level pinprick scores (Supplementary Table e-2; see online supplementary material at http://www.liebertpub.com).

Discussion

The extent to which safety concerns are likely to occur in acute spinal cord injury clinical trials is unknown currently.¹ There is already precedence for neuropathic pain to emerge, however, as a consequence of cell-based intervention intended to enhance motor outcomes (e.g., autologous bone marrow mesenchymal stem cells).^16,17 Unfortunately, neuropathic pain is arguably among the worst possible outcomes for an acute intervention aimed at regenerating or enhancing plasticity in the central nervous system.^6,18 This is particularly true if signs and symptoms of neuropathic pain are unaccompanied by other neurological improvements (e.g., increased muscle strength)—a type of “unmitigated failure.”¹⁹ Given that pain measures in animal models do not reflect exactly clinical signs of neuropathic pain in humans, sensitive benchmarks are needed for human clinical trials.²⁰

The present analysis utilized two large, independent, observational studies to generate aggregate probability estimates for the progression of acute neuropathic pain after spinal cord injury. Neuropathic pain status changed considerably over the course of the first year. This included individuals with no neuropathic pain at one month who had symptoms developing at later time-points, as well as individuals whose initial neuropathic pain symptoms resolved at follow-up. The estimates could be incorporated as benchmarks to evaluate the safety of early phase clinical trials in patients with acute spinal cord injury.

This study highlights the likelihood of developing or resolving neuropathic pain over the course of the first year after spinal cord injury. Trajectories of neuropathic pain have been presented in periods relevant to acute clinical trials (i.e., beginning at 1 month, with follow-up at 6/12 months). As is evident by our observations (and not entirely surprising), the probability of neuropathic pain developing at a later time point is dependent on earlier pain status. Unlike the report of prevalence, measures of pain progression (e.g., ongoing incidence during a trial) should be considered as a safety benchmark for clinical trials.

As an example, consider a trial in which all the individuals are recruited without neuropathic pain, but at six month follow-up, 50% report symptoms. This estimate may not be concerning initially when compared with previously published estimates of overall prevalence.²¹ Our benchmarks, however, suggest only 23% of an initially pain-free population is expected to have symptoms develop (Fig. 1). A less obvious example of an adverse outcome is a treatment that reduces the likelihood of pain relief. Without incorporated benchmarks, such a subtle change easily could go overlooked.

The proportions outlined in Figure 1 (and in supplementary material; see online supplementary material at http://www.liebertpub.com) should, however, be interpreted cautiously. Recruitment for acute spinal cord injury clinical trials is difficult, and many early phases will only include a small number of patients.²² As a result, the proportion developing signs and symptoms of neuropathic pain will be highly variable. To avoid erroneously penalizing trials tracking neuropathic pain, sample size needs to be considered. For example, our aggregate estimates indicated that 23% of initially pain-free individuals are expected to present with symptoms at six months (Fig. 1). Compared with this benchmark, 40% developing symptoms of neuropathic pain in a trial of 46 subjects would represent cause for major concern (i.e., a significant increase), whereas 30% would not (alpha = 0.05, power = 0.8, binomial tests).²³

A similar process could also be applied to determine the effectiveness of an acute intervention to prevent neuropathic pain (i.e., a beneficial outcome). With some success, the concept of prophylactically managing chronic pain has emerged in other health conditions (e.g., post-surgical).²⁴ To our knowledge, carbamazepine, a first-generation anticonvulsant, is the only medication trialed so far to prevent the onset of neuropathic pain symptoms after spinal cord injury.²⁵ While unsuccessful in the long-term (i.e., pain emerged when carbamazepine was withdrawn), newer generation medications, such as gabapentin and pregabalin, may be more effective in this regard (see Supplementary Table E-3; see supplementary material at http://www.liebertpub.com).²⁶ To plan future trials aimed at preventing neuropathic pain after spinal cord injury, an understanding of progression is important.

For prognosis and treatment planning purposes, predictors of neuropathic pain early after injury are of high clinical value. Understanding factors associated with developing neuropathic pain symptoms are also important in terms of gaining novel insights into mechanisms. In our exploratory analysis, age was the most consistent subject-level predictor of neuropathic pain. The logistical regression analyses revealed an association between developed neuropathic pain and older age at injury (both at-level and below-level). An age effect has been reported elsewhere^21,27 and is not entirely surprising given that older individuals are at increased odds of other forms of neuropathic pain.²⁸

Although younger age at injury was significantly protective against developed pain, the odds of persistent at-level pain increased. This is difficult to explain in light of the fact that other neuropathic pain conditions with persistent symptoms are associated with older age.^28,29 Further, the small effect sizes presented here may fall below clinical significance.

Individuals with preserved motor sparing were at increased odds of below-level neuropathic pain developing. This suggests that sparing at the lesion site acts as an anatomical substrate for neuropathic pain to develop, protecting those with complete injuries (i.e., AIS-A). Based on a previous study,¹⁵ sensory scores and their subscores and differences were also considered in the logistic regression models. In line with earlier observations, a larger difference between total light touch and pinprick scores at one month, such that pinprick demonstrated greater deficits than light touch, was associated with a higher likelihood of at-level neuropathic pain developing. This association may be attributable to preferential sparing in the dorsal columns relative to the spinothalamic tract, which has been postulated as a mechanism of neuropathic pain.¹⁵

The association between greater light touch scores and the development of below-level neuropathic pain follows a similar pattern. Persistent at-level pain, however, was associated with both increased at-level light touch and pinprick scores, indicating more general sparing at the lesion site (which was not the case for persistent below-level pain).

A strength of our analysis is that both datasets are from multi-center studies. This is important because the design of acute clinical trials will almost certainly involve multiple centers.^30
–32 The diagnosis of neuropathic pain, however, presents with some risk of misclassification. Overall, there was high correspondence between the two independently collected datasets, which illustrates the robustness of neuropathic pain progression after spinal cord injury. Nonetheless, the Swedish/Danish cohort tended toward a higher incidence of neuropathic pain through significantly higher proportions of developed at-level and overall neuropathic pain (likely driven by the at-level proportions). This could be attributed to differences in methodology, including, for example, a bedside examination to assess evoked neuropathic pain sensations (e.g., allodynia) in the Swedish/Danish cohort but not EMSCI.⁸

Another difference exists in the timing of the initial pain measurement: the initial EMSCI assessment was administered within the first six weeks after injury, and the initial assessment in the Swedish/Danish occurred between 1–3 months after injury. This may have introduced some variability regarding the earlier reported rates of pain. Further, individuals in the EMSCI cohort were limited to reporting their top three sources of pain, which may have caused some underreporting.

Another limitation exists in the elusive nature of reporting neuropathic pain: questions about pain were specified at the given examination, and these timelines may have missed pain that developed and relieved within a period of time. It has also been reported that neuropathic pain at one time point may progress into non-painful sensations (e.g., dysesthesia) at another time point, and be classified as “no pain” when the symptoms actually have not resolved.³³ Other discrepancies may be the result of individual and study related differences, including dropout. Indeed, the dropout rate in the EMSCI was markedly higher than the Swedish/Danish cohort.

This study comprehensively explored the progression of distinct forms of acute neuropathic pain after spinal cord injury. Further, we have identified factors associated with developing and persisting neuropathic pain. In summary, we have provided an initial framework by which to assess the risks and benefits of future acute therapeutic interventions administered in spinal cord injury.

Footnotes

Acknowledgments

We would like to acknowledge the participating centers in the EMSCI network (http://emsci.org/members) that were involved in the patient care and collection of data necessary for this study.

Author Disclosure Statement

No competing financial interests exist.

References

Cote

D.J.

, Bredenoord

A.L.

, Smith

T.R.

, Ammirati

, Brennum

, Mendez

, Ammar

A.S.

, Balak

, Bolles

, Esene

I.N.

, Mathiesen

, and Broekman

M.L.

(2017). Ethical clinical translation of stem cell interventions for neurologic disease. Neurology, 88, 322–328.

Anderson

K.D.

, Guest

, Dietrich

W.D.

, Bartlett Bunge

, Curiel

, Dididze

, Green

B.A.

, Khan

, Pearse

D.D.

, Saraf-Lavi

, Widerstrom-Noga

, Wood

, and Levi

A.D.

(2017). Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J. Neurotrauma, 34, 2950–2963.

Gomes-Osman

, Cortes

, Guest

, and Pascual-Leone

(2016). A systematic review of experimental strategies aimed at improving motor function after acute and chronic spinal cord injury. J. Neurotrauma, 33, 425–438.

Assinck

, Duncan

G.J.

, Hilton

B.J.

, Plemel

J.R.

, and Tetzlaff

(2017). Cell transplantation therapy for spinal cord injury. Nat. Neurosci. 20, 637–647.

Fan

, Zheng

, Cheng

, Qi

, Bu

, Luo

, Kim

D.H.

, and Cao

(2012). Transplantation of D15A-expressing glial-restricted-precursor-derived astrocytes improves anatomical and locomotor recovery after spinal cord injury. Int. J. Biol. Sci. 9, 78–93.

Hofstetter

C.P.

, Holmström

N.A.

, Lilja

J.A.

, Schweinhardt

, Hao

, Spenger

, Wiesenfeld-Hallin

, Kurpad

S.N.

, Frisén

, and Olson

(2005). Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat. Neurosci. 8, 346–353.

Levi

A.D.

, Okonkwo

D.O.

, Park

, Jenkins

A.L.

3rd , Kurpad

S.N.

, Parr

A.M.

, Ganju

, Aarabi

, Kim

, Casha

, Fehlings

M.G.

, Harrop

J.S.

, Anderson

K.D.

, Gage

, Hsieh

, Huhn

, Curt

, and Guzman

(2018). Emerging safety of intramedullary transplantation of human neural stem cells in chronic cervical and thoracic spinal cord injury. Neurosurgery, 82, 562–576.

Finnerup

N.B.

, Norrbrink

, Trok

, Piehl

, Johannesen

I.L.

, Sørensen

J.C.

, Jensen

T.S.

, and Werhagen

(2014). Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study. J. Pain, 15, 40–48.

Siddall

P.J.

, Taylor

D.A.

, McClelland

J.M.

, Rutkowski

S.B.

, and Cousins

M.J.

(1999). Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury. Pain, 81, 187–197.

10.

Kirshblum

S.C.

, Burns

S.P.

, Biering-Sorensen

, Donovan

, Graves

D.E.

, Jha

, Johansen

, Jones

, Krassioukov

, Mulcahey

, Schmidt-Read

, and Waring

(2011). International standards for neurological classification of spinal cord injury (revised 2011). J. Spinal Cord Med. 34, 535–546.

11.

Cragg

J.J.

, Haefeli

, Jutzeler

C.R.

, Röhrich

, Weidner

, Saur

, Maier

D.D.

, Kalke

Y.B.

, Schuld

, Curt

, and Kramer

J.K.

(2016). Effects of pain and pain management on motor recovery of spinal cord-injured patients: a longitudinal study. Neurorehabil. Neural Repair, 30, 753–761.

12.

Warner

F.M.

, Cragg

J.J.

, Jutzeler

C.R.

, Röhrich

, Weidner

, Saur

, Maier

D.D.

, Schuld

; EMSCI sites, Maier

D.D.

, Curt

, and Kramer

J.K.

(2017). Early administration of gabapentinoids improves motor recovery after human spinal cord injury. Cell Rep. 18, 1614–1618.

13.

Siddall

P.J.

, Taylor

D.A.

, and Cousins

M.J.

(1997). Classification of pain following spinal cord injury. Spinal Cord, 35, 69–75.

14.

Hassanpour

, Hotz-Boendermaker

, Dokladal

; European Multicenter Study for Human Spinal Cord Injury Study group, Curt

(2012). Low depressive symptoms in acute spinal cord injury compared to other neurological disorders. J. Neurol. 259, 1142–1150.

15.

Levitan

, Zeilig

, Bondi

, Ringler

, and Defrin

(2015). Predicting the risk for central pain using the sensory components of the International Standards for Neurological Classification of Spinal Cord Injury. J. Neurotrauma, 32, 1684–1692.

16.

Kishk

N.A.

, Gabr

, Hamdy

, Afifi

, Abokresha

, Mahmoud

, Wafaie

, and Bilal

(2010). Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabil. Neural Repair, 24, 702–708.

17.

Oraee-Yazdani

, Hafizi

, Atashi

, Ashrafi

, Seddighi

A.S.

, Hashemi

S.M.

, Seddighi

, Soleimani

, and Zali

(2016). Co-transplantation of autologous bone marrow mesenchymal stem cells and Schwann cells through cerebral spinal fluid for the treatment of patients with chronic spinal cord injury: safety and possible outcome. Spinal Cord, 54, 102–109.

18.

Macias

M.Y.

, Syring

M.B.

, Pizzi

M.A.

, Crowe

M.J.

, Alexanian

A.R.

, and Kurpad

S.N.

(2006). Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp. Neurol. 201, 335–348.

19.

Schulzer

, and Mancini

G.B.

(1996). “Unqualified success” and “unmitigated failure”: number-needed-to-treat-related concepts for assessing treatment efficacy in the presence of treatment-induced adverse events. Int. J. Epidemiol. 25, 704–712.

20.

Kramer

J.L.

, Minhas

N.K.

, Jutzeler

C.R.

, Erskine

E.L.

, Liu

L.J.

, and Ramer

M.S.

(2017). Neuropathic pain following traumatic spinal cord injury: models, measurement, and mechanisms. J. Neurosci. Res. 85, 1295–1306.

21.

Burke

, Fullen

B.M.

, Stokes

, and Lennon

(2017). Neuropathic pain prevalence following spinal cord injury: a systematic review and meta-analysis. Eur. J. Pain, 21, 29–44.

22.

Thibault-Halman

, Rivers

C.S.

, Bailey

C.S.

, Tsai

E.C.

, Drew

, Noonan

V.K.

, Fehlings

M.G.

, Dvorak

M.F.

, Kuerban

, Kwon

B.K.

, and Christie

S.D.

(2017). Predicting recruitment feasibility for acute spinal cord injury clinical trials in Canada Using National Registry data. J. Neurotrauma, 34, 599–606.

23.

Faul

, Erdfelder

, Lang

A.G.

, and Buchner

(2007). G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods, 39, 175–191.

24.

De Oliveira

G.S.

Jr. , Almeida

M.D.

, Benzon

H.T.

, and McCarthy

R.J.

(2011). Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology, 115, 575–588.

25.

Salinas

F.A.

, Lugo

L.H.

, and García

H.I.

(2012). Efficacy of early treatment with carbamazepine in prevention of neuropathic pain in patients with spinal cord injury. Am. J. Phys. Med. Rehabil. 91, 1020–1027.

26.

Cardenas

., Nieshoff

E.C.

, Suda

, Goto

S.I.

, Sanin

, Kaneko

, Sporn

, Parsons

, Soulsby

, Yang

, Whalen

, Scavone

J.M.

, Suzuki

M.M.

, and Knapp

L.E.

(2013). A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury. Neurology, 80, 533–539.

27.

Margot-Duclot

, Tournebise

, Ventura

, and Fattal

(2009). What are the risk factors of occurence and chronicity of neuropathic pain in spinal cord injury patients?. Ann. Phys. Rehabil. Med. 52, 111–123.

28.

Boogaard

, Heymans

M.W.

, de Vet

H.C.

, Peters

M.L.

, Loer

S.A.

, Zuurmond

W.W.

, and Perez

R.S.

(2015). Predictors of persistent neuropathic pain—a systematic review. Pain Physician, 18, 433–457.

29.

Jung

B.F.

, Johnson

R.W.

, Griffin

D.R.

, and Dworkin

R.H.

(2004). Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology, 62, 1545–1551.

30.

Bracken

M.B.

, Shepard

M.J.

, Collins

W.F.

, Holford

T.R.

, Young

, Baskin

D.S.

, Eisenberg

H.M.

, Flamm

, Leo-Summers

, and Maroon

, et al. (1990). A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N. Engl. J. Med., 322, 1405–1411.

31.

Inada

, Takahashi

, Yamazaki

, Okawa

, Sakuma

, Kato

, Hashimoto

, Hayashi

, Furuya

, Fujiyoshi

, Kawabe

, Mannoji

, Miyashita

, Kadota

, Someya

, Ikeda

, Hashimoto

, Suda

, Kajino

, Ueda

, Ito

, Ueta

, Hanaoka

, Takahashi

, and Koda

(2014). Multicenter prospective nonrandomized controlled clinical trial to prove neurotherapeutic effects of granulocyte colony-stimulating factor for acute spinal cord injury: analyses of follow-up cases after at least 1 year. Spine (Phila. Pa. 1976). 39, 213–219.

32.

Fehlings

M.G.

, Theodore

, Harrop

, Maurais

, Kuntz

, Shaffrey

C.I.

, Kwon

B.K.

, Chapman

, Yee

, Tighe

, and McKerracher

(2011). A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J. Neurotrauma, 28, 787–796.

33.

Finnerup

N.B.

, Jensen

M.P.

, Norrbrink

, Trok

, Johannesen

I.L.

, Jensen

T.S.

, and Werhagen

(2016). A prospective study of pain and psychological functioning following traumatic spinal cord injury. Spinal Cord, 54, 816–821.

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