ARTICLE IN PRESS

The Journal of Pain, Vol 00, No 00 (), 2021: pp 1−9

Available online at www.jpain.org and www.sciencedirect.com

Original Reports
Characterization of Hyperacute Neuropathic Pain after
Spinal Cord Injury: A Prospective Study

langer,g Angela Tsang,g Leanna Ritchie,g
Jan Rosner,a,d,e Michael Negraeff,a,f Lise M. Be
Jean-Marc Mac-Thiong,h,n Sean Christie,i Jefferson R. Wilson,j Sanjay Dhall,k
Rapha€ele Charest-Morin,b John Street,a,b Tamir Ailon,c Scott Paquette,a,c Nicolas Dea,c
Charles G. Fisher,b Marcel F. Dvorak,a,b Nanna B. Finnerup,l,m Brian K. Kwon,a,b,# and
John L.K. Kramera,f,#
a
International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, British Columbia, Canada,
b
Vancouver Spine Surgery Institute, Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia,
Canada, cDivision of Neurosurgery, University of British Columbia, Vancouver, British Columbia, Canada, dSpinal Cord Injury
Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland, eDepartment of Neurology, University Hospital
Bern, Inselspital, University of Bern, Bern, Switzerland, fDepartment of Anesthesiology, Pharmacology, and Therapeutics, Faculty
of Medicine, University of British Columbia, British Columbia, Canada, gVancouver Spine Program, Vancouver General Hospital,
Vancouver, British Columbia, Canada, hHo^pital du Sacre
-Coeur de Montre
al, Montre
al, Quebec, Canada, iDivision of
Neurosurgery, Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada, jDivision of Neurosurgery,
Department of Surgery, University of Toronto, St Michael’s Hospital, Toronto, Ontario, Canada, kDepartment of Neurological
Surgery, University of California, San Francisco, San Francisco, California, lDanish Pain Research Center, Department of Clinical
Medicine, Aarhus University, Aarhus, Denmark, mDepartment of Neurology, Aarhus University Hospital, Aarhus, Denmark,
n
Faculty of Medicine, Universite
de Montre
al, Montre
al, Quebec, Canada

Abstract: There is currently a lack of information regarding neuropathic pain in the very early stages
of spinal cord injury (SCI). In the present study, neuropathic pain was assessed using the Douleur Neu-
ropathique 4 Questions (DN4) for the patient’s worst pain within the first 5 days of injury (i.e., hyper-
acute) and on follow-up at 3, 6, and 12 months. Within the hyperacute time frame (i.e., 5 days), at- and
below-level neuropathic pain were reported as the worst pain in 23% (n = 18) and 5% (n = 4) of individ-
uals with SCI, respectively. Compared to the neuropathic pain observed in this hyperacute setting, late
presenting neuropathic pain was characterized by more intense painful electrical and cold sensations,
but less itching sensations. Phenotypic differences between acute and late neuropathic pain support
the incorporation of timing into a mechanism-based classification of neuropathic pain after SCI. The
diagnosis of acute neuropathic pain after SCI is challenged by the presence of nociceptive and neuro-
pathic pains, with the former potentially masking the latter. This may lead to an underestimation of
the incidence of neuropathic pain during the very early, hyperacute time points post-injury.
Trial registration: ClinicalTrials.gov (Identifier: NCT01279811)
Perspective: This article presents distinct pain phenotypes of hyperacute and late presenting neu-
ropathic pain after spinal cord injury and highlights the challenges of pain assessments in the acute
phase after injury. This information may be relevant to clinical trial design and broaden our under-
standing of neuropathic pain mechanisms after spinal cord injury.
© 2021 by United States Association for the Study of Pain, Inc.
Key words: Acute neuropathic pain, spinal cord injury, pain phenotype, clinical trials.

Received September 12, 2020; Revised June 19, 2021; Accepted June 25,
2021.
#
shared last authors
Address reprint requests to John L.K. Kramer, PhD, Blusson Spinal Cord
Center, 818 West 10th Avenue, Vancouver, British Columbia V5Z 1M9,
Canada. E-mail: kramer@icord.org
1526-5900/$36.00
© 2021 by United States Association for the Study of Pain, Inc.
https://doi.org/10.1016/j.jpain.2021.06.013

1
 ARTICLE IN PRESS
2 The Journal of Pain
T
he vast majority of individuals with longstanding
spinal cord injury (SCI) report chronic pain,11 and
about 50% have neuropathic pain.37 Compared
to other forms of pain (e.g., musculoskeletal), neuro-
pathic pain is often more severe and refractory to con-
ventional pharmacological interventions.15 The
negative impact on quality of life and societal burden
(e.g., healthcare expenses) highlight the unmet and
urgent need for novel therapies.33,40
A mechanism-based classification system is widely
regarded as paramount to developing more effective
treatment options for neuropathic pain.4,5 The current
classification system for SCI neuropathic pain is based
on the proximity of signs and symptoms to the lesion
level, differentiating between pains “at-“ and “below-
level”.8 In support of distinct mechanisms, at- and
below-level neuropathic pain develop over different
timelines, with at-level typically preceding the onset of
below-level pain.18,30,37 Without distinguishing proxim-
ity to lesion level, a retrospective review of patient
charts demonstrated the potential for very early neuro-
pathic pain, emerging within the first week of injury.6
The presence of early neuropathic pain after SCI is also
apparent in patients enrolled in therapeutic trials.2
Novel interventions for the management of neuro-
pathic pain are most commonly trialed in persons whose
signs and symptoms have reached chronic stages (i.e.,
persistent for > 3 months). The knowledge gained in
the course of investigating chronic neuropathic pain (e.
g., effectiveness of an intervention) is, in the case of SCI,
translated into acute management practices. While logi-
cal to initiate treatment ahead of nominally being
labelled “chronic”, the extent by which acute neuro-
pathic pain can be equivalently managed by interven-
tions effective for chronic neuropathic pain is largely
unknown.
The present study aimed to address the hypothesis that
neuropathic pain, at- and below-level, is present very
early, i.e., in the hyperacute phase of SCI. To this end,
neuropathic pain was prospectively examined within the
first 5-days of injury using the Douleur Neuropathique 4
Questions (DN4) questionnaire. The DN4 has been used
previously in SCI and was recently recommended by Hans-
son and colleagues in their proposal to study acute neuro-
pathic pain.22 A secondary analysis addressed the
hypothesis that neuropathic pain during the hyperacute
phase of SCI was phenotypically different from that
observed at later (i.e., >3 months) time points.
Methods
Study Cohort
Information pertaining to SCI and neuropathic pain
was prospectively collected in a longitudinal multicenter
study (ClinicalTrials.gov, NCT01279811). In brief, individu-
als were recruited from six participating level-one trauma
centers in Canada and the United States. After enroll-
ment, neuropathic pain and SCI details (described below)
Hyperacute Neuropathic Pain after Spinal Cord Injury
were routinely assessed during the 5-day hyperacute
post-injury period and at fixed time intervals, i.e., 3, 6,
and 12 months after injury. Individuals with non-pene-
trating, traumatic cervical and thoracic spinal cord injuries
were enrolled within 48 hours of their injury. Exclusion
criteria included individuals with cauda equina injury,
major concomitant trauma to extremities, trunk or abdo-
men, and/or pre-existing neurological conditions. A
detailed list of the inclusion and exclusion criteria can be
found on ClinicalTrials.gov (Identifier: NCT01279811). The
study was ethically approved by all participating centers
and all individuals provided written informed consent.
Neurological Examination and Pain
Assessments
A neurological examination was performed according
to the International Standards for Neurological Classifi-
cation of Spinal Cord Injury (ISNCSCI). From this exam,
the severity of injury was characterized according to the
American Spinal Injury Association Impairment Scale
(AIS). The lesion level was defined as the most rostral
spinal segment with intact sensorimotor function.24
Pain medication was derived from the patient charts
reflecting the current medication regime at each time
point. This information was only recorded for individu-
als with DN4-positive pain. The DN4 was performed by
trained personnel to characterize the individual‘s worst
pain.7 The DN4 was originally developed as a screening
tool for neuropathic pain, and includes 10 components.
Seven items encompass specific pain descriptors (burn-
ing, painful cold, electric shocks) as well as paresthesias
and dysesthesias (tingling, pins and needles, numbness,
itching). The remaining three items are derived from a
focused sensory bedside examination in the painful
area (touch hypoesthesia, pinprick hypoalgesia,
dynamic mechanical allodynia). Dynamic mechanical
allodynia (DMA) was assessed by lightly stroking the
skin within a non-painful area (above the lesion level)
and within the painful area with a brush. "Painful" sen-
sations such as burning and stinging were considered
evidence of allodynia. For scoring, one is assigned to
each positive and a zero to each negative item, yielding
a total score from 0 to 10. A score of ≥4 indicates that
the pain examined is likely to be neuropathic.7 The
questionnaire has previously been used in individuals
with chronic neuropathic pain following SCI.34 More-
over, recently the use of this questionnaire has been
suggested to characterize acute neuropathic pain.22
In the present study, only "worst pain with neuro-
pathic characteristics" was fully characterized using the
DN4 questionnaire. Each session over the course of the
first 5 days post-injury, as well as later follow-ups,
started with a brief conversation with the patient about
“nerve pain”. This was performed by a trained examiner
and involved distinguishing neuropathic from nocicep-
tive pains. To familiarize patients with neuropathic
pain, patients were instructed to identify areas associ-
ated with burning, painful cold, electrical shock,
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Rosner et al The Journal of Pain 3

tingling, pins and needles, numbness, and/or itching
sensations (i.e., descriptions of neuropathic pain cap-
tured by the DN4) and ignore other painful sensations
(e.g., aching shoulder pain). Patients were also
instructed to ignore pain arising from surgery at the
incision site, even if there was a neuropathic pain qual-
ity (e.g., burning). In the area reported as the “worst”,
which was, in any way, characterized by neuropathic
symptoms, the DN4 was fully examined. If the DN4 score
was ≥4, the intensity of corresponding sensory symp-
toms was evaluated using a numerical pain rating (NRS)
scale (0-no pain/sensation, 10-worst pain imaginable/
most intense sensation imaginable).
DMA could not always be assessed at chronic time
points. This was due to various technical reasons, includ-
ing that, on occasion, at chronic time points, the DN4
was administered by telephone. In these cases, the DN4
was calculated based on remaining questions. To assess
the effect this would have on the data, we verified all
scores, specifically investigating if there were any bor-
derline scores (i.e., 3) that could conceivably have led to
DN4-positive pain, had DMA been assessed and also
tested positive. This revealed that all DN4-negative
patients scored 0 to 2, which means that the additional
presence of DMA would have had no effect on neuro-
pathic pain outcome. The classification of at-, below-,
and above-level pain was done following the
recommendations of the International Spinal Cord
Injury Pain (ISCIP) Classification group.8 We defined SCI
neuropathic pain as pain with a positive DN4, present at
or below the level of injury in an area with sensory
abnormalities indexed by the DN4 questionnaire and
the ISNCSCI exam.
Data Analyses
The primary analysis addressed the number of
patients presenting with at- and below-level neuro-
pathic at any of the time points during the hyperacute
phase (initial 5 days) after SCI. The term "hyperacute"
was chosen in order to highlight the immediate to very
early onset after injury during the phase of acute care,
which encompasses day 0-15 in most SCI studies.31,37 A
secondary analysis addressed phenotypes of neuro-
pathic pain in patients with hyperacute compared to
late presenting neuropathic pain. All patients in the
hyperacute neuropathic pain group were DN4-positive
for worst pain in the first 5 days after injury. A second
and completely independent, late presenting group
included patients that were DN4-negative during the
hyperacute phase but positive on follow-up at any
chronic time point. This analysis addressed differences
in the intensity of symptoms reported for the DN4
between groups.

Table 1. Subject Characteristics

CHARACTERISTICS HYPERACUTE NEUROPATHIC PAIN LATE PRESENTING NEUROPATHIC PAIN NO NEUROPATHIC PAINy
(<5 DAYS, N = 19) (>3 MONTHS, N = 17) (N = 32)

Age [y] 46.3 § 20.6 41.2 § 18.2 40.2 § 15.9

Sex [%]
Male 72 94 76
Female 28 6 24
Etiology [%]
Falls 35 6 48
Transport 18 29 31
Violence / 6 3
Sports 29 41 14
Others 18 12 3
Level of Injury [%]
Tetraplegia 44 47 62
Paraplegia 56 53 38
AIS grade [%]
A 67 71 79
B 11 12 7
C 22 18 14
Neuropathic Pain
DN4 score 5.0 § 1.0* 4.6 § 0.9 0.9 § 1.0
DMA [%] 23* NA
Pain medication [%]
Gabapentinoids 33 71 NA
Antidepressants 6 24 NA
Opiods 83 12 NA
Others 33 41 NA

Data is shown as mean § standard deviation or percentage (as indicated). Pain medication “other” included mostly paracetamol and topical ketamine/amitriptylin
ointment.
Abbreviations: AIS, American Spinal Injury Association (ASIA) Injury Severity at baseline; DN4, Douleur Neuropathique 4 Questions (neuropathic pain screening ques-
tionnaire); DMA, dynamical mechanical allodynia.
*n=22, as the analysis was performed across all pain areas, and some individuals had at- and below-level pain.
yat neither hyperacute, nor chronic time points.
 ARTICLE IN PRESS
4 The Journal of Pain
All statistical analyses and data visualizations were per-
formed in GraphPad Prism (Version 8). Normality of distri-
bution was tested by visual inspection of data histograms
and the Shapiro−Wilk test. Descriptive statistics (mean
with standard deviation (SD), or median with interquar-
tile range (IQR), where applicable) were used to report
cohort and pain characteristics. Mann-Whitney tests
were used to compare intensities of DN4-derived pain
symptoms between hyperacute and late presenting pain.
Results
Overall 79 individuals were included in the study. 11
were excluded due to missing data, leaving 68 individu-
als with complete datasets. The cohort demographics
are summarized in Table 1.
There were no significant differences in demo-
graphics between the three groups (i.e., "hyperacute
neuropathic pain", "late presenting neuropathic pain",
and "no neuropathic pain"). Pain treatment differed
between individuals who presented with neuropathic
pain as their worst pain during the hyperacute period
(1-5 days post-injury) and those with late presenting
neuropathic pain, while the latter received more gaba-
pentinoids and antidepressants, but significantly less
opioids (Fisher‘s exact p=0.01).
Frequencies of Acute and Chronic
Neuropathic Pain
Out of 79 individuals, 19 presented with neuropathic
pain (i.e., DN4-positive, at or below the lesion level of
spinal cord injury) as their most severe pain within the
first 5 days of injury. At- and below-level neuropathic
pain were reported as the worst pain in 23% (n = 18)
and 5% (n = 4) of all individuals, respectively (Fig 1). In
approximately 50% (n = 9), neuropathic pain in the
hyperacute phase was reproducibly present at multiple
time points within the first 5 days (i.e., ≥2 times docu-
mented DN4-positive pain in the same location). Below-
level pain was located, on median, 4 spinal segments
caudal to the level of lesion (range= 4 to 17). Pain draw-
ings for the 4 individuals with below-level neuropathic
pain are illustrated in Fig 2.
In the chronic phase, 17 individuals that were DN4-
negative for worst pain in the acute phase were DN4-
positive at 3, 6, or 12 months. Relative to injury level,
14% (n = 11) and 8% (n = 6) were classified as at- and
below-level neuropathic pain, respectively (Fig 1).
Time-Dependent Phenotypic Differences
The numeric ratings of DN4-derived symptoms based
on timing are illustrated in Fig 3. Significant differen-
ces were detected for cold (Mann-Whitney U = 29,
p = 0.03) and electrical sensations based on timing
(Mann-Whitney U = 17, p < 0.001,), with higher ratings
for late presenting neuropathic pain compared to
neuropathic pain with hyperacute onset. In contrast,
itching was more intense in hyperacute neuropathic
pain (Mann-Whitney U = 78.5, p = 0.02).
Hyperacute Neuropathic Pain after Spinal Cord Injury
Figure 1. Frequencies of Acute and Late Presenting DN4-
positive Worst Pain. In 19 individuals the worst pain was
DN4-positive in the immediate aftermath (<5 days) of spinal
cord injury. Among those whose worst pain was not DN4-
positive during the acute phase, 17 presented with possible
neuropathic pain at the chronic stage. At = at-level pain (i.
e., occurring within 3 segments of the spinal lesion level),
below = below-level pain (i.e., occurring >3 segments below
the lesion level). In some individuals at- and below-level
pain were concurrently present and counted separately.
Abbreviation: DN4, Douleur Neuropathique 4 Questions
(neuropathic pain screening questionnaire).
Discussion
Our study provides the first characterization of at-
and below-level neuropathic pain in the immediate to
very early aftermath of SCI using a validated question-
naire. Hyperacute neuropathic pain was often reported
as severe and encompassed spontaneous and paroxys-
mal symptoms, as well as dynamic mechanical allodynia.
A phenotypic difference was detected between acute
and late presenting neuropathic pain, with more severe
electrical shock and cold sensations characterizing that
observed in the chronic phase (i.e., >3 months after
injury). These findings address a major knowledge gap
regarding the onset of neuropathic pain after spinal
cord injury and have important implications regarding
potential underlying mechanisms.
The results for incidence of at-level neuropathic pain
within 5 days of injury are comparable to those reported
previously at 2 weeks30 and 1-month.37 This provides
empirical support that at-level neuropathic pain in the
very early stages of injury may reflect rapidly evolving
pathophysiological mechanisms. The most obvious
source, which would explain the radicular distribution
and early onset, is peripheral nerve damage, caused by
mechanical perturbation and compression of spinal
nerves adjacent to the lesion level.3 Severe concurrent
peripheral nerve damage at the lesion site (e.g., median
and ulnar nerves after damage in the cervical cord) has
been estimated in up to 20% of acute spinal cord inju-
ries12 − although never correlated with signs of at-level
pain. Nerve root avulsion may also be present and a
potential source of neuropathic pain. Painful sensations
from damage to peripheral nerves, proximal or distal to
the dorsal root ganglion, can arise due to spontaneous
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Rosner et al The Journal of Pain 5

Figure 2. Location and Clinical Signs of DN4-positive Below-level Worst Pain. Pain locations of DN4-positive pain were superim-
posed on standardized pain drawings.27 Injury mechanisms including etiology and fracture location are reported. Sensory signs
derived from the DN4 (or ASIA exam) are listed below. Formally, all individuals qualify as having definite neuropathic pain accord-
ing to the NeuPSIG grading system16, while the presence of musculoskeletal pain was not accounted for. Case 3 highlights the dif-
ficulty of disentangling musculoskeletal from neuropathic pain in the acute phase of SCI with DN4-positive pain present in an
area of sensory loss overlying a vertebral burst fracture. Note that only worst pain is captured and the information regarding
pain location was not documented on standardized pain drawings but based on predefined body regions. Therefore, the draw-
ings are not a true reflection of the spatial extent of pain and merely serve illustrative purposes. Moreover, it is not clear whether
at- and below-level pain were present concurrently. Abbreviations: PP, pinprick sensation; LT, light touch sensation;
DMA, dynamic mechanical allodynia.

ectopic discharge in damaged sensory neurons, which
fire in the hours to days following injury.10,13
It is important, however, to recognize that at-level
pain is also developing over time. Previous studies have
demonstrated the prevalence of at-level pain as rela-
tively consistent from acute to chronic time points.29
This ignores, however, that in some patients, early at-
level pain resolves, whereas in others, at-level pain
develops.37 We observed 11 new cases of at-level pain
at chronic time-points (>3 months). These cases may ulti-
mately reflect different underlying processes.
Compared to at-, below-level neuropathic pain was
rarer within the first 5 days of injury (n=4, »5% of total
sample). This estimate is less than half of that reported
at 2 weeks30 and 1-month.37 Such low incidence very
early after injury is consistent with the notion that
below-level neuropathic pain observed at chronic time
points has primarily developed over weeks to months
after injury.35 To this end, progressive and maladaptive
changes in spinal and supraspinal structures, which pre-
sumably take time to develop, may be involved.35 From
a clinical perspective, a delayed mechanism for the
majority of below-level neuropathic pain suggests that
there is a window of opportunity to prevent pain devel-
opment after spinal cord injury. A prophylactic
approach to managing neuropathic pain has been tri-
aled for carbamazepine, yielding temporary evidence of
efficacy (i.e., prevention so long as carbamazepine was
administered).28 New trials aiming to prevent the devel-
opment of neuropathic pain after acute spinal cord
injury have been registered for pregabalin (e.g.,
NCT03748290 on clinicaltrials.gov). Based on our obser-
vations, initiating prophylactic anti-neuropathic treat-
ment within 5 days will markedly increase recruitment
opportunities of participants without below-level neu-
ropathic pain.
While relatively rare (»5%), below-level neuropathic
pain at hyperacute time points is non-trivial. In general,
symptoms in the hyperacute phase of injury (e.g., DN4-
positive pain in the foot of a person with a high thoracic
injury, see Fig 1) conflict with the concept that progres-
sive changes in the CNS are requisite and precede the
development of below-level neuropathic pain.19,42 A
number of factors may contribute to rapid pain onset,
including disruption of ascending and descending path-
ways by the primary injury,1,20,38 ectopic activity arising
from the lesion site,17 and unmasking of silent synapses
at the lesion site as a result of segmental hyperexcitabil-
ity with referral of pain into more caudal spinal
segments.36
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6 The Journal of Pain Hyperacute Neuropathic Pain after Spinal Cord Injury

Figure 3. Symptom Profiles of DN4-positive Hyperacute and Late Presenting Worst Pain. Violin plots (median + IQR) of symptom
intensity derived from the DN4 questionnaire based on timing are displayed. The upper row shows descriptors related to painful
sensations, the lower row those related to paresthesias and dysesthesias. Symptoms were rated on a numerical rating scale (NRS)
from 0 (no sensation) to 10 (most painful imaginable). Non-parametric Mann-Whitney tests were used for group comparisons. Pain-
ful cold sensations (p=0.03) and electrical sensations (p>0.001) were significantly more intense in late presenting neuropathic pain,
while itching sensations (p=0.02) were significantly more intense in acute neuropathic pain. Abbreviation: DN4, Douleur Neuropa-
thique 4 Questions (neuropathic pain screening questionnaire).

Regardless of the biological mechanism and sub-
strates involved, the complexity of neuropathic pain
represents an obvious challenge for effective manage-
ment during the continuum of care for acute SCI indi-
viduals. To this end, the development of a mechanism-
based classification for neuropathic pain has been a top
priority of clinical research.4 At present, classification is
based on location of pain relative to the lesion level.8
Previous studies have not, however, identified different
phenotypes for at- and below-level neuropathic pain.18
This may reflect, on a whole, that at-level pain often-
times shares similar mechanisms to below-level pain. In
contrast, we observed that the timing of neuropathic
pain onset (i.e., hyperacute versus later) yielded a num-
ber of significant differences in phenotype, with late
presenting neuropathic pain exhibiting significantly
higher severities of electrical shock and painful cold sen-
sations compared to hyperacute neuropathic pain. Sig-
nificantly more intense itching sensations were also
observed in hyperacute neuropathic pain. Postoperative
pruritus is one potential explanation for higher rates of
itch.39 However, “intramedullary pruritis"32 has also
been reported for spinal lesions and linked to hemosid-
erin-laden phagocytes fostering ectopic discharge of
adjacent neurons.14 Regardless, timing of onset could
be useful in terms of future development of a mecha-
nism-based classification of spinal cord injury neuro-
pathic pain.
Another important factor with a potential impact on
the sensory phenotype is the pattern of prescribed pain
medications at acute and chronic time points. The signif-
icantly higher number of patients on opioid medication
in the acute phase might contribute to the higher inten-
sity of itching sensations within that cohort. Itching is a
common side-effect of opioid use.26 Moreover, mor-
phine was shown to suppress mechanical and cold
hypersensitivities in animal models of neuropathic
pain.23
The assessment of neuropathic pain in the very early
stages of SCI represents a major diagnostic challenge.
This relates to the complexity of acute SCI care and the
time needed to adequately perform a comprehensive
assessment of neuropathic pain in parallel to the exami-
nation of sensory and motor function to assess the neu-
rological level of injury. In the acute phase, these
assessments need to be arranged between priority clini-
cal care procedures and routine examinations, including
other and arguably more time-sensitive diagnostic tests
(e.g., MRI). Moreover, patients in the acute phase of
injury may be sedated and thus are in varying states of
consciousness. Collectively, these challenges have, in all
likelihood, led to an underestimation of the real inci-
dence of at- and below-level neuropathic pain very early
after injury. One important point to consider is that, due
to the constraints of testing in the acute phase of spinal
cord injury, only “worst pain” was reported. While
 ARTICLE IN PRESS
Rosner et al
examiners focused on detecting neuropathic pain, this
approach means that an individual with both at- and
below-level signs and symptoms would only be included
for whichever was “worse”. A complete picture of neu-
ropathic pain can only satisfactorily be determined if all
potential neuropathic pain locations and severities
were examined with the DN4. In the hyperacute phase
of SCI this may simply never be feasible.
Given the longitudinal nature of our study, tracking
progression also represents a reasonable study objec-
tive. However, it is critical to understand that this was
not the aim of our study, nor can our results be inter-
preted in such a manner. One issue we face is that, com-
pared to previous longitudinal studies, we have a much
lower sample size. Large sample sizes are needed to con-
tend with multiple divisions of neuropathic pain (i.e., at-
and below-level), as well as that only a proportion of
patients ever develop signs and symptoms of neuro-
pathic pain. Beyond this, several considerations need to
be made to track the progression of neuropathic pain
during the transition from acute to chronic injury. Chief
among them is the potential for a rostro-caudal shift in
neurological level.25,41 One potential problem this cre-
ates is that below-level neuropathic pain may transition
to at-level neuropathic pain with an accompanying cau-
dal shift (i.e., recovery of spinal segments) in the neuro-
logical level of injury, without any meaningful change
in sensation. In addition to changes in neurological level
of injury, neuropathic pain could dynamically shift over
time. This will result in cases where neuropathic pain
presents in one location at very early time points,
resolves in this location only to develop in another, dis-
tinct area at follow-up. To account for changes in loca-
tion, one would need to adopt an approach that targets
testing of known and emerging locations of neuro-
pathic pain. To our knowledge, none of the previous
longitudinal studies provide evidence to support that
pain present early after injury is actually the same or
related to that reported in chronic phases.18,29,30,37
Overall, this points to an urgent need for guidelines and
consensus for diagnosing and tracking the progression
of neuropathic pain during the transition from acute to
chronic SCI.
While previous studies have demonstrated the sensi-
tivity and accuracy of the DN4 to measure spinal cord
injury neuropathic pain, even outperforming other
questionnaires,21 ruling out musculoskeletal pain in the
acute phase of SCI is a major challenge. The difficulty
with the DN4 is that, by the nature of injury in the spinal
cord, any pain at- or below-level will, by default, often
score a minimum of 2 (i.e., diminished light touch and
pinprick sensation). This means only 2 other symptoms
or 1 symptom combined with allodynia technically
meets the designation of neuropathic pain. Patient 3
presented in Fig 2 highlights this conundrum. The
reported symptoms fulfil all criteria of below-level neu-
ropathic pain but from a clinical perspective, the pain
may well arise from the vertebral burst fracture.
The Journal of Pain 7
Importantly, examiners in our study were trained in
acute SCI and were specifically applying the DN4 to
identify sources of relevant neuropathic pain. This
meant that areas associated with probable musculoskel-
etal pain, arising from surgery or the spinal injury itself
for example, were avoided. Moreover, injuries with con-
current peripheral nerve damage and severe poly-
trauma, including extremity fractures, were excluded,
thus ruling out a number of other probable sources of
neuropathic pain.
A notable strength of our study is the repeated, daily
assessment for the presence of DN4-positive pain during
the acute phase. In contrast, previous studies have relied
entirely on examinations at a single time
point.9,18,29,30,37 After a traumatic injury to the spinal
cord with subsequent surgical stabilization, musculo-
skeletal and neuropathic pain types most likely co-exist,
at times within overlapping areas (e.g., nociceptive
shoulder pain in an area of neuropathic at-level pain).
Some pains may only be transient in nature, e.g., chang-
ing with body position or responding differentially to
the dosing and tapering of various pain medications.
From a research perspective, identifying a reproducible
(i.e., temporally stable) pain pattern might be more
informative than an exhaustive account of all different
pain types.
Conclusion
Therapeutic studies on neuropathic pain after SCI
have traditionally focused on chronic pain. The present
study reveals that neuropathic pain may be present in
the hyperacute phase of injury, primarily as at-level, but
also below-level neuropathic pain. Pain phenotypes dif-
fer with regard to time since injury, which may mean
there are novel opportunities to intervene in the acute
stages. This study highlights the major challenges of
tracking neuropathic pain after spinal cord injury.
Disclosures
The authors gratefully acknowledge the funding sup-
port of the Praxis Spinal Cord Institute (formerly Rick
Hansen Institute), Michael Smith Foundation for Health
Research, and the VGH & UBC Hospital Foundation. Jan
Rosner is supported by the Clinical Research Priority Pro-
gram of the University of Zurich (CRPP Pain). Marcel
Dvorak is the Paetzold Chair in Spinal Cord Injury
Research. Brian Kwon is the Canada Research Chair in
Spinal Cord Injury and the Dvorak Chair in Spine
Trauma. John Kramer is supported by the International
Foundation for Research in Paraplegia and Wings for
Life.
Conflict of interest
None of the authors reports any conflicts of interest.
 ARTICLE IN PRESS
8 The Journal of Pain
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