Randomized, Double-blinded, Controlled Trial of Early-intervention TENS for the Reduction of the Prevalence and Severity of Chronic Neuropathic Pain During the First Year After Spinal Cord Injury
Phase: NA
Conditions: Spinal Cord Injuries
Sponsor: University of Miami

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RANDOMIZED, DOUBLE-BLINDED, CONTROLLED 
TRIAL OF EARLY-INTERVENTION TENS  
FOR THE REDUCTION OF THE PREVALENCE AND 
SEVERITY OF CHRONIC NEUROPATHIC PAIN 
DURING THE FIRST YEAR AFTER  
SPINAL CORD INJURY 
 
IRB Number: 20160951 
Protocol Version Number: 0.11 
Protocol Version Date: 7/18/2022 
PI Name: Elizabeth Felix, PhD 
NCT Number: NCT03267810 
 
 
 

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1) 
Protocol Title 
Randomized, double-blinded, controlled trial of early-intervention TENS for the reduction of the 
prevalence and severity of chronic neuropathic pain during the first year after spinal cord injury 
(SCI)  
 
2) 
Objectives* 
The primary objectives of our site-specific project are to test a non-invasive, non-pharmacologic, 
inexpensive intervention (i.e., transcutaneous electrical nerve stimulation; TENS) to prevent the 
development and reduce the severity of chronic neuropathic pain in the first year post-spinal cord 
injury (SCI) (Aim 1), and to increase the understanding of the time-course of the development of 
chronic neuropathic pain and the factors that increase the risk for neuropathic pain onset or 
worsening by longitudinally tracking pain symptoms, somatosensory function, and key injury-
related and psychosocial factors during the first 12 months post-SCI (Aim 2).   
Aim 1: Assess the effectiveness of preemptive/early-intervention TENS therapy to decrease the 
risk of developing chronic neuropathic pain, and to reduce the severity of neuropathic pain, 
following SCI. 
Hypothesis 1a: Enhanced somatosensory stimulation using TENS within preserved 
dermatomes at or above the neurological level of injury will reduce the prevalence and 
severity of chronic neuropathic pain at 12 months post-injury when compared with 
neuropathic pain in those who receive Sham TENS. 
Hypothesis 1b: Subjects for whom TENS effectively reduces evoked pain sensations (i.e., 
increased pain thresholds and/or decreased ratings of perceived intensity of noxious 
suprathreshold stimuli) at, and including three levels below, the level of injury after an 8-
week TENS treatment protocol will be less likely to report chronic neuropathic pain 

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symptoms at 12 months post-injury than subjects for whom TENS does not reduce evoked 
pain sensations. 
Aim 2: Evaluate demographic, psychological, and physiological characteristics that are 
potential risk factors for the development and severity of chronic neuropathic pain at 12 months 
post-injury. 
Hypothesis 2a (Demographic predictors): Increased age and Hispanic/Latino background will 
be positively associated with increased presence and severity of chronic neuropathic pain at 
12 months post-injury. 
Hypothesis 2b (Psychological predictors): Greater levels of pain catastrophizing and 
depressive symptoms, and lower levels of resilience measured at baseline will be positively 
associated with increased presence and severity of chronic neuropathic pain at 12 months 
post-injury. 
Hypothesis 2c (Physiological predictors): Sensitivity to evoked pain in the dermatomes at, 
and including the three levels below, the LOI after SCI will be associated with the presence 
and severity of chronic neuropathic pain at 12 months post-injury. 
Completion of the aims outlined above will advance knowledge regarding the potential of a non-
invasive, non-pharmacologic, inexpensive therapy (i.e., TENS) for the prevention or reduction of 
chronic neuropathic pain after SCI, and will lead to a greater understanding of the factors linked 
to chronic pain after SCI. This information has the potential to directly impact individuals with 
SCI by reducing pain and thus improving long-term outcomes and quality of life. 
 
3) 
Background* 
 
In order to orient the reader, a brief introduction to the topic of pain is presented first, along 
with definitions and explanations of some of the terminology used throughout (Box 1).  

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Pain is defined by the International Association for the Study of Pain as “an unpleasant 
sensory and emotional experience associated with actual or potential tissue damage, or described 
in terms of such damage.” 1 Acute pain is time-limited by the inciting injury or disease and 
serves a protective function, while chronic pain is a persistent pain experience that outlasts the 
inciting injury and is thought to have limited biologic utility.2 In some studies “chronic pain” is 
defined as pain persisting for at least three months, and in other studies is defined as pain 
persisting for at least six months. For the purpose of this proposal, we operationally define 
chronic neuropathic pain as neuropathic pain that has persisted for three months or more. 
Pain taxonomies typically differentiate between two main types of pain: nociceptive and 
neuropathic. Nociceptive pain is pain that occurs in the intact nervous system and arises from 
normal activation of nociceptors, while neuropathic pain is defined as pain due to a nerve lesion. 
Neuropathic pain symptoms feature spontaneous pain (pain without stimulation) that is 
frequently described as burning, pricking, or electric-shock-like3 and that occurs in an area 
affected by a lesion of the somatosensory nervous system which results in negative (i.e., 
Box 1: Pain definitions and notes 
• Allodynia: pain due to a stimulus that does not normally provoke pain. Allodynia involves a 
change in the quality of a sensation – the original modality (e.g., tactile, thermal) is normally 
nonpainful, but is now evoking a sensation of pain.  
• Dorsal column-medial lemniscus system (DC-MLS): the major ascending pathway for 
information about innocuous tactile/mechanical and proprioceptive stimulation. Information 
from Aβ fibers (which are activated by vibratory or pressure stimuli) in the periphery travel to 
the dorsal region of the spinal cord and ascend to the brainstem, thalamus, and cortex via the 
DC-MLS.  
• Hyperalgesia: increased pain from a stimulus that normally provokes pain. Hyperalgesia does 
not involve a change in quality of a sensation, but, instead involves a heightened sensation of 
pain from a stimulus that typically evokes a less painful sensation. 
• Neuropathic pain: pain caused by a lesion or disease of the somatosensory nervous system; 
typified by “burning,” and “electric” spontaneous pain, and may include allodynic or 
hyperalgesic responsiveness 
• Nociceptive pain: pain that arises from actual or threatened damage to non-neural tissue and is 
due to the activation of nociceptors 
• Spinothalamic tract (STT): the major ascending pathway for information about pain and 
temperature. Information from Aδ and C fibers (which are activated by noxious stimuli) in the 
periphery travel to an anterior region of the spinal cord and ascend to brainstem, thalamus, and 
cortex via the spinothalamic tract.  

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increased thresholds to tactile or thermal stimuli) and/or positive sensory signs (i.e., allodynia or 
hyperalgesia)4 (See Box 1 for definitions.). In those with traumatic SCI, a lesion of the nervous 
system is present that can affect the spinothalamic tract (STT) and/or the dorsal column-medial 
lemniscus system (DC-MLS). Lesions to the somatosensory system can be investigated using 
quantitative sensory testing, to assess DC-MLS dysfunction (responses to innocuous tactile 
stimuli) and STT dysfunction (responses to thermal or noxious stimuli). It has been suggested 
that a better understanding of the impact of SCI on these pathways and the interactions between 
them may be key to understanding risk factors for neuropathic pain after SCI. 5-8 
Significance of the problem 
Chronic pain is one of the most common and debilitating long-term secondary consequences 
of SCI, 9-12 with approximately 70% of injured individuals reporting persistent neuropathic 
and/or nociceptive pain that can worsen over the months and years after injury.13-16  Chronic pain 
significantly contributes to increased psychological distress and decreased participation in 
rehabilitation programs, social activities, and employment.13, 17-20  
While the mechanisms for many nociceptive pain syndromes are often straight-forward, the 
mechanisms involved in neuropathic pain associated with SCI are less well characterized, at least 
partly contributing to the paucity of effective treatment options for this type of pain.3 Because 
chronic neuropathic pain has been reported to occur in approximately 50% to 75% of 
individuals with SCI,5, 21, 22  is associated with significant impairment in quality of life, 23 and its 
presence and severity typically do not decrease with time or pharmacologic treatment,15, 16, 24-26 
neuropathic pain represents a significant problem that deserves further study in order to provide 
new, more effective interventions.  
Background and rationale 
Early intervention with TENS may help prevent the development of neuropathic pain. 
(Aim 1) 
TENS has been used for the treatment of acute and chronic musculoskeletal pain conditions 
for decades, but evidence supporting its use for treating neuropathic pain is relatively recent.3, 27 
Two types of TENS have traditionally been used: high frequency (typically > 50Hz), low 
intensity (below motor contraction and pain threshold) TENS, and low frequency (< 10Hz), high 
intensity (may produce motor contractions but is below pain threshold) TENS. Both types have 

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been shown to be effective for reducing some types of pain, but the mechanisms by which they 
exert their effects partly differ.28 Evidence suggests that high frequency, low intensity TENS 
works primarily via activation of Aβ fibers, producing an inhibitory effect on nociceptive fiber-
evoked responses within the dorsal column – medial lemniscal system (DC-MLS) (i.e., via “Gate 
control” mechanisms in the spinal cord29), but also via supra-spinal descending inhibitory 
mechanisms. 28, 30 Low frequency, high intensity TENS is often referred to as “acupuncture-like” 
TENS and has been associated primarily with activation of Aδ and C fibers within the 
spinothalamic tract (STT) resulting in supra-spinal descending inhibition of pain,31 including  via 
opioidergic mechanisms.32 (In the proposed trial, we will use both low- and high-frequency 
TENS stimulation within a treatment session to engage these multiple mechanisms of pain 
inhibition.) 
Despite survey studies indicating that the majority of individuals with SCI and pain have 
tried non-pharmacologic interventions, including TENS, 25, 26, 33, 34 few clinical trials have tested 
the effectiveness of TENS for diagnosed neuropathic pain specifically in persons with SCI. 35, 36 
Celik et al. reported significant decreases in neuropathic pain after a 10-day trial of low-
frequency, high intensity TENS in 33 participants36 while a study by Norrbrink did not find 
significant decreases after two weeks of either high frequency, low intensity or low frequency, 
high intensity TENS in 24 people (although 25% of subjects requested to continue TENS 
treatment after the study was concluded).35 The greater effectiveness of TENS in the Celik et al. 
study36 may be related to the fact that subjects were more recently injured (2 to 27 months post-
SCI) than were those in the Norrbrink study35 (average of 6.8 years post-SCI).  
Evidence from trials of TENS as a preventative therapy for pain in other patient populations 
supports the idea that early-intervention may be an effective approach to hinder the potentially 
irreversible changes in the nociceptive system that occur during the first few months after a SCI. 
Several studies have shown that intra- or post-operative TENS can reduce the severity of post-
surgical pain when compared to placebo.37-39 With regards to neuropathic pain, a recent study 
using TENS treatment initiated during acute herpes zoster, suggested that TENS may prevent 
later development of painful post-herpetic neuralgia. 40 Because neuropathic pain associated 
with SCI often does not develop until at least a few months after the injury, 5, 15 there is a window 
of opportunity to prevent the acute hyperactivity of spinal nerves believed to be partially 

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responsible for central sensitization associated with the onset and maintenance of chronic 
neuropathic pain.41, 42  
Animal studies provide evidence for the potential beneficial effects of early-intervention 
TENS: The same neurochemicals that are dysregulated after SCI-induced neuropathic pain can 
be returned to normal levels with TENS treatment. Allodynic and hyperalgesic responses in 
rodent models have been associated with decreased GABAergic43 and serotonergic function,44 
and increased glutamate45 and pro-inflammatory cytokines after SCI.46 Changes in the opposite 
direction in levels of these same nociceptive mediators  have been shown to occur with TENS 
therapy27: TENS has been shown to increase GABA, 47 serotonin, 48 and blood-flow and rate of 
healing after surgical incision,49 and to decrease glutamate in the dorsal horn50 and inflammatory 
cytokines in the area of injury.49 Additionally, in an animal model of neuropathic pain due to 
sciatic nerve injury, TENS delivered soon after injury was able to decrease the incidence of pain-
like behaviors, 47, 51, 52 and to maintain levels of proinflammatory cytokines and opioid receptors 
to those comparable to uninjured animals.52 These findings suggest that TENS can be used to 
decrease the central barrage of injury-induced nociceptive hyperactivity, via peripheral and 
central mechanisms, thus potentially preventing the central sensitization that results in chronic 
neuropathic pain after SCI. 
It has recently been suggested that early, preemptive treatment using gabapentin or selective 
serotonin re-uptake inhibitors should be undertaken in patients with SCI to reduce neuronal 
hyperexcitability and neuropathic pain.5 TENS, however, provides a less expensive, non-invasive 
treatment with a better side-effect profile and fewer contraindications than these pharmacologic 
agents, and a clinical trial of TENS during the pre-chronic phase of SCI is warranted based on 
its ability to mediate endogenous substances linked to spontaneous and evoked activity within 
SCI-affected nociceptive pathways, and to increase activation in brain areas associated with 
descending pain-inhibitory pathways.53  
Demographic, psychological, and physiological factors that may help identify those at risk 
for developing neuropathic pain (Aim 2) 
The investigation of whether particular subgroups of people with SCI are more at-risk for 
developing neuropathic pain can guide resource allocation, and the longitudinal assessment of 

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covariation among psychological, physiological, and pain characteristics after SCI will provide 
needed information with regard to optimal time points for preventive treatment. 
Age, and Race as risk factors for neuropathic pain (Demographic risk factors)  
Increasing age and minority status have generally been found to increase the presence and 
severity of various chronic pain conditions.54, 55 Support for a relationship between older age and 
chronic pain status in those with SCI has also been reported, 56 but whether this age-pain 
relationship differs depending on the type of chronic pain (neuropathic or nociceptive) has 
received little attention. Similarly, differences in pain severity between Whites/Caucasians with 
SCI and non-White patients with SCI have been documented,57, 58 but whether  race influences 
the presence and severity specifically of neuropathic pain after SCI is not clear. Additionally, 
because of imbalanced frequencies of subjects across different racial and ethnic groups, these 
studies have simply compared Whites to non-Whites, pooling all minority groups together as 
though they were one homogenous group. The diversity of the South Florida community allows 
for a relatively more balanced representation of persons with SCI across minority and non-
minority groups (i.e., 37% Black/African American; 34% Hispanic; 53% White, in our previous 
spinal cord injury subject samples). Thus, comparison among minority groups will be possible. 
Indeed, results from our center (see “Preliminary data,” below) suggest greater rates of the 
presence of chronic nociceptive pain in Black/African Americans, and greater rates of the 
presence of chronic neuropathic pain in persons with a Latino or Hispanic background.59  
 
Pain catastrophizing, depressive symptoms, and low resilience as risk factors for 
neuropathic pain (Psychological risk factors): 
Because pain is defined as a “sensory and emotional experience,” 1 it is not surprising that 
psychosocial factors, including pain coping style, depression, and resilience characteristics, have 
been linked to pain intensity and impact.60-67  Some studies have looked at these factors and their 
relationship to pain specifically in persons with SCI,8, 68 but: 1) whether these psychological 
factors predict pain development and severity differentially for neuropathic pain and nociceptive 
pain after SCI; and 2) the covariance of these factors with specific types of pain (neuropathic, 
nociceptive) across time during the first year after SCI have not been well documented in SCI. 
Thus, we will collect assessments of depression, pain catastrophizing, and resilience at baseline 

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to determine their predictive ability for the presence and severity of neuropathic pain at 12 
months post-injury (Hypothesis 2b). In addition, we will also collect these assessments at three 
other time points (approximately 4-6 months and 12 months post-injury), in order to explore the 
time-course of changes in these variables and their interrelationships with pain during the first 
year post-injury. 
STT and DC-MLS dysfunction as risk factors for neuropathic pain (Physiologic risk factors): 
Investigations examining the relationship between the presence of chronic neuropathic pain 
and injury severity (i.e., complete vs. incomplete) 15, 21, 69-71 or radiologic evidence of the extent 
of damage to the spinal cord72 have generally reported negative findings. These investigations 
were unable to link severity or location of the spinal cord lesion to neuropathic pain, suggesting 
that these factors are only marginally related to the presence of neuropathic pain, or that these 
measurement tools are too crude to reveal an association. 
Several studies have used more sensitive quantitative sensory testing (QST) techniques to 
identify the potential contributions of STT and DC-MLS damage to the presence and severity of 
chronic neuropathic pain after SCI.6-8, 69, 73-76 Although results across these studies seem to 
suggest that lower levels of  impairment within the STT are linked to increased severity of 
neuropathic pain,6, 7, 74  the cross-sectional nature of the data does not provide insight with 
regards to whether STT dysfunction is the cause, or result, of chronic neuropathic pain after SCI.  
A few recent studies have approached this question by investigating longitudinal changes in 
somatosensory function and pain after SCI.5, 21, 42, 76  Of these studies, only one has used QST 
techniques to track STT and DC-MLS function across time after SCI in 30 subjects,42 while the 
others utilized less sensitive bedside sensory exams.5, 21, 76 Although details of the results from 
these studies differ, overall findings generally point to early post-injury sensitivity to evoked 
pain (pin prick or cool stimulus) as a predictor for the later development of neuropathic pain,5, 21, 
42, 76 though the QST study additionally reported a relationship between higher thermal detection 
thresholds (i.e., decreased sensitivity to detecting non-painful changes in temperature) and 
development of neuropathic pain.42 
Thus, by undertaking the proposed study, we will substantially advance the ‘state of the art’ 
by evaluating the contribution of STT function and DC-MLS function to neuropathic pain via 

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prospective, longitudinal tracking, using sensitive measurement techniques (QST) in a large 
sample (n = 98) of subjects with SCI. 
Greater knowledge regarding the factors that increase the risk for neuropathic pain after 
SCI will assist with identifying patients to target with early intervention and increased clinical 
monitoring of neuropathic pain. Implementing preemptive strategies, particularly those with 
little or no contraindications and side effects, such as will be examined in the proposed project 
(TENS), will be particularly important for those at risk for chronic neuropathic pain. 
Preliminary data 
Previous work by the PI and Co-investigators supports the feasibility of the project with 
regards to subject recruitment, study personnel training and expertise, and methodologies to be 
used.  
 
Neuropathic pain characteristics and diagnosis in persons with SCI: Evaluation of pain 
characteristics in persons with chronic SCI and pain by investigators in our group has shown 
that: 1) persons with SCI can differentiate between pain types (i.e., nociceptive pain and 
neuropathic pain) that they experience, and that the majority of those with chronic pain report 
having more than one pain (that varies based on location, sensory quality, and/or temporal 
pattern) [Figure 1]; 2) neuropathic pains tend to be more bothersome than non-neuropathic pain 
types (for those who have more than one pain) [Figure 2]; and 3) minority status may be related 
to the prevalence of different pain types [Figure 3]. 
 
(a) Results based on in-person interviews with 194 subjects with chronic traumatic SCI (at least 1 year 
Figure 1: The majority of subjects with traumatic SCI and pain report having at 
least two different chronic pain conditions. 
 
 
 
       (a) 
 
 
 
 
        (b) 

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post-injury) and chronic pain (at least 6 months post duration).77 (b) Results based on phone interviews 
with 50 chronic traumatic SCI patients.59  
 
 
We have recently presented data59 from a phone survey in people with chronic traumatic 
SCI (between 1 and 4 years post-injury) in which we used the International Spinal Cord Injury 
Pain Basic Dataset, version 2.0 (ISCIPBDS2), which was developed by a team headed by Dr. 
Widerström-Noga,78, 79 and the Spinal Cord Injury Pain Inventory (SCIPI80), to identify pains 
that were likely to be neuropathic in nature. Of the 50 subjects interviewed, 41 (82%) reported 
having a persistent pain problem (at least 3 months in duration), and for 30 (60%) respondents, at 
least one of their pains was identified as neuropathic (based on location of the pain at- or below- 
the neurologically-determined level-of-injury and a SCIPI score of ≥ 2). This percentage is 
similar to a recent prospective study in the literature which found 59% of its participants had 
neuropathic pain at one year post-SCI.21  
 
Relationships between Neuropathic pain and somatosensory function (quantitative sensory 
testing; QST)  
Figure 3: Persons with SCI and pain 
identify neuropathic pains as worse than 
non-neuropathic pains. 
Figure 2: Persons with Hispanic/Latino 
background reported more neuropathic 
pains, while Black/African Americans 
reported more nociceptive pains. 
Results from 50 people with chronic SCI (white, 
non-Hispanic = 9; white, Hispanic = 18; black, 
non-Hispanic = 21) who completed a phone 
survey using screening tools for neuropathic 
pain (SCIPI, ISCIPBDS).59 
Data is from 29 subjects with chronic 
traumatic SCI who differentiated at least 2 
pains. Neuropathic pain was more likely to 
be labeled as their worst pain than non-
neuropathic pain (p < 0.05).59 
 

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We have utilized a number of psychophysical techniques to investigate the association 
between both DC-MLS- and STT-mediated function and the severity of chronic Neuropathic 
pain after SCI. We have shown (Table 1) that the test-retest reliability of threshold measures 
across most somatosensory submodalities in subjects  
with SCI is substantial, and comparable, or superior to, the reliability of these measures in 
nondisabled control subjects. Hot and cold pain thresholds are more variable over time, but are 
still significantly related. 
Thus, these measures are 
appropriate for assessing 
changes in sensory function 
across time, as proposed in 
this application. Several 
publications from our 
studies have linked 
heightened evoked pain 
sensitivity at- and below- 
the LOI (as measured with 
QST techniques including 
pain thresholds) and greater 
severity of chronic neuropathic pain symptoms, in participants with chronic SCI.6, 8, 74, Figure 4 
shows that, in test sites in body areas where neuropathic pain symptoms were present, lower pain 
thresholds (i.e., increased pain sensitivity) were associated with more severe neuropathic pain 
scores.  
Thus, previous work by the study investigators demonstrates that the study is feasible and 
that they have the skills and tools necessary to perform the proposed study. Results from this 
body of work support the rationale of the proposed site-specific study.  
 
Table 1: Test-retest reliability for thresholds in persons with SCI 
and NeuP compared to thresholds in nondisabled control subjects 
Modality 
SCI 
 
Nondisabled 
ICC (95% CI) 
# total 
test sites 
 
ICC (95% CI) 
# total 
test sites 
Log MDT 
0.84 (0.75-0.90) 
56 
 
0.63 (0.45-0.76) 
58 
Log VDT 
0.90 (0.84-0.94) 
67 
 
0.86 (0.79-0.91) 
80 
Log CDT 
0.90 (0.83-0.94) 
55 
 
0.68 (0.54-0.78) 
80 
Log WDT 
0.95 (0.91-0.97) 
50 
 
0.70 (0.57-0.80) 
79 
CPT 
0.50 (0.28-0.67) 
56 
 
0.49 (0.31-0.64) 
80 
HPT 
0.50 (0.28-0.66) 
62 
 
0.68 (0.55-0.79) 
79 
MDT = mechanical detection threshold; VDT = vibration detection threshold; CDT 
= cool detection threshold; WDT = warm detection threshold; CPT = cold pain 
threshold; HPT = hot pain threshold 

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4) 
Inclusion and Exclusion Criteria* 
Inclusion criteria:  
• Age ≥ 18;  
• Traumatic spinal cord injury;  
• Date of injury occurring within four months of study enrollment. 
Exclusion criteria:  
• More than four months since date of injury;   
• Contraindications for the study intervention, transcutaneous electrical nerve 
stimulation (TENS),88 including:  
o Implanted electronic device such as a pacemaker; 
o Cardiovascular problems; 
o Pregnancy;  
o Epilepsy;  
o Cancer; 
• Persons with a spinal cord injury at the C2 level, as placement of TENS electrodes on 
the neck is not recommended;  
• Cognitive dysfunction which limits the ability of the participant to adequately 
understand procedures and risks. 
• Prisoners  
NPSI total score
0
20
40
60
80
100
Z-score (re: matched control site)
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
r = 0.58*
Figure 4: Pain threshold is negatively related to severity of NeuP in those with SCI 
Subjects with SCI and NeuP (n = 22) completed 
sensory testing at sites within the area affected 
by NeuP. Thresholds were also obtained in 
control subjects at the same test sites on the 
body and used to calculate z-scores for the 
thresholds obtained in those with SCI. Subjects 
with less loss of pain sensation (z-scores close 
to 0) had significantly higher NPSI scores than 
those with greater loss of pain sensation (higher 
z-scores).74 (Z-scores reflect the degree to 
which thresholds in participants with SCI vary 
from the distribution of thresholds obtained in 
nondisabled control subjects, and allow for 
comparison of measures obtained at different 
locations on the body.)  

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• Pregnant Women 
Special populations:  
• Adults unable to consent: excluded from study 
• Individuals -who are not yet adults: individuals who are less than 18 years old will be 
excluded from the study 
• Pregnant women: Women who are known to be pregnant will not be recruited into the 
study. A pregnancy test will be administered to females prior to enrollment in TENS (or 
sham) treatment. Women who become pregnant before or during the 8-week TENS 
treatment period will be discontinued from the study. Women who become pregnant after 
the 8-week TENS treatment portion of the study will continue to be enrolled, and 
followed according to protocol guidelines (no information will be collected specifically 
on the pregnancy or fetus). 
• Prisoners: excluded from study 
• Neonates: not applicable 
 
 
5) 
Number of Subjects* 
This is a single-site study and 98 potential participants with newly-acquired spinal cord 
injuries will be enrolled. See section 22, for more information. 
 
6) 
Study-Wide Recruitment Methods* 
This is not a multi-center study. See section 21. 
 
7) 
Study Timelines* 
It is anticipated that subjects will be enrolled in the study for 12 months (see Figure 
5, in section 10, below, for procedures timeline). 
It is anticipated that enrollment of subjects will occur between November 1, 2016 
and January 1, 2022. This enrollment end date is 12-months prior to the end of the 
funding cycle for this grant, which will allow for complete follow-up of all subjects 
before study termination. 
The estimated date for the investigators to complete this study is October, 2022.   

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8) 
Study Endpoints* 
The primary study endpoints/outcomes are: 1.) the percentage of subjects who 
develop chronic neuropathic pain at the 12-month post-spinal cord injury time point (as 
defined by a score of ≥2 on the Spinal Cord Injury Pain Inventory (SCIPI), a self-report 
scale of symptoms); and 2.) the severity of chronic neuropathic pain (as measured by a 
self-report rating of neuropathic pain symptoms) measured at the 12-month post-spinal 
cord injury time point. The secondary study endpoints/outcomes include other aspects of 
pain symptoms and physical and emotional function. All outcomes and other variables 
are listed in Table 2 and described in detail below, within the “Procedures Involved” 
section. 
Safety endpoints include frequency and severity of adverse events and increased 
likelihood of developing chronic pain due to TENS treatment. Please see section 13: 
“Provisions to monitor the data to ensure the safety of subjects,” describes the monitoring 
of the safety endpoints. 
 
9) 
Procedures Involved* 
Overview:  
The primary study design will be a randomized, double-blinded, controlled trial of early 
intervention TENS compared to Sham TENS, with longitudinal tracking of signs and symptoms 
of NeuP, as well as symptoms and severity of non-neuropathic pains, pain impact, and  
psychological function, for 12 months post-SCI. Figure 5 diagrams the study procedures, subject 
flow, and assessment time points.  
 
Patients will be eligible for recruitment into the study as soon as they have been admitted 
to the SCI inpatient rehabilitation unit at UM/JMH/Lynn Rehabilitation Center (see Section 21 
for full recruitment procedures). Treatment TENS or Sham TENS sessions (see “Randomization 
procedures,” below) will be initiated within four months post-injury (with four weeks post-injury 
as the target, if feasible).  
 
 

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Figure 5: Timeline of subject participation and study procedures 
  
 
* Note the above diagram depicts the anticipated average time course of study procedures across subjects. Due to varying 
times between injury and admission to/discharge from inpatient SCI rehabilitation, not all subjects will begin participation in 
the study precisely at the two-month post-injury timepoint. 
 
Subjects will be enrolled and randomized regardless of whether they have NeuP symptoms at 
initial assessment. Because approximately 25% of SCI patients who report chronic neuropathic 
pain at 1 year post-injury had initial neuropathic pain symptoms at 1 month post- injury, 21 
initiating treatment at four weeks post-injury will capture approximately 75% of patients before 
their neuropathic pain symptoms manifest. In those patients who do have neuropathic pain 
symptoms at the baseline assessment, we will be able to test the ability of TENS to interfere with 
the transition from acute to chronic neuropathic pain, by comparing the decrease in severity of 
neuropathic pain symptoms from baseline to 12 months post-injury between the two study 
groups (Treatment TENS vs Sham TENS).  
Once baseline assessments are completed, treatment will be administered twice a week, for 
30 minutes each session, for 8 weeks.  
Assessments of primary and secondary outcome measures will occur at the time points 

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diagramed in Figure 5. Details regarding the specific assessment tools and measures to be used 
are described below and listed in Table 2. The primary outcome variables for Aim 1 (Spinal 
Cord Injury Pain Instrument (SCIPI)80 score of ≥ 2, and Neuropathic Pain Symptom Inventory 
score89) will be collected during each scheduled assessment (full and abbreviated assessments), 
with additional outcome measures recorded less frequently (during full assessment sessions only: 
4 times during the study).  
Randomization and blinding procedures:  
A blocked randomization procedure will be used, so that for each eight patients enrolled, four 
will be allocated to TENS and four to Sham TENS. A computer-generated random assignment 
sequence will only be accessible to the study staff member responsible for delivering TENS 
treatments. The PI of the study, the researchers evaluating pain diagnoses, and the research 
subject will not be informed of the treatment allocation assigned. All subjects will be told that 
they may or may not feel the stimulation from the TENS unit during treatment sessions due to 
the parameters of the study. The stimulation parameters of the TENS unit will not be visible to 
the subject, so that subjects will not obviously know to which study group they were 
randomized. 
Treatment procedures: 
(a) TENS device: The TENS 7000 Dual Channel battery-powered digital stimulator (Roscoe 
Medical, Ohio, USA) will be used. This device provides for adjustable frequency/pulse rate, 
pulse width, and amplitude, as well as recording of session data (settings and duration of 
treatment session). The TENS 7000 device has two channels. Each channel will be connected to 
two self-stick square electrodes (thus, a total of 4 electrode pads will be used) with dimensions of 
2 inches by 2 inches. New electrode pads will be used for each treatment session. 
(b) TENS parameters: A combination of high frequency stimulation (postulated to induce 
activity in Aß fibers and related DC-MLS pathways which can block pain via the Gate 
Control)28, 30, 90 and low frequency stimulation (postulated to activate Aδ fibers, and associated 
STT pathways, resulting in supraspinal descending modulation of pain28, 31) will be used. 
Combinations of high and low frequency TENS has been suggested to obtain optimal benefit for 
neuropathic pain.47 Based on Celik et al.36 and Norrbrink et al.,35 who performed TENS in 
persons with chronic SCI and chronic neuropathic pain, we have set the following stimulation 

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parameters for high frequency TENS: 80Hz pulse frequency, 200µsec pulse duration; and for 
low frequency TENS: 4Hz pulse frequency, 200µsec pulse duration. Slight adjustments to 
frequency and pulse duration may be made based on subject preference or new information from 
the literature. Subjects will receive 15 mins of high frequency TENS immediately followed by 
15 mins of low frequency TENS, for a total of 30 minutes of TENS during each treatment 
session. The starting frequency (high or low) will be randomized for the first session, and then 
the order will be alternated with each subsequent session.  
Intensity of stimulation will be set for each subject in the TENS group based on 
individualized perceptual level, so that the amplitude is above perception threshold and just 
below pain threshold, as this dose of stimulation amplitude is often effective and has been 
recommended.91 Amplitude level will be adjusted at the beginning of low frequency TENS 
stimulation and again at the beginning of high frequency TENS for each session based on 
individual sensitivity, to account for potential adaptation effects across sessions. These parameter 
values will be recorded for use as possible covariates in statistical analyses. Each stimulation 
session will last for 30 minutes, as has been previously used for TENS in SCI patients,35, 36 and 
as has been recommended by Bennett et al.91 
(c) Electrode placement: Surface electrodes are typically placed in the area overlapping the 
pain. However, because persons with SCI may have reduced or absent sensory function in these 
areas due to their injury, and, because the goal of the study is to prevent pain (i.e., the majority of 
our subjects will not have developed any area of neuropathic pain when they are initially 
enrolled in the study) we will place electrodes according to neurological level of injury, so that 
the location of all electrodes fall within the dermatome of the level of injury or the dermatome 
just above the level of injury, as described in Norrbrink’s study,35 in order for stimulation to 
occur in a location where normal sensation is present.88 Two electrodes from one channel will be 
placed paraspinally at the level of injury. The other channel’s two electrodes will be placed at 
distal aspects within the same dermatome (at the level of injury) except for subjects who do not 
have appropriate skin locations available (e.g., due to presence of skin lesions/damage, or levels 
of injury with limited accessible skin surface area). Both stimulation channels will be set with the 
same stimulation parameters. If adjustments are needed to positioning of the electrodes outside 
of the prescribed area (at the level of injury or one dermatome above the level of injury), 
consideration of best placement will be discussed among the research and clinical study team on 

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a case-by case basis. 
(d) Sham TENS parameters: Electrode placement for subjects randomized to Sham TENS 
will be based on their level of injury as described above for those in the TENS group. At the 
beginning of each session, the stimulus will be turned up until the subject just reports sensation 
(as with the TENS group), but then will be adjusted down so that no electrical stimulus is 
delivered. 
Data collected / Assessments performed: 
(a) Assessment procedures: Table 2 lists measures that will be collected during full and 
abbreviated assessments, as well as before and after each TENS session. Full assessment 
sessions will occur at three time points: baseline (prior to treatment initiation); termination of the 
8-week treatment protocol; and 12 months post-injury. The full assessment protocol will require 
approximately 180 minutes to complete and may be completed in multiple sessions due to 
participant availability. An abbreviated assessment protocol will be administered at the 4-week 
treatment time point (i.e., halfway through the full series of treatment sessions), and over the 
phone each month after treatment has ended, until the 12-month post-injury time point. The 
abbreviate assessment will require 30 minutes to complete. In addition, numerical ratings of pain 
and the Neuropathic Pain Symptom Inventory89  will be assessed before and immediately after 
each 30-minute TENS session. (It is expected that, for most patients, pain ratings will be “0,” as 
many will not have developed neuropathic pain symptoms in the first few months after injury 
when TENS is being administered. Collection of this information is important in order to insure 
that TENS is not related to any increase in pain symptoms during treatment.) Adverse events/ 
side effects will also be captured at the end of each TENS session. The assessment schedule is 
depicted by the blue and yellow boxes at the bottom of Figure 5.  
 
Table 2: List of assessment tools to be used  
Assessment 
domain 
Assessment 
Full 
assessment 
Abbreviated  
assessment 
Treatment 
sessions 
Pain classification 
   SCIPI, and  ISCIPBDS2 
X 
X 
 
Pain intensity and 
symptoms 
NRS for pain  
X 
X 
X 
ISCIPBDS2 
X 
X 
 

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(b) Assessment tools: Copies of all instruments to be used are uploaded within the eProst UM-IRB 
application for this study.  
i. 
Pain classification:  
• The Spinal Cord Injury Pain Instrument (SCIPI)80 will be used to identify pains that 
are likely to be neuropathic in nature. This four-item questionnaire has shown 
sensitivity and specificity of 78% and 73%, respectively, for diagnosing neuropathic 
pain when using a cutoff score of  ≥ 2 on this scale.80 The pain classification 
definitions and guideline presented within the International SCI Pain Basic Data Set 2 
(ISCIPBDS2) will also be used to assist with classification of pain type. 
This assessment will be used as the primary outcome measure for Aim 1, indicating 
the presence or absence of neuropathic pain at each follow-up time point.    
ii. 
Pain intensity and symptoms: 
Based on differentiated pains, as reported by the study subject, the intensity of each 
pain will be rated using a 0 – 10 numerical rating scale (NRS), with 0 being equal to 
“no pain” and 10 being equivalent to “pain as bad as you can imagine.” Subjects will 
be asked to “Rate your pain by indicating the number that best describes your pain on 
average over the past 24 hours,” “over the past week,” and “over the past 3 months.” 
 
ISCIPEDS [“pain symptoms” subset ] 
X 
 
 
NPSI 
X 
X 
X 
sf-MPQ-2 
X 
 
 
Maladaptive pain 
coping 
PCS 
X 
 
 
Sensory function 
ASIA sensory scores* 
X 
 
 
QST 
X 
 
 
Emotional 
function 
PHQ-9* 
X 
X 
 
SCI-QOL Resilience scale – short form * 
X 
X 
 
  Treatments 
Frequency, dose, effectiveness (from 
ISCIPEDS) 
X 
X 
 
  Adverse events 
Incidence and severity 
 
 
X 
Time required (minutes) 
120 
30 
5 
* measures/assessments that overlap with national database Form I/II 
** assessments that will only be carried out at 12-months post-injury  
 

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This scale, including the phrasing of the anchors and the recall time points, has been 
suggested as a primary  
endpoint for chronic pain clinical trials.92 Changes in pain intensity for neuropathic 
pains will be calculated across the assessment time points to measure the 
effectiveness of TENS treatment for those who present with neuropathic pain at 
baseline [Aim 1], and to assess correlations among pain severity and demographic 
and psychological factors [Aim 2]. 
• We will use the components of the International SCI Pain Basic Data Set, version 2.0 
(ISCIPBDS2),79 to record the presence of pain, the interference of pain on activities 
of daily living, mood, and sleep, locations of pains, intensity of pain, the onset of the 
pain condition, and whether treatments are currently being used for the pain 
condition. The guidelines provided in the ISCIPBDS2 regarding diagnosis of pain 
will be used to classify each pain condition a subject reports. For each research 
subject at each full assessment session (baseline, end of treatment,  and 12 months 
post-injury), two experienced SCI pain researchers (Drs. Felix and Widerström-Noga) 
will evaluate the characteristics of each pain a subject has to make a determination of 
diagnosis. These characteristics will be taken from the ISCIPBDS2 and the 
International SCIPEDS questions and other assessments regarding pain characteristics 
(e.g., location relative to LOI, quality of pain) and sensory testing results (see 
“Quantitative Sensory Testing” section, below). If the two assessors differ with 
regard to diagnosis, review of data and evaluations will be discussed by the assessors 
and consensus will be reached. These pain classifications will be used to compare 
with NeuP classification identified by a SCIPI score of ≥2, and to evaluate 
relationships between different pain types and other variables measured [Aims 2]. 
• We will use selected components from the newly-published International SCI Pain 
Extended Data Set (ISCIPEDS),93 to record temporal characteristics of the pain 
(“How long does your pain usually last?”, and “When during the day is the pain most 
intense?”), as well as treatments the subject is using for pain (“treatments” section of 
the ISCI Pain Extended Data Set). For each treatment the subject can respond with 
regard to whether he/she is currently using the treatment, how often, the dose, and 
adverse effects, and his/her global impression of change94 Responses to the treatment 

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section will be used as a supplemental assessment of pain severity 92[Aim 1]. Lower 
doses of pain treatments suggest lower pain severity, while higher doses suggest a 
greater need for pain relief/ higher pain severity. 
• The Neuropathic Pain Symptom Inventory (NPSI)89 will be used to quantify the 
severity of neuropathic pain-specific characteristics. This questionnaire has been 
validated and used in a number of patient populations with various neuropathic pain 
conditions89, 95-98 including those with SCI.8, 74 A total NPSI score will be calculated 
as an indication of the severity of neuropathic pain.89 This questionnaire should be 
distinguished from the SCIPI, which is also used for neuropathic pain, but is intended 
as a dichotomous diagnostic screening tool for neuropathic pain in SCI, whereas the 
NPSI is intended as an ordinal measure of neuropathic pain severity. For those 
subjects with neuropathic pain symptoms at entry into the study, the NPSI total score 
will be used to determine whether a reduction in neuropathic pain severity is present 
after TENS treatment, and during longitudinal follow-up [Aim 1]. This measure will 
also be used to examine associations between neuropathic pain severity and 
demographic and psychosocial factors [Aim 2]. 
• We will also capture specific information about the presence and severity of different 
qualities of the pain experience for each pain location the subject describes using the 
short-form McGill Pain Questionnaire 2 (SF-MPQ2)99 as secondary outcome 
measures of sensory and affective components of pain. The SF-MPQ2 is a revised 
version of the SF-MPQ100 to include both qualities of pain associated with 
nociceptive pain types and those associated with neuropathic pain types. Desirable 
psychometric properties of the SF-MPQ2 have been documented in a number of pain 
patient populations.99, 101-103 Responses to specific pain qualities will assist with pain 
diagnosis, and total scores and subscale scores of “continuous pain,” “intermittent 
pain,” “neuropathic pain,” and “affective descriptors” will be used in secondary 
analyses of TENS effectiveness [Aim 1] and relationships with other outcomes of 
interest [Aims 2]. 
iii. 
Maladaptive pain coping: 

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• The Pain Catastrophizing Scale (PCS)104 measures the degree to which individuals 
engage in a maladaptive pain coping style that is characterized by exaggerated and 
ruminating negative cognitions and emotions during painful situations. The PCS has 
demonstrated high validity and reliability.105 Measures obtained from the PCS will be 
used to prospectively track its potential as a pre-disposing factor for the development 
of chronic pain after SCI [Aim 2]. 
iv. 
Sensory function: 
• Quantitative sensory testing (QST) techniques will be used as reliable and sensitive 
measures of STT and SC-MLS function74, 106, 107 in areas above, at, and below the 
neurological level of injury using a TSA-II device (Medoc, Ltd). Measures of 
vibratory, warm, and cool detection thresholds, hot and cold pain thresholds, and 
temporal summation of thermal pain will be recorded during full assessment sessions. 
The longitudinal tracking of these measures will allow for the assessment of: 1) 
whether use of TENS early after injury that alters STT and/or DC-MLS function is 
related to the effectiveness of TENS on measures of chronic neuropathic pain at 12 
months post-injury [Aim1];and  2) the predictability of chronic neuropathic pain 
based on specific somatosensory sensitivity measures (i.e., thresholds to innocuous 
tactile and thermal stimuli; thresholds to noxious stimuli; pain ratings for 
suprathreshold pain stimuli) [Aim 2]. These measures and device (TSA-II) have been 
previously used by our group to investigate associations between sensory function 
and chronic pain across cohorts of subjects with chronic SCI7,8, 74, , 108 and have been 
used in many other chronic pain populations to examine mechanisms, diagnoses, and 
relationship to analgesic response.109-111  
• A neurological examination utilizing the International Standards for Neurological 
Classification of Spinal Cord Injury112 will be obtained from the medical record if 
available. The sensory/motor scores for each dermatome/myotome will be recorded, 
as well as the neurological level of injury and American Spinal Injury Association 
Impairment Scale. These variables will be used as bedside assessments of sensory 
function for comparison with QST measures and for their potential predictive ability 
for the later development of chronic neuropathic pain [Aim 2].  

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v. 
Emotional function: 
• The Patient Health Questionnaire 9 (PHQ-9)113 will be used to assess depression 
symptom severity. It is a 9-item questionnaire based on the Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition, Revised (DSM-IVR)114 criteria for major 
depression and that has been validated across a number of patient populations,113, 115 
including SCI.116  
• The SCI –QOL Resilience scale has been developed and calibrated specifically for 
those with SCIs 117 and is included in follow-up interviews for the SCIMS national 
database. This measure will be used for the assessment of resilience as a potential 
mediating factor for the development and trajectory of pain following SCI [Aim 2]. 
vi. 
Medications: 
• While it is not feasible to restrict medication usage throughout the participant’s 
enrollment in a longitudinal study, recording of medications at baseline and changes 
in medications and dosages across time will be recorded at each study time point as 
suggested for pain clinical trials.118 Use of medications traditionally prescribed for 
analgesic purposes will serve as a secondary outcome measure for the presence and 
severity of pain92 [Aim 1]. 
vii. 
Adverse events: 
• Information regarding side effects/ adverse events that are temporally related to the 
treatment protocol will be collected from all participants. A questionnaire will be 
administered after all treatment sessions to prompt subjects to report new or increased 
symptoms and discomfort experienced during the TENS stimulation period. If the 
subject reports any symptoms, he/she will be asked to indicate the duration of the 
symptom, the severity, and the associated distress.92 These records will be used to 
address any potential safety concerns and compare the frequency and severity of 
events across Treatment TENS and Sham TENS groups. 
 
10) Data and Specimen Banking* 
No specimens will be collected in this study. Data that is collected on paper will be stored 
securely in a locked cabinet in a locked office that is accessible only to study staff as described in 

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section 26: Confidentiality. Electronic data will be collected and stored on a secure server within 
the University of Miami network, with access limited only to those personnel listed on the IRB 
application for this study. 
 
11) Data Management* 
Power / sample size:  
Based on a total sample size of 98 subjects, and an estimated 15% drop-out rate, we expect 
that approximately 82 subjects will complete the study (i.e., 41 subjects per treatment arm). 
Based on previous work,21, 59  we project that 60% of subjects in the Sham TENS (control) group 
will have at- or below-level neuropathic pain at the 12 month follow-up time point. Thus, with 
41 subjects in each group, α = 0.05, power of at least 80%, and an analysis based on a two-sided 
Z-test (for group difference in proportion of subjects with neuropathic pain) for Hypothesis 1a, 
we will be able to detect at least a 50% reduction in the rate of subjects with chronic neuropathic 
pain in the TENS treatment group compared to the Sham group at 12 months post-SCI (i.e., 
Sham TENS = 60% with neuropathic pain; Treatment TENS = 30% neuropathic pain).  
For t-test analyses assessing differences between groups (Sham vs. Treatment) using 
continuous variables (e.g.,NRS, NPSI), 41 subjects in each group will allow for detection of a 
medium-to-large effect size (i.e., Cohen’s d = 0.6) with α set at 0.05 and power of 0.80.  Paired 
correlations will also be used for additional analyses (Aim 2). For correlations within group (n = 
41), with power set at 0.80 and α = 0.05, we will be able to detect a medium-to-large effect size 
(i.e., Cohen’s f2 = 0.20), and we will be able to detect a small-to-medium effect size for across-
group analyses (n = 82; Cohen’s f2 = 0.10). 
 
Data analysis plan: 
Descriptive evaluations of the data will be performed for all variables to check the integrity 
of the data and to verify the underlying assumptions of the statistical tests that are planned. If 
necessary, and as appropriate, data will be transformed prior to any parametric analyses, or non-
parametric techniques will be used with untransformed data. Statistical analyses will use two-
tailed tests and an a-priori α of 0.05.  
In addition to direct tests of hypotheses (described in detail below), descriptive analyses and 
graphical representations (e.g., spaghetti plots) of data will be used to describe longitudinal 

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characteristics of clinical pain, somatosensory function, and other physical and psychological 
outcomes across the 12-month timeline of study participation.  
Hypothesis 1a: 
The primary statistical analysis, to test the effectiveness of prophylactic TENS for 
neuropathic pain after SCI will be via a two-proportion z test, comparing the percentage of 
subjects in the TENS treatment group who are “positive” for neuropathic pain at 12 months post-
injury to the percentage of subjects in the Sham TENS group who are positive for neuropathic 
pain at 12 months post-injury. Subjects who score a 2 or more on the SCIPI for a pain located at 
or below their neurological level of injury at the 12 month follow-up time point will be 
considered positive for neuropathic pain. Subjects who do not have a pain at- or-below the level 
of injury or a score of 2 or more on the SCIPI will be considered negative for neuropathic pain. 
For those subjects who have neuropathic pain symptoms early after injury (i.e., prior to entering 
the study), a “positive” result for neuropathic pain will be defined as having neuropathic pain 
that is moderate or greater (rated at least a 4 out of 10) at the 12 month follow-up assessment.  
Additional analyses will be conducted using secondary outcomes collected at the 12-month 
time point: 1) comparison of pain severity (using the NRS and NPSI scores) between the groups 
(This analysis will be especially important if the primary analysis does not show a difference in 
rates of the presence of neuropathic pain at 12 months.); 2) comparison of use of analgesics 
between groups; and 3) comparison of response to pain interference questions from the 
ISCIPBDS2. General linear model analyses will be used, with TENS group (Treatment vs. 
Sham) as a categorical predictor of these secondary outcome measures. 
Separate analyses for at-level neuropathic pain and below-level neuropathic pain, as well as 
nociceptive pains, will also be conducted to examine whether TENS differentially impacts their 
development or severity. Additional analyses will be conducted, using the diagnosis of each pain 
type according to ISCIPBDS guidelines, as determined and agreed upon by our study staff pain 
experts, as a confirmation of the primary neuropathic pain metric (SCIPI ≥ 2). 
Hypothesis 1b: 
To investigate factors that may be related to patient responsiveness to TENS as a preventive 
treatment for chronic neuropathic pain, we will assess correlations between changes in evoked 
pain (before and after TENS treatments) and the presence and severity of neuropathic pain 

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symptoms at the 12 month post-injury time point. It is anticipated that those who show reduced 
sensitivity to noxious stimuli after TENS treatments will exhibit a lower risk for chronic 
neuropathic pain. A repeated measures regression analysis, including appropriate covariates 
(e.g., demographic and injury-related factors, concomitant treatments, amplitude setting of TENS 
treatments ), will assess whether changes in evoked pain sensitivity will be a significant predictor 
of neuropathic pain at 12 months post-injury in the TENS treatment group. 
Hypotheses 2a, 2b, and 2c: 
Chi square analyses, t-tests, and correlations across all subjects (with TENS group 
assignment as a covariate) will be used to separately examine whether demographic variables 
(age and minority status), psychological characteristics (pain catastrophizing, depressive 
symptoms severity, and levels of resilience), and measures of evoked pain sensitivity (pain 
thresholds and ratings of suprathreshold noxious stimuli) measured at baseline can predict the 
presence and severity of chronic neuropathic pain at 12 months post-SCI. Separate sub-analyses 
will also be conducted with regard to the impact of these factors on pains with different 
diagnostic categories (nociceptive pain, neuropathic pain).  
 
Data security / Quality control: 
All research personnel will complete and maintain trainings regarding privacy and data 
security as required. All personnel will receive training regarding all study procedures as 
required for their role, as assigned and overseen by the PI, to insure data quality and integrity of 
the science.  
Data for the study will be recorded on paper, using the most-updated and approved study 
forms. These paper documents will be stored in locked file cabinets in rooms 3.156 and 3.153B 
of the Christine E. Lynn Rehabilitation  Center (1611 NW 12th Ave., Miami, FL 33136). This 
room is locked and is accessible only by those who have been given card access. These paper 
documents will be stored for at least 3 years after the final termination of the grant. 
Data from the paper documents will be entered into a password protected electronic database 
that will receive periodic and thorough data quality checks through established procedures. This 

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electronic file will not contain any personally-identifiable information, and will be maintained 
for at least 3 years after the final termination of the grant.  
The PI will assign access to rooms, filing cabinets, and electronic files as necessary for 
completion of the study.  
As this is a single site study, all data will remain on the University of Miami medical school 
campus, with access under the control of the PI. 
 
12) Provisions to Monitor the Data to Ensure the Safety of Subjects* 
Safety endpoints include frequency and severity of adverse events and increased 
likelihood of developing chronic pain due to TENS treatment. It is anticipated that only 
infrequent and mild adverse events (e.g., temporary skin irritation from surface electrode 
adhesive, brief mild pain during initial adjustment of TENS stimulation amplitude) will 
occur. These events will be handled on an individual basis and may be cause for the PI to 
discontinue participation of a subject who may be especially sensitive to the study 
treatment. If these mild adverse events are recorded at higher than expected frequency 
(i.e., greater than 10% of treatment sessions) or if an unexpected or moderate-severe 
adverse event occurs, the PI will re-evaluate the treatment parameters and adjust 
accordingly. All events will be reported to the IRB according to regulations.  
Preliminary analyses will be performed after each group of 20 subjects completes 
the study to determine the efficacy of the treatment by comparing the primary endpoints 
between the two study groups (TENS and sham TENS). More frequent analyses will be 
performed if warranted. If these preliminary analyses at any point provide overwhelming 
support that the experimental intervention (TENS) reduces the development of chronic 
neuropathic pain or has a substantial clinically meaningful reduction in the severity of 
chronic neuropathic pain present, then the PI will pursue a change in protocol to provide 
the active TENS treatment to all available participants. Conversely, if the preliminary 
analyses reveal that the active TENS treatment puts patients at higher risk for pain or 
other undesirable outcomes, the PI will seek to terminate the intervention, but continue 
follow-up on enrolled participants.  
 

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13) Withdrawal of Subjects* 
Subjects will be withdrawn from the research without their consent if the PI or other 
study staff, including trained clinicians, determine that the subject may experience 
adverse events of greater than mild severity and of greater than 10% frequency. If the 
TENS stimulation is not tolerated after adjustment of electrode location and/or after 
reduction of stimulus amplitude, then the subject will be withdrawn from the study and 
will receive no further treatments.  
Participants who either self-withdraw from treatment or who are withdrawn by the PI 
or study staff from the treatment portion of the study, will continue to be followed during 
all time points after the treatment sessions have terminated, unless the participant does 
not want to participate in follow-up session for the study.  
 
14) Risks to Subjects* 
TENS therapy poses minimal risks to patients, as outlined below.  
a. Skin irritation:  Persons undergoing TENS treatment may experience minor 
skin irritation as a result of the electrode placement.  
b. Painful or unpleasant sensory sensations: TENS may evoke painful or 
unpleasant sensations for a brief period of time while the appropriate intensity 
level is being determined.  
c. Emotional upset: Persons with disability may become upset at having questions 
asked about their disability and the pain conditions associated with their SCI.  
Use of the TSA-II device also poses risks: 
d. Thermal pain testing can result in sensations that are unpleasant and which may 
lead to short-lived, mild-to-moderate anxiety and discomfort. Temporary mild 
redness around the area tested may occur but will be short-lasting. 
To minimize the specific risks outlined above, the following procedures will be in 
place: 
a. Electrode skin irritation can be reduced by cleaning the skin before electrode 
placement. The risk of this occurring is low. Electrodes will not be placed near 

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open wounds. The treatment and control groups will be monitored by the research 
staff continually throughout each treatment session. 
b. The research assistant or other research staff responsible for delivering the 
TENS treatments will be present during the entire 30 minute treatment session so 
that if discomfort occurs,  the stimulus level can easily be reduced or  the TENS 
electrodes can be removed, and summon one of the study physicians if evaluation 
is needed.  
c. During questionnaires, participants will be reminded that they can refuse to 
answer any questions that they feel are emotionally upsetting. If a participant 
indicates that he or she has suicidal ideations, the psychologist will be notified 
immediately. The risk frequency is low and the severity of mild to moderate, 
although all of the subjects will have already consented to participate in data 
collection from the SCIMS, and therefore would have already answered similar 
questions. 
d. The PI will be responsible for administering testing using the TSA-II and for 
training any other study staff who will perform assessments with this device. She 
has 17 years of experience with the equipment that will be utilized in the proposed 
study (TSA-II; Medoc, Ltd.), including 12 years of experience using the 
equipment to test individuals with spinal cord injuries. The TSA-II has cut-off 
temperature values (0ºC, 50ºC) that are built-in limitations of the equipment. This 
prevents the machine from delivering stimuli that could potentially cause tissue 
damage. The short duration of stimulus presentations in this study (up to a 
maximum of 5 seconds per trial) will also limit any lasting effects of noxious 
stimulation. Temperatures in the ranges to be presented in the proposed study 
have been used by our laboratory for several years, including in individuals with 
spinal cord injury, with no adverse events other than nonpainful slight reddening 
of the skin that lasted for approximately 60 minutes. In addition, any severe 
anxiety or discomfort reported by the subject will be grounds for termination of 
the study session. 
 

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15) Potential Benefits to Subjects* 
The primary benefit of this interventional study is the potential reduction or 
elimination of chronic neuropathic pain in subjects randomized to the TENS treatment 
arm. There is no anticipated benefit for subjects randomized to the sham TENS arm. In 
addition, no direct benefit can be promised to those in the TENS treatment group, as this 
is an experimental intervention for prevention of neuropathic pain in this patient group. 
 
16) Vulnerable Populations* 
No vulnerable populations will be recruited or enrolled in the study. 
 
 
17) Sharing of Results with Subjects* 
Results of the study assessments will not be routinely disclosed to research subjects. 
However, study staff will discuss results with those subjects who specifically ask for information 
from their assessments.  
For those subjects who screen positive for mild or moderate depressive symptoms (scores 
between 5 and 14 on the PHQ-9 assessment), study staff will provide them with this information 
and give them contact information to make an appointment with a psychologist at UM or JMH. In 
addition, for those subjects who score greater than moderate depression or who endorse the 
question “Thoughts that you would be better off dead or hurting yourself in some way,” the PI 
will contact the SCI psychologist on duty, or another staff psychologist, to discuss results and 
request immediate clinical follow-up.  
 
18) Setting 
• Activities related to recruitment and access to medical records may occur at the 
Jackson Rehabilitation Hospital/Lynn Rehabilitation Center, during the 
participant’s inpatient rehabilitation stay.  
• 
Data collection (quantitative sensory testing and questionnaire completion) and 
TENS intervention sessions will occur within the Department of Physical Medicine & 
Rehabilitation  at the Lynn Rehabilitation Center (rooms 3.153a, 3.153b, 3.154, 
3.155, or 3.156)). 

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• Due to the frequency of TENS sessions (twice per week) during the treatment 
period, some of these sessions may take place in the participant’s home. If 
necessary to promote compliance, the research staff member will travel to the 
participant’s place of residence to administer TENS, if the participant approves of 
this arrangement. 
• 
 Data storage, administrative, and data analysis activities will occur in the offices 
of the PI, collaborators, and study staff within the Department of Physical Medicine 
& Rehabilitation at the Lynn Rehabilitation Center (rooms 3.153a, 3.153b, 3.154, 
3.155, or 3.156). 
 
19) Resources Available 
 
The training and experience of our core project faculty and staff, as well as other key 
personnel involved in the research project, are appropriate for the oversight and performance of 
the study, as described below: 
Elizabeth R. Felix, Ph.D., PI; Research Assistant Professor, Department of PM&R, University of 
Miami:  
Dr. Felix holds joint appointments as Research Associate Professor within the 
Department of PM&R at the UMMSM and as Research Health Scientist within the Miami VA 
Healthcare System, and has researched pain in human subjects for almost 20 years, with an 
emphasis on pain in spinal cord injury patients for the past 16 years. She has investigated the 
potential somatosensory system mechanisms associated with chronic neuropathic pain after 
spinal cord injury (using the devices (TSA-II sensory analyser, and TENS devices) proposed for 
the current study); the psychometric properties of measurement questionnaires and scales for 
chronic pain; and the potential predictors of the development and severity of chronic pain after 
spinal cord injury, including the contributions of various psychosocial factors and injury 
characteristics. She has recent experience as PI of funded studies on pain in spinal cord injury, 
including one clinical intervention trial. Dr. Felix will provide oversight of all aspects of the 
study. 
 
Other co-investigators are included on the project that fulfill several roles: clinical experts 
in SCI and in pain management, and research experts in SCI and in pain measurement and 

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assessment. The study staff also includes a research coordinator, study nurse, and other research 
assistants. All staff that will participate in conducting the study, including recruitment, data 
collection, data review, etc., and their associated duties, are listed within the IRB application in 
eProst. Regularly-scheduled meetings will be held with all study staff in order to insure that all 
are up-to-date on study procedures, training, and oversight efforts. 
 
Financial resources for this work, including study staff effort, device procurement, 
subject payments, and miscellaneous supplies are provided for as appropriate via grant funding 
obtained by the PI. 
 
20) Prior Approvals 
In addition to UM IRB approval, review by Jackson Memorial Hospital will be obtained prior to 
commencing the study. 
 
21) Recruitment Methods 
Potential participants for this study will be recruited through the JMH inpatient SCI 
rehabilitation services. All subjects who are at least 18 years of age and who are admitted to the 
Jackson Rehabilitation Hospital/Lynn Rehabilitation Center with a traumatic spinal cord injury 
will be assessed for eligibility. Using the inclusion and exclusion criteria provided above, the 
inpatient SCI rehabilitation physician (Dr. Kevin Dalal) will access Jackson electronic medical 
record information for this purpose.  If the patient meets criteria, the study physician will 
approach the patient and ask if he/she would agree to have a study team member talk to them 
about the study for possible enrollment. 
All those who agree will be approached in person or over the phone by a research staff 
member for possible enrollment within 4 months of their injury. Patients who express interest in 
the study will be informed in detail of the procedures and timeline of the study. The research 
staff member will then review the informed consent document with the participant, including 
potential risks and benefits of the study, and assurance that their refusal to be a part of the study, 
or to withdraw from the study, will not influence their clinical services at UM/JMH. Any 
questions the patient has will be answered by the study staff member or referred to the PI and/or 
study physicians for further discussion with the patient.  (See section #27 for full consenting 
procedures.) 

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Cash and check payments will be made to subjects based on completion of each treatment 
and assessment portion of the study: 1) $25 will be paid for each treatment session attended; 2) 
$150 will be paid for each full assessment session completed (partial payment, in the amount of 
$75, may be paid if the participant completes only the questionnaire portion of this visit, but does 
not complete the sensory assessment portion); 3) $25 will be paid for each brief assessment 
session completed; and 4) a $50 bonus will be conferred at the end of the study for subjects who 
complete 90% or more of study treatments, visits, and phone assessments. Up to a total of $1075 
at completion of the study is available for each subject. Cash payments will be given to the 
subject immediately after each treatment session and in-person assessment session. Check 
payments may be made via mail for phone assessment if payment in person is not feasible. 
 
22) Local Number of Subjects 
We anticipate that, over the 5 year recruitment period (Jan 2017 – January 2022), 
approximately 175 patients with new traumatic spinal cord injuries admitted to Jackson 
Rehabilitation Hospital/Lynn Rehabilitation Center will be eligible for the study. Of these, we 
estimate that approximately 98 subjects will consent to enter the study. We will not enroll more 
than 98 subjects without prior approval by the IRB.  
 
23) Confidentiality 
This is a single-site study. All investigators and study staff involved in this study will protect 
the participant’s personal and medical information by removing his or her name and other 
identifiable information (e.g., birth date, address) from any forms where it is not necessary. A 
study identification number will be assigned to the study subject’s records and his or her name 
and other personal information will only be accessed when necessary for follow-up contact. All 
study forms will be secured in a locked file cabinet in a locked room that is accessible only to 
research staff members (Lynn Rehabilitation Center (rooms 3.153b and 3.156)). Any information 
related to this study that will be saved on electronic files will be password protected so that only 
certified study staff members can access these files.  
No specimens will be collected in this study.  

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24) Provisions to Protect the Privacy Interests of Subjects 
For recruitment purposes, the study team physician(s) will access information from medical 
records to assess eligibility for the study. These source documents will not be retained – the 
information confirming inclusion and exclusion criteria will be noted in the study 
records/documents. 
After documented consent is obtained, and HIPAA form is signed, appropriate study staff, as 
appointed by the PI, will be permitted access to medical records to re-confirm eligibility.  
During the initial consenting procedures, subjects will be ensured that they do not have to 
fully complete all questions, if they are not comfortable answering, and may still participate in 
the study. Subjects will be reminded of this throughout assessment sessions as needed. Research 
staff will make every effort to provide a friendly atmosphere and assurances of privacy and 
confidentiality in any way possible. Paper documents for data collection will only include 
assigned subject ID numbers, that cannot be easily linked to subject identity. A password-
protected log of subject ID numbers associated with subject identity and contact information will 
be maintained only until all activities of the study are completed. 
All study-related interviews or completion of questionnaires and assessments will be 
conducted in private areas where others will not be able to see or hear participant responses, and 
study staff will not discuss personal information with other study staff members unless they are 
in a private location where others cannot hear. Patients’ study-related information will not be 
discussed or disclosed to anyone that is not a part of the research study unless indicated by law.  
 
25) Compensation for Research-Related Injury 
Injury due to research participation is not expected. Funds are not available for research-
related injury and would need to be covered by the patient or the patient’s insurance.  
 
26) Economic Burden to Subjects 
We anticipate minimal, if any, expenses to be incurred by the subject. Only the time 
that will be required for coming in for treatment and assessment sessions may produce an 
economic burden to subjects, if it requires that they take unpaid leave from work to 
participate. The research grant under which this study is funded includes a budget amount 

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for subject payment (as outlined above), and for transportation costs which will include 
public, private, and parking expenses as needed. 
 
27) Consent Process 
 Patients who express interest in the study will be informed in detail of the procedures 
and timeline of the study, and study payments for time, as well as coverage of travel 
expenses for necessary study visits. If the patient is interested in the study, he/she will 
undergo the full consent process. Consent will occur in private office or lab space 
associated with the study at UM. We will follow HRP-090 with regard to UM SOP for 
the informed consent process. 
There will not be a required waiting period instituted between informing the potential subject 
and obtaining written consent, but, if the subject requests, he/she will be given a copy of the 
consent form for consideration and re-approached at another time to assess his/her desire to 
participate. 
The research staff member will review the informed consent document with the 
participant, including potential risks and benefits of the study, and assurance that their 
refusal to be a part of the study, or to withdraw from the study, will not influence their 
clinical services at UM/JMH. Any questions the patient has will be answered by the study 
staff member or referred to the PI for further discussion with the patient. 
Non-English Speaking Subjects 
At the present time, only those comfortable communicating in English will be 
enrolled in the study, due to the fact that many of the evaluation questionnaires are only 
available in English or have not been validated for use in non-English speaking persons. 
Based on our previous studies, we anticipate this only affecting a very small proportion 
of the potential eligible patients. 
 
28) Process to Document Consent in Writing 
The subject’s consent to participate in this research study will be documented in 
writing according to standard UM IRB SOP (HRP-091).  

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29) Drugs or Devices 
The study will make use of two devices, neither of which is an investigational device: 
1. TENS 7000 (Roscoe Medical; Ohio). This device is a commercially available device 
used to deliver transcutaneous electrical nerve stimulation via surface electrodes for 
the relief of pain. It will be used in accordance with its approved labeling. Based on 
the FDA 510(k) for this device, the TENS 7000 is “intended for use for (1) 
Symptomatic relief and management of chronic (long term) intractable pain and (2) 
adjunctive treatment in the management of post surgical and post traumatic pain 
problems.” 
 
This research is not intended to be reported to the FDA in support of a new 
indication and there is no intent to use it to support any other significant change in the 
labeling of the device. 
 
This research is not intended to support a change in the advertising for the device.  
 
This research does not involve a route of administration, dose, or other factor that 
significantly increases the risk associated with use of the device.  
 
Storage of the devices and the self-stick electrodes will be in the offices of the 
research staff (Lynn Rehabilitation Center (rooms 3.153b, 3.154, or 3.156), 1611 NW 
12th Ave., Miami, FL 33136. ) when not being used for study subject treatment 
sessions. These rooms are secured with key cards and have filing cabinets with key 
locks in which the devices and associated supplies will be kept. When they are 
removed for use during treatment sessions, they will be in the possession of research 
study staff. All such devices will be labeled with ownership information, including PI 
name, research coordinator name, and contact information. 
2. Thermo-Sensory Analyzer II (TSA-II; Medoc Ltd.; Israel). This device will be used 
for the longitudinal assessment of tactile and thermal sensory and pain thresholds. 
This device is not being tested as an intervention, nor for the purpose of altering 
labeling or advertising of the device. It is being used as an assessment tool only, and 
in accordance with all labeling by the manufacturer (Medoc Ltd.). The TSA-II has 
been used in our lab in multiple studies, and by other labs around the world, for 
research in human subjects. For the current study, we will use the vibration and 

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thermal testing apparatus to quantitatively assess tactile, thermal, and pain thresholds 
in subjects during the full assessment sessions (4 times during the 12-month 
enrollment). The TSA-II is a precise, computer-controlled device which delivers 
calibrated thermal stimuli as programmed through the associated software. The 
device and laptop used to run the equipment are mounted to a mobile cart for easy 
transport to any location. The TSA-II has been used extensively in human subjects’ 
research, including studies in spinal cord injury patient populations, and the PI has 
over ten years previous experience using this equipment for the evaluation of 
somatosensory function in patient groups and control subjects. 
 
Storage of the TSA-II will be in the offices of the research staff (Lynn 
Rehabilitation Center (rooms 3.153b, 3.154, or 3.156), 1611 NW 12th Ave., Miami, 
FL 33136). These rooms are secured with key cards that are only accessible to 
research staff, under the supervision of the PI. Access to controlling the device is 
obtained via the laptop/software program which requires a password to access. The 
device will be labeled with ownership information, including PI name, research 
coordinator name, and contact information.  

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