The Journal of Pain, Vol 13, No 12 (December), 2012: pp 1206-1214

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

Effects of Nicotine on Spinal Cord Injury Pain Vary Among

Subtypes of Pain and Smoking Status: Results From a Randomized,
Controlled Experiment

Elizabeth J. Richardson,* Timothy J. Ness,y David T. Redden,z Christopher C. Stewart,x

and J. Scott Richards*
Departments of *Physical Medicine and Rehabilitation, yAnesthesiology, and zBiostatistics, University of Alabama at
Birmingham, Birmingham, Alabama.
x
Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Abstract: Smoking has been associated with increased pain severity in general chronic pain popu-
lations. Less is known about the effects of smoking and nicotine on the multifaceted and often com-
plex subtypes of pain that frequently occur following spinal cord injury (SCI). The purpose of this
study was to examine the effects of nicotine on self-reported pain among individuals with SCI and
to determine if the effect of nicotine varied by pain subtype. A randomized, placebo-controlled cross-
over design was used to determine the effect of nicotine exposure on subtypes of SCI-related pain
among smokers and nonsmokers. A complex relationship emerged, such that the degree of reported
pain with exposure to 2 mg of nicotine compared to placebo varied according to pain type and
smoking status of the subject. Pain sites that had characteristics of both neuropathic and musculo-
skeletal symptoms (deemed complex neuropathic pain sites) exhibited pain reduction after nicotine
exposure in nonsmokers. In sharp contrast, smokers with this form of pain exhibited an increase in
pain severity. Data were also examined descriptively to determine potentially unique factors associ-
ated with complex neuropathic pain that may explain trends associated with clinically relevant
changes following nicotine exposure. In sum, smoking or tobacco use history may determine the
analgesic (or enhanced pain perception) effect of nicotine on post-SCI pain.
Perspective: Pain characterized by both neuropathic and musculoskeletal symptoms decreased in
severity after nicotine exposure in nonsmokers with SCI but increased in severity among smokers
with SCI. The analgesic (or enhanced nociceptive) effect of nicotine may depend on tobacco use history.
ª 2012 by the American Pain Society
Key words: Pain severity, nicotine, spinal cord injury, smoking, neuropathic pain.

P
ersistent pain is a frequent secondary complication
following spinal cord injury (SCI), with approxi-
mately 70% of persons with SCI reporting some
form of pain.7 SCI-related pain has been shown to
interfere with a variety of activities and domains of
functioning11,20,55,59,67 and is consistently associated
with lower quality of life postinjury.39,47,53
Complicating this problem is that pain following SCI is
Received May 8, 2012; Revised August 24, 2012; Accepted September 17,
2012.
This study was funded by the National Institute on Disability and Rehabil-
itation (NIDRR) grant H133N060021.
There are no conflicts of interests associated with any of the authors.
Address reprint requests to Elizabeth J. Richardson, UAB Department of
Physical Medicine & Rehabilitation, SRC 530, 619 19th Street South, Bir-
mingham, AL 35249-7330. E-mail: ejrichar@uab.edu
1526-5900/$36.00
ª 2012 by the American Pain Society
http://dx.doi.org/10.1016/j.jpain.2012.09.005
not a unitary phenomenon. There are in fact several
subtypes of pain, each with different purported
mechanisms and therefore requiring different
interventions. While numerous schemes for classifying
the subtypes of SCI pain have been proposed,29 it is
only within recent years that any substantial work has
been done on establishing the reliability and validity of
these schemes,49,50,52 thereby providing greater
accuracy and consistency in conducting and analyzing
clinical trial outcomes.
Development of therapeutic interventions most often
follows from laboratory discoveries that lead to trials for
efficacy in clinical settings. However, the reverse can be
true as well: attention to clinical observations of factors
associated with both pain exacerbation and pain relief
can help drive the agenda at the workbench. Important
clinical observations, when well controlled, may lead to
increased understanding of mechanisms and more

1206
Richardson et al
effective treatments. One such clinical observation is ex-
acerbation of pain by smoking among persons with SCI.
Although the relationship between smoking and SCI
pain was noted in a clinical observation over a half cen-
tury ago,8,15 there has been little in the way of formal
investigation of this relationship. One longitudinal
study found that smokers with SCI, compared to
their nonsmoking counterparts, reported more
musculoskeletal pain across time.57 These findings are
similar to non-SCI pain populations, with increased levels
of musculoskeletal pain in the limbs and backs of non-SCI
persons being associated with smoking.21,45
Case reports also suggest that smoking affects a partic-
ular subtype of SCI-related pain: neuropathic pain. Ri-
chards et al54 noted 2 individuals with SCI who
experienced worsening of neuropathic pain from smok-
ing. Two men with long-standing paraplegia were habit-
ual smokers of ½ to 1 pack of cigarettes per day. When
required to stop smoking prior to a surgical procedure
to repair nonhealing pressure sores, the men complied
and subsequently reported a marked reduction in neuro-
pathic pain levels. After discharge, both men resumed
smoking and reported an immediate return of the pain
to the level experienced prior to their abstinence. The
purpose of the present study was to further examine
this potentially exacerbating effect of nicotine on spe-
cific subtypes of pain following SCI via a randomized,
placebo-controlled crossover experiment.
Methods
Participants
Smokers and nonsmokers with SCI were recruited from
the University of Alabama at Birmingham (UAB) SCI model
system of care. Nonsmokers were defined as no use of
tobacco presently and no history of habitual use of to-
bacco. Individuals were considered eligible if they were
between 19 and 59 years of age, had chronic pain that de-
veloped following injury, and had SCI of more than 3
months’ duration. Exclusion criteria included having
a history of moderate-to-severe traumatic brain injury or
diagnosis of severe psychiatric disorder. Due to the admin-
istration of a stimulant (nicotine), those with cardiovascu-
lar disease or untreated hypertension (ie, those with
systolic pressure greater than 160 mm Hg or a diastolic
pressure greater than 95 mm Hg), gastric/peptic ulcer, or
diabetes were also excluded. Women were excluded if
they were pregnant or breastfeeding. This study was
approved by the UAB Institutional Review Board, and all
participants gave informed consent to participate.
Pain Classification
Consistent with the recommendations of the Interna-
tional Spinal Cord Injury Basic Pain Data Set (ISCIBPDS),66
up to 3 worst pain sites were identified and assessed per in-
dividual. Two interviewers, trained to criteria on the Bryce-
Ragnarsson pain classification scheme,10 simultaneously
but independently classified participants’ pain sites. Pain
sites were classified as musculoskeletal (MS), pure neuro-
pathic (NP), or complex neuropathic (cNP) pain. A pain
The Journal of Pain 1207
site was classified as cNP pain when participants described
their pain site(s) as having some combination of both neu-
ropathic symptoms (eg, burning, ‘‘pins and needles,’’ or
tingling sensations) and musculoskeletal symptoms (eg,
‘‘aching’’ or ‘‘dull’’ as additional self-reported pain quali-
ties and/or the pain was made worse with movement).
Such pain types could not be classified exclusively as
musculoskeletal or neuropathic subtypes. We have used
this methodology successfully in peer-reviewed studies
of SCI pain classification schemes.49,50,52
Procedures
The procedural flow diagram, as suggested by the
CONSORT group for reporting clinical trials,61 is shown
in Fig 1. For ethical reasons, participants were not asked
to discontinue pain medications, but were instructed to
not make changes in their pain medication regimen dur-
ing the trial. Smokers were asked to refrain from smok-
ing the day of testing. Among smokers, compliance
with the request to refrain from smoking was tested by
measuring the amount of carbon monoxide (CO), in
parts per million (ppm), on expiration using a portable
CO breath analyzer (Micro 4 Smokerlyzer; Bedfont Scien-
tific, Haddonfield, NJ). Level of breath CO is sensitive to
recent smoking and has been shown to have a stronger
negative correlation to time since last cigarette com-
pared to saliva cotinine.40 A cut-off of 10 ppm has been
found to be sensitive and specific when determining
a person’s smoking status on a given day,33 and readings
above 12 indicate that smoking has probably taken place
within the preceding 8 to 12 hours.60 On 2 separate occa-
sions, participants were presented a sequence of gum
stimuli involving nicotine gum or placebo gum. Both
the placebo and nicotine gum were commercially avail-
able and matched on taste, appearance, and texture.
Both types of gum were identically packaged and wrap-
ped to maintain blinding of both the examiner and par-
ticipant. Participants were also instructed not to look at
the gum when opening and placing it in their mouths.
To minimize the possibility of carryover effect given the
crossover design, the participants were randomized to
order of exposure, and an approximate 1-week washout
period was used between the 2 arms of the trial. During
each trial exposure, participants were given 1 mg nico-
tine gum (or placebo) in the first hour and 2 mg nicotine
(or placebo) in the second hour. These dosages were cho-
sen to determine a potential dose-dependent response
and represent the range of nicotine absorbed from 1
cigarette from commercially available brands.28 Heart
rate and pain ratings were collected at 10-minute inter-
vals over the 120-minute period in each arm. A 0 to 10
numeric rating scale (NRS) was used to rate pain. Ratings
collected at 30 minutes postadministration of dose for
each hour were used in the analyses because this time
frame parallels time to peak nicotine blood plasma levels
via nicotine gum.27 To further assess adequacy of blind-
ing, participants were queried at the end of each trial
about whether they believed they had been given nico-
tine or placebo gum. Participants were allowed to select
‘‘nicotine,’’ ‘‘placebo,’’ or ‘‘unsure.’’ Following unblind-
ing at the end of the study, a response of ‘‘unsure’’ or
1208 The Journal of Pain Effects of Nicotine on Spinal Cord Injury Pain

Excluded (n=37)
(Declined or had condition
Enrollment (n=43) contraindicated with use of
nicotine*)

Randomization

Placebo Nicotine
Allocated (n=19) Allocated (n=24)
Discontinued, anticipated Condition A Discontinued, anticipated
side effect** (n=2) side effect (n=0)

1 Week Washout 1 Week Washout

Lost to Follow-Up (n=0) Lost to Follow-Up (n=1)

Placebo Nicotine
Allocated (n=23) Allocated (n=17)
Discontinued, anticipated Condition B Discontinued, anticipated
side effect (n=0) side effect** (n=1)

Analyzed (n=39)
Excluded from analysis:
(Had visceral pain site only, n=1)
(Discontinued or lost, n=3)

Figure 1. CONSORT flow diagram depicting phases of the study. *Conditions leading to exclusion included hypertension and diabe-
tes. **Anticipated side effects included feelings of nausea/upset stomach and lightheadedness.

the incorrect gum type within a trial was keyed as ‘‘incor-
rect.’’ Responses that correctly identified the gum type
for that particular trial were classified as ‘‘correct.’’
Statistical Analysis
Descriptive statistics were calculated for demographic
characteristics. Due to the nesting of pain sites within
an individual and the fact that multiple pain sites per in-
dividual were included in the statistical analysis, common
regression methodologies (eg, repeated measures analy-
sis of variance, multiple regression, analysis of covariance)
were deemed inappropriate due to the nonindepen-
dence of observations across pain sites within an individ-
ual. Therefore, a mixed linear model was employed to
examine the effect of pain type, smoking, and the interac-
tion between smoking status and pain type on changes in
pain rating. In this model, the correlation among observa-
tions within an individual was calculated using the
intraclass correlation coefficient. By this approach, the
variance attributable to the effect of the individual can
be accounted for, thereby preventing inflation of the
type I error rate. To calculate a change score between pla-
cebo and nicotine, pain ratings reported at 30 minutes af-
ter exposure to 1 mg placebo were subtracted from pain
ratings reported 30 minutes after exposure to 1 mg nico-
tine. Change scores following exposure to 2 mg nicotine
were also calculated in this manner. Because the design
was a crossover design, tests for significant carryover
were conducted, also using a mixed linear model. McNe-
mar’s chi-square test was performed to determine
differences in accuracy of participant beliefs across the 2
trials. Histograms and residuals plots were constructed
to examine the statistical assumption of normality. All
analyses were conducted using SAS v.9.2 (SAS Institute
Inc, Cary, NC).
Results
Demographic composition of the study sample is
shown in Table 1. The mean number of pain sites re-
ported per individual was 2.45 (SD = .67). A total of 103
pain sites were classified. There were 42 (40.8%) sites
classified as MS, 39 (37.9%) sites classified as NP, and 20
(19.4%) sites deemed cNP. The rarest pain type found in
the sample was visceral pain and was classified in
2 (1.9%) of the participants. Given the small number, vis-
ceral pain was not included in the primary analyses.
Prior to conducting the main analyses, the data were
examined for potential confounds inherent in the design
used. A statistical test of carryover effect did not achieve
Richardson et al The Journal of Pain 1209
Table 1. Sample Demographics (n = 42) nicotine (P = .58 and P = .21, respectively), suggesting that
despite evidence that some participants were not absti-
CATEGORICAL VARIABLES n (%) nent for a full 24 hours prior to testing, this did not
Race pose as a significant confound to the results observed.
Caucasian 20 (47.6) Participants’ belief as to which type of gum that they re-
African American 22 (52.4) ceived did not differ across experimental conditions (c2
Gender (1) = .048, P = .827), suggesting that blinding of partici-
Men 26 (61.9)
pants was maintained and that response bias was not
Women 16 (38.1)
likely a confounder in the primary results.
Smoker
No 11 (26.2)
Yes 31 (73.8) Primary Analyses
Gunshot wound
No 28 (66.7)
Outcomes of 1 mg Nicotine
Yes 14 (33.3) The overall mixed model produced a nonsignificant
Injury level statistical test of interaction between smoking status
Tetraplegia 15 (35.7) and pain type (F[2,51] = 1.15, P = .324). These results
Paraplegia 27 (64.3) are displayed in Fig 2. Following administration of 1
Injury severity
mg of nicotine, no difference emerged between smokers
Complete 9 (21.4)
and nonsmokers with respect to changes in severity of
Incomplete 33 (78.6)
MS or NP pain sites. For sites reported as cNP, exposure
CONTINUOUS VARIABLES M (SD) MIN, MAX to 1 mg nicotine created different changes in reported
pain, albeit nonsignificantly. A nonsignificant increase
Age 43.6 (10.7) 19.0, 59.0
Injury duration 12.5 (10.1) .5, 34.5
in pain was reported (D = .30, 95% confidence interval
Education 12.8 (2.0) 10, 18 [CI]: .90, 1.49) by smokers and a nonsignificant decrease
Years smoked* 25.4 (11.9) 1, 40 in pain was reported (D = 1.07, 95% CI: 2.86, .71) by
nonsmokers.
*Number of years as a regular smoker was available for 25 of the 31 participants
classified as smokers. Outcomes of 2 mg Nicotine
The analysis of change scores following administration
statistical significance (P = .81). Among smokers, non- of 2 mg of nicotine produced a significant statistical test
compliance with smoking cessation 24 hours prior to of interaction between smoking status and pain type (F
each trial condition was also examined as a potential con- [2,51] = 5.74, P = .006) and is shown in Fig 3. For pain sites
founder to the main analyses. The mean level of ppm CO classified as cNP, exposure to nicotine created markedly
just prior to nicotine exposure trial was 14.12 (SD = 10.34) different changes in reported pain. For smokers, a signif-
and was 12.74 (SD = 9.17) prior to placebo exposure, indi- icant increase in pain was reported (D = 1.30, 95% CI: 15,
cating that some smokers may not have refrained from 2.44). For nonsmokers, a significant decrease in pain was
smoking for a full 24 hours preceding testing. When us- reported (D = 2.88, 95% CI: 4.57, 1.19). Pain re-
ing placebo and nicotine pretrial CO levels as a marker ported at MS pain sites decreased, but in a nonsignificant
for time since last cigarette,40 CO levels were not related manner for both smokers (D = .18, 95% CI: .99, .63)
to changes in pain following 1 mg of nicotine (P = .23 and and nonsmokers (D = .73, 95% CI: 2.03, .57). For NP
P = .91, respectively) or changes in pain following 2 mg of pain sites, reported pain increased with 2-mg nicotine

Figure 2. Confidence intervals (95%) for mean change in pain between 1 mg of nicotine and placebo.
1210 The Journal of Pain Effects of Nicotine on Spinal Cord Injury Pain

Figure 3. Confidence intervals (95%) for mean change in pain between 2 mg of nicotine and placebo.

exposure for smokers (D = .43, 95% CI: .40, 1.26) and sia symptoms as compared to MS pain. No pain site
nonsmokers (D = .33, 95% CI: .99, 1.65), although with a neuropathic component was located above the
changes in NP pain were nonsignificant. level of injury. The majority of MS pain sites were expe-
rienced unilaterally. Higher proportions of NP pain sites
Post Hoc Analyses were experienced both unilaterally and bilaterally on
the body, whereas cNP pain sites appeared fairly evenly
The differential effect observed in cNP pain between
distributed in terms of bodily laterality. Lastly, when
smokers and nonsmokers raised further questions re-
categorizing pain sites by type and response, defined
garding potentially unique factors (or confounds) and
as a 630% change in pain following 2-mg nicotine
clinically relevant trends associated with cNP that may
exposure, the majority within all pain subtypes were
explain the significant interaction observed in the pri-
shown to have minimal or no response. However,
mary analyses. Therefore, follow-up analyses were con-
approximately 42.2% of MS pain sites showed a de-
ducted in order to further understand the primary
crease and 35.5% of NP pain sites showed an increase
findings. Pain-site level variables including location of
pain relative to injury, laterality of pain on the body, an-
algesia, and hyperalgesia were examined with respect to Pain-Site Level Variables Cross-
Table 2.
each subtype of pain in a post hoc exploratory manner. Tabulated by Subtype of SCI Pain
Participant-level variables, including demographics and
MS NP cNP
injury characteristics, were also examined by type of
n (%) n (%) n (%)
pain response (positive, negative, or minimal/non)
when exposed to nicotine. Total 42 (41.6) 39 (38.6) 20 (19.8)
Pain symptoms
Pain-Site Level Variables Allodynia 2 (4.8) 17 (43.6) 5 (26.3)
Hyperalgesia 2 (5.1) 8 (23.5) 3 (21.4)
Subtypes of pain were cross-tabulated with pain-site Location relative to injury
level variables available. Again, due to the multiple Above level 14 (33.3) 0 (.0) 0 (.0)
pain sites reported per participant, the most appropri- At level 7 (16.7) 4 (10.3) 3 (15.0)
ate approach for this test would be a generalized mixed Below level 13 (31.0) 32 (82.1) 12 (60.0)
linear model in order to produce the most reliable re- At and below 8 (19.1) 3 (7.7) 5 (25.0)
sult. However, these models are statistical methods Laterality
that require algorithms to iteratively maximize the like- Unilateral 17 (40.5) 17 (43.6) 6 (30.0)
lihood functions in order to estimate P values. Unfortu- Bilateral 9 (21.43) 16 (41.03) 4 (20.0)
Midline 12 (28.6) 1 (2.6) 7 (35.0)
nately, for multinomial outcomes such as pain type, and
Mixed 4 (9.5) 5 (12.82) 3 (15.0)
moderate sample sizes, these methods can fail to
Response to nicotine*
converge to a solution. This was the case for our post Increase ($30%) 3 (9.1) 11 (35.5) 5 (27.8)
hoc models involving subtype of pain; therefore, tests <30% change 16 (48.5) 12 (38.7) 8 (44.4)
of independence were not reported for these analyses. Decrease ($30%) 14 (42.4) 8 (25.8) 5 (27.8)
However, descriptive information is provided. The pro-
portions of each pain subtype with respect to each *An increase or decrease in pain was defined by a 30% or greater positive or
negative change in pain ratings. Percent change could not be calculated as
pain-site level variable category are shown in Table 2.
some participants reported an NRS pain level of 0/10 following 2 mg nicotine;
As expected, higher proportions of pain sites classified therefore, counts in each response category do not reflect total counts for
as NP or cNP were positive for allodynia and hyperalge- subtype.
Richardson et al The Journal of Pain 1211
in pain severity following nicotine exposure. Identical Person-Level Variables Cross-
Table 3.
proportions of cNP showed a 30% or more increase Tabulated by Pain Response to Nicotine
and decrease in pain.
NEGATIVE POSITIVE
RESPONDER <30% CHANGE RESPONDER
Participant-Level Variables n (%) n (%) n (%)
A $30% change in pain is considered clinically mean- Total 12 (32.4) 15 (40.5) 10 (27.0)
ingful in clinical trial research17,22; therefore, Race
participants in the present study were classified as Caucasian 4 (25.0) 8 (50.0) 4 (25.0)
positive responders if they experienced a $30% African American 8 (38.1) 7 (33.3) 6 (28.6)
reduction in pain, negative responders if they Gender
experienced a $30% worsening in pain, and Men 6 (26.1) 9 (39.1) 8 (34.8)
nonresponders if there was <30% increase or decrease Women 6 (42.9) 6 (42.9) 2 (14.3)
Etiology
in pain following 2 mg of nicotine. Because most
Violent 5 (41.7) 5 (41.7) 2 (16.7)
participants had more than 1 pain site and it was
Nonviolent 7 (28.0) 10 (40.0) 8 (32.0)
possible to have both MS and NP or cNP forms of pain, Injury level
response categories were based on clinically significant Tetraplegia 4 (28.6) 6 (42.7) 4 (28.6)
changes observed in NP or cNP pain sites only, resulting Paraplegia 8 (34.8) 9 (33.1) 6 (26.1)
in a total number of 37 participants classified. There Injury severity
were no participants who showed a 30% increase (or Complete 5 (55.6) 3 (33.3) 1 (11.1)
decrease) in NP and a contrasting decrease (or increase) Incomplete 7 (25.0) 12 (42.9) 9 (32.1)
in cNP to confound classification to responder status.
NOTE. N = 37. Participants were classified as negative responders ($30% wors-
The proportions of participant demographics and in-
ening in reported pain) and positive responders ($30% reduction in reported
jury characteristics (person-level variables) with respect pain) with respect to NP or cNP pain. Percentage values were rounded and
to responder status are shown for descriptive purposes may not sum exactly to 100.
in Table 3. Among African Americans, the highest pro-
portion (38.1%) had $30% worsening of NP or cNP. Com-
pared to women, a higher proportion of men (34.8%
via nACh receptor agonists can reduce transmission of
versus 14.3%) experienced improvement in NP or cNP fol-
nociceptive input and promote analgesia.3,6,16,43 It is this
lowing exposure to 2 mg of nicotine. In terms of injury
mechanism that is thought to underlie the analgesic
characteristics, persons with paraplegia (34.8%) repre-
effects of nicotine on experimentally induced pain23,32,46
sented the highest proportion classified as negative re-
and postsurgical pain.24,25,30 We similarly found that
sponders (increase in NP or cNP). Similarly, the majority
exposure to 2 mg of nicotine resulted in a trend for
of those whose injury was characterized as complete
reduced MS pain in both smokers and nonsmokers, and
(55.6%) experienced a worsening of NP and cNP. These
a significant decrease in cNP pain among nonsmokers.
associations between responder status and participant-
However, smokers in this study experienced a contrast-
level variables were examined via chi-square tests of
ing increase in cNP pain following nicotine exposure, sug-
independence; however, none of these tests reached
gesting that tolerance to nicotine may modify the effects
statistical significance.
of nicotine. In rat models, acute administration of nico-
tine produces analgesia, but the antinociceptive effect
Discussion of nicotine is attenuated with chronic exposure to nico-
The results from the present study showed that follow- tine.1,62,65 Further, rats chronically exposed to nicotine
ing exposure to 1 mg of nicotine, administered orally, exhibited greater mechanical hyperalgesia following
nonsignificant changes in pain severity for MS and NP nerve injury compared to nicotine-free counterparts.9,35
pain sites occurred for both smokers and nonsmokers. Exposure to nicotine exerts pro-excitatory actions on pri-
While a differential effect emerged with regard to cNP mary afferent neurons and dorsal horn neurons5,12,34 and
pain sites, such that smokers experienced a slight in- sensitizes TRPV1 receptor channels.37,38 This suggests
crease in cNP pain while nonsmokers experienced a de- that chronic nicotine exposure, as occurs with habitual
crease in cNP pain, this difference failed to produce smokers or tobacco users, may alter the structural,
a significant interaction. When the nicotine dose was functional, and potentially biochemical integrity of
doubled, a similar pattern emerged across the subtypes nociceptive pathways. Consequently, the analgesic (or
of pain. Most notably, following 2-mg exposure, the dif- enhanced nociceptive) effect of nicotine would be
ferential effect on cNP pain sites for nonsmokers and determined by habitual smoking or tobacco use.
smokers became significant and was more pronounced In an attempt to further understand potential factors
compared to the 1-mg dose of nicotine. This interaction associated with a clinically meaningful response follow-
revealed that while smokers experienced an increase in ing nicotine administration, demographics and injury
cNP pain severity, nonsmokers experienced contrasting characteristics were examined descriptively with respect
analgesia in cNP following 2 mg of nicotine. to degree of change in pain. Several potential trends
The central nervous system is replete with nicotinic ace- emerged that may warrant further investigation in the
tylcholine (nACh) receptors, especially in regions involved SCI-pain population. A higher proportion of men, com-
with processing of nociceptive stimuli.14,44,51,63 Activation pared to women, was classified as experiencing a 30%
1212 The Journal of Pain
or more reduction in pain, while the proportions of
women experiencing minimal change and 30% or more
increase in pain following 2 mg of nicotine were equiva-
lent. This is similar to findings that men who underwent
prostatectomy who were given transdermal nicotine re-
duced the amount of morphine needed following sur-
gery,25 whereas no such effect was seen among women
following uterine surgery.13 Moreover, in animal models,
female rats have been found to have a higher baseline
density of nACh receptors, and when given nicotine on
a chronic basis, only males exhibited up-regulation.36 Al-
though the data presented here do not offer statistical
support for this notion, it is possible that women are
less sensitive to the effects of nicotine than men.
A higher proportion of African Americans were classi-
fied as negative responders, meaning that a 30% or
greater increase in pain was experienced. In the general
pain literature, African Americans show increased pain
sensitivity during experimentally induced pain and in
clinical pain,18,19 which may, in part, be due to
alterations in endogenous pain-regulatory mecha-
nisms.42 However, race may serve as a marker variable
for the etiology of the injury, as a greater number of Af-
rican Americans from the UAB SCI model system of care,
compared to non-Hispanic Caucasians, sustained an SCI
by acts of violence such as gunshot wounds.31 Injuries re-
sulting from gunshot have been associated with more se-
vere neuropathic forms of pain.56,58 The physics of
gunshot wound are inherently different from other
traumatically sustained SCIs64 and may underlie the in-
creased likelihood of additional vascular, nerve, or vis-
ceral injury from shock-wave crush injury.41 A different
neuropathic symptom profile may be present in persons
injured by gunshot that may be associated with a worsen-
ing of pain in response to nicotine, although more data
are needed to clarify this.
It is puzzling that the greatest effect was observed in
a subtype of pain that was not clearly classifiable into
a pure neuropathic or musculoskeletal form of pain.
The majority of pain sites classified as cNP were below
the level of injury. It is possible that cNP pain actually rep-
resented 2 adjacent sites subjectively indistinguishable
by the participant, especially if experienced in regions
where sensation was compromised. Should an adjacent
MS pain site show a reduction in severity, as the trend
we observed here with MS sites in response to nicotine,
the adjacent NP site may become more saliently per-
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Effects of Nicotine on Spinal Cord Injury Pain
ceived and translate into a reported increase in severity.
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Several limitations to the present study should be high-
lighted when considering these results. First, 1 and 2 mg
were administered 60 minutes apart. Therefore, residual
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to first classify pain into nociceptive and neuropathic
forms, with pain sites that exhibited symptoms of both,
and therefore unable to be classified as either NP or
MS, defined as ‘‘complex.’’ Neuropathic symptoms are
multidimensional yet often poorly discriminate among
a variety of etiologies and locations, and between cen-
tral or peripheral nerve damage.2 Similarly, in SCI, subjec-
tive qualities of pain do not always clearly specify
presence of NP pain.48 The lack of a strong relationship
between subjective pain report, physical symptoms,
and underlying mechanisms26 has prompted others to
conceptualize pain as a continuum of ‘‘more or less’’ neu-
ropathic.4 Allowing for this variability in neuropathic ex-
pression would complement our understanding of
individual variability in the neuroplastic changes
thought to contribute to NP pain,68 including varying de-
grees of supraspinal plasticity associated with SCI-related
NP pain.69 Future studies examining the effects of nico-
tine in SCI-related pain should delineate symptom pro-
files and degree of specific NP pain symptoms
experienced. From these current data, a nonlinear rela-
tionship would be hypothesized given that the greatest
effects were seen with a subtype of pain that could be
relatively centered on the continuum.
Whereas the findings within this paper indicate that
the effect of nicotine on pain may be a function of
pain type and smoking status, these findings should be
considered preliminary. Larger studies, with a greater
number of SCI individuals balanced between smokers
and nonsmokers, should be designed to detect a priori
and clinically relevant differences among smokers and
nonsmokers.
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