Anesthesiology 2005; 102:509 –14 © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Increased Sensitivity to Thermal Pain and Reduced

Subcutaneous Lidocaine Efficacy in Redheads
Edwin B. Liem, M.D.,* Teresa V. Joiner, B.S.N.,† Kentaro Tsueda, M.D.,‡ Daniel I. Sessler, M.D.§

Background: Anesthetic requirement in redheads is exagger- population.4 The red hair phenotype results from excess
ated, suggesting that redheads may be especially sensitive to pheomelanin production due to dysfunctional MC1Rs.5,6
pain. Therefore, the authors tested the hypotheses that women
with natural red hair are more sensitive to pain and that red-
In contrast, when a normal (consensus) MC1R is ex-
heads are resistant to topical and subcutaneous lidocaine. pressed, the predominant pigment produced by melano-
Methods: The authors evaluated pain sensitivity in red-haired cytes is eumelanin, resulting in a high eumelanin-to-
(n ⴝ 30) or dark-haired (n ⴝ 30) women by determining the pheomelanin ratio.
electrical current perception threshold, pain perception, and In a previous study, we found that women with red
maximum pain tolerance with a Neurometer CPT/C (Neurotron,
Inc., Baltimore, MD). They evaluated the analogous warm and
hair required 19% more desflurane to suppress move-
cold temperature thresholds with the TSA-II Neurosensory An- ment in response to noxious electrical stimulation than
alyzer (Medoc Ltd., Minneapolis, MN). Volunteers were tested women with dark hair, making red hair a distinct phe-
with both devices at baseline and with the Neurometer after 1-h notype associated with anesthetic requirement in hu-
exposure to 4% liposomal lidocaine and after subcutaneous mans.7 The effects of human MC1R dysfunction on an-
injection of 1% lidocaine. Data are presented as medians (inter-
quartile ranges).
esthetic requirement were further supported by the
Results: Current perception, pain perception, and pain toler- finding that anesthetic requirement is slightly, but signif-
ance thresholds were similar in the red-haired and dark-haired icantly, increased in melanocortin-1 receptor knockout
women at 2,000, 250, and 5 Hz. In contrast, redheads were more mice.8 And finally, the recent work of Mogil et al.9 also
sensitive to cold pain perception (22.6 [15.1–26.1] vs. 12.6 suggests involvement of MC1R in pain modulation.
[0 –20]°C; P ⴝ 0.004), cold pain tolerance (6.0 [0 –9.7] vs. 0.0
[0.0 –2.0]°C; P ⴝ 0.001), and heat pain (46.3 [45.7– 47.5] vs. 47.7
MC1R expression has been identified in human pitu-
[46.6 – 48.7]°C; P ⴝ 0.009). Subcutaneous lidocaine was signifi- itary tissue, glial cells, and in cells of the human periaq-
cantly less effective in redheads (e.g., pain tolerance threshold ueductal gray matter.10,11 However, the central nervous
at 2,000-Hz stimulation in redheads was 11.0 [8.5–16.5] vs. > system is not a major site of MC1R expression.6 There-
20.0 (14.5 to > 20) mA in others; P ⴝ 0.005). fore, it remains unclear why MC1R mutation should alter
Conclusion: Red hair is the phenotype for mutations of the
melanocortin-1 receptor. Results indicate that redheads are
anesthetic requirement. Because anesthetic requirement
more sensitive to thermal pain and are resistant to the analgesic in previous studies was measured in the context of a
effects of subcutaneous lidocaine. Mutations of the melanocor- response to a noxious stimulus, these results suggest that
tin-1 receptor, or a consequence thereof, thus modulate pain MC1R dysfunction could possibly modulate a response
sensitivity. to any stimulus that might be perceived as painful. A
possible explanation is that MC1R mutation up-regulates
RED hair nearly always results from mutations of the production of the receptor’s primary ligands, melano-
melanocortin-1 receptor gene (MC1R).1–3 The human cortins including ␣-melanocyte-stimulating hormone,
melanocortin-1 receptor (MC1R) is expressed on the which also stimulates other melanocortin receptors—
surface of melanocytes and is a key regulator of intracel- including the melanocortin-4 receptor that modulates
lular signaling to the melanin biosynthetic pathway gov- cold and mechanical allodynia in a rat neuropathic pain
erning pigment formation. In general, the balance of model.12
pheomelanin (yellow-red) and eumelanin (dark brown) To the extent that this theory is correct, one might
pigments determines hair and skin color in the white expect baseline pain sensitivity to be exaggerated in
redheads. Anecdotal reports support this theory: After
* Assistant Professor, OUTCOMES RESEARCH™ Institute and Department of Anes- reports of our previous study7 were published in the lay
thesiology and Perioperative Medicine, † Research Coordinator, OUTCOMES RE- press, we received more than a hundred communica-
SEARCH™ Institute, § Vice Dean for Research and Associate Vice President for
Health Affairs, Director OUTCOMES RESEARCH™ Institute, Lolita & Samuel Weakley tions from redheads who claimed that anesthesia often
Distinguished University Research Chair, and Interim Chair and Professor of failed or that unusually large doses of local anesthetics
Anesthesiology. ‡ Deceased. Formerly Associate Professor, Department of
Anesthesiology and Perioperative Medicine. were required to achieve adequate analgesia. Therefore,
Received from the OUTCOMES RESEARCH™ Institute and the Department of we tested the hypotheses that natural redheads are more
Anesthesiology and Perioperative Medicine, University of Louisville, Louisville, sensitive to pain than women with dark hair and that
Kentucky. Submitted for publication July 26, 2004. Accepted for publication
October 21, 2004. Supported by grant No. GM 061655 from the National redheads are resistant to topical and subcutaneous
Institutes of Health, Bethesda, Maryland; the Gheens Foundation, Louisville, lidocaine.
Kentucky; the Joseph Drown Foundation, Los Angeles, California; and the Com-
monwealth of Kentucky Research Challenge Trust Fund, Louisville, Kentucky.
None of the authors have any personal financial interest related to this research.
Materials and Methods
Address reprint requests to Dr. Sessler: OUTCOMES RESEARCH™ Institute, 501
East Broadway, Louisville, Kentucky 40202. Address electronic mail to:
[email protected]. On the World Wide Web: www.or.org. Individual article
With institutional approval (University of Louisville,
reprints may be purchased through the Journal Web site, www.anesthesiology.org. Louisville, Kentucky) and informed written consent, we

Anesthesiology, V 102, No 3, Mar 2005 509

510 LIEM ET AL.

studied healthy (American Society of Anesthesiologists modified to deliver currents from 0 to a maximum of
physical status I) white female volunteers aged 18 – 40 yr 20 mA.
who had natural bright red, black, or dark brown hair. For determination of the baseline sensory, pain per-
We considered volunteers to be white if they reported ception, and pain tolerance thresholds, pairs of gold
being primarily of northern European descent. Volun- electrodes were positioned on glabrous skin of both the
teers were monetarily reimbursed for their time. right and left ring fingers. For each specific threshold
Other studies indicate that women report different measurement, both sides (dominant and nondominant
pain experiences and more negative responses to pain hand) were tested sequentially, with the order deter-
than men,13–16 as well different responses to analge- mined by random assignment. The skin was prepared for
sics.17 Therefore, we restricted our study population to testing with a gentle abrasive cleaning preparation. A
women. A higher sensitivity to pain stimuli has been pair of gold electrodes (1-cm diameter) separated by a
observed during the luteal phase of the menstrual cy- 1.7-cm Mylar spreader was coated with a thin layer of
cle.18,19 We therefore also restricted studies to the first chloride-free electroconductive gel and taped to the fin-
10 days of the participants’ menstrual cycles unless they ger. Volunteers were instructed as to how to respond to
were using hormonal contraceptives. each stimulus according to a standardized script and
Exclusion criteria included chemical hair treatment, were blinded at all times to the threshold measurement
any history of medical or psychiatric problems, history results displayed on the Neurometer device.
of current or past chronic pain conditions, skin abra- The baseline current perception (sensory) thresholds
sions or lesions on testing sites, pregnancy, body mass were tested first at 2,000, 250, and 5 Hz. The operator
index greater than 30 kg/m2, recreational drug use, or slowly increased the stimulus until the volunteer consis-
use of medications other than oral contraceptives. Based tently reported detecting the stimulus at 0.02 mA and
on the means and SDs obtained from preliminary test not detecting the stimulus 0.2 mA below this value. The
results on the Neurometer CPT/C device (Neurotron, manual intensity alignment was followed by auto test
Inc., Baltimore, MD),20 an a priori sample-size estimate cycles controlled by the device. Auto test cycles with
suggested that 18 subjects in each group would provide true or false testing confirmed that the volunteer re-
a 90% power for detecting a 40% reduction in pain sponses were within ⫾0.04 mA. After repeated and
tolerance thresholds at a two-tailed, unpaired ␣ level of consistent crossovers occurred, the device determined
0.05. Therefore, we enrolled 30 volunteers with red hair the exact milliampere current value.
and 30 with dark hair. After completing the baseline current perception
All studies were started at 8:00 AM. Volunteers fasted threshold measurements on both hands, baseline pain
and refrained from smoking for at least 8 h before the perception thresholds and then pain tolerance thresh-
start of the protocol. Studies were conducted in a quiet olds were measured on both hands. For pain perception
room that was maintained at a comfortable ambient and pain tolerance threshold measurements, the volun-
temperature. Each volunteer’s height, weight, and age teer initiated the stimulation by pushing a button on the
were recorded. Sensory and pain thresholds for each device. As long as the volunteer depressed the button,
volunteer were tested with two devices: the Neurometer the amount of stimulation slowly increased automati-
CPT/C and the TSA-II Neurosensory Analyzer (Medoc cally. We asked volunteers to release the button when
Ltd., Minneapolis, MN). they perceived the stimulus as painful (for pain percep-
The Neurometer CPT/C produces a biphasic sinusoid tion thresholds) or when it became intolerable (for pain
alternating current waveform stimulus at frequencies of tolerance thresholds). We allowed at least 2 min, or until
2,000, 250, and 5 Hz.20,21 Sine waves at 2,000, 250, and sensation in the finger had returned to baseline, between
5 Hz correspond to depolarization periods of 0.25, 2, and successive stimuli. In summary, three different frequen-
100 ms, respectively. The large-diameter fibers can re- cies of stimulation (2,000, 250, and 5 Hz) were used to
spond to the rapid 2,000-Hz stimulus, whereas the small obtain three different threshold measurements (current
unmyelinated fibers require several milliseconds of a perception, pain perception, and maximum pain toler-
continuous depolarization period to respond. However, ance). These baseline sensory and pain thresholds in
large fibers repolarize faster than the slow increase of the response to electrical stimulation were normally
5-Hz stimulus can depolarize them and therefore do not distributed.
achieve threshold potential with that stimulation. To- To determine baseline thermal sensory, pain percep-
gether, these factors result in the 2,000, 250 and 5-Hz tion, and pain tolerance thresholds, contact heat stimuli
sine wave depolarizations selectively evoking responses were delivered using a computer-controlled thermal sen-
from the large myelinated A-␤, the small myelinated A-␦, sory analyzer (TSA-II Neurosensory Analyzer). This de-
and the small unmyelinated C fibers, respectively.22,23 vice has been used extensively for quantitative assess-
The Neurometer automatically compensates for alter- ment of thermal sensory and pain thresholds.18,24 The
ations in skin resistance by adjusting the voltage to maximum delivered temperature was 50°C, and the min-
maintain a constant current.21 Our Neurometer was imum temperature was 0°C.

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REDUCED LOCAL ANESTHESIA EFFICACY IN REDHEADS 511

For temperature threshold testing, a 3 ⫻ 3-cm Table 1. Demographic and Morphometric Characteristics,
square thermode was positioned on the volar area of Baseline Current Perception, Pain Perception, and Pain
Tolerance Thresholds
the volunteer’s forearm. Both the dominant and non-
dominant arms were tested sequentially, with the or- Red Hair Dark Hair P Value
der determined randomly. From a baseline of 32°C, Height, cm 163 ⫾ 8 161 ⫾ 6 0.25
probe temperature was increased or decreased at a Weight, kg 65 ⫾ 11 62 ⫾ 10 0.35
rate of 0.5°C/s until the volunteer responded. The Age, yr 27 ⫾ 5 27 ⫾ 6 0.86
Current threshold
slow increase presumably evokes mainly stimulation
perception, mA
of C-nociceptive afferents.25 Volunteers were in- 2,000 Hz 2.16 ⫾ 0.44 2.02 ⫾ 0.38 0.20
structed as to how to respond to each stimulus ac- 250 Hz 0.78 ⫾ 0.18 0.74 ⫾ 0.20 0.40
cording to a standardized script and were always 5 Hz 0.44 ⫾ 0.18 0.46 ⫾ 0.22 0.75
Pain perception threshold,
blinded to results. Four trials of warm and cold sen- mA
sory thresholds were given to each volunteer, fol- 2,000 Hz 6.8 ⫾ 2.8 7.2 ⫾ 3.3 0.60
lowed by four trials of heat pain and cold pain (per- 250 Hz 2.8 ⫾ 1.3 3.2 ⫾ 2.1 0.33
5 Hz 1.9 ⫾ 1.1 2.2 ⫾ 1.1 0.35
ception) thresholds and then four trials of heat pain Pain tolerance threshold,
and cold pain tolerance thresholds. Volunteers were mA
instructed to press a button to interrupt the stimulus 2,000 Hz 10.5 ⫾ 3.8 10.9 ⫾ 4.0 0.68
250 Hz 4.2 ⫾ 1.7 4.7 ⫾ 2.9 0.42
whenever they thought that the appropriate threshold
5 Hz 2.8 ⫾ 1.4 3.3 ⫾ 1.9 0.27
had been reached. The four trials were averaged to
determine the thresholds. A few volunteers reported Data are presented as mean ⫾ SD. Comparisons are made with unpaired,
two-tailed t tests.
mild tenderness at the testing site after maximum
intensity stimulation; in these volunteers, the position
of the thermode was altered slightly between trials to Data Analysis
avoid either sensitization or habituation of cutaneous We compared the demographics and other volunteer
receptors. In addition, we allowed at least 60 s be- characteristics with unpaired, two-sided t tests for con-
tinuous variables and chi-square or Fisher exact tests for
tween successive stimuli. Subjects were blinded at all
categorical variables. The analysis of perception and
times to the temperature threshold values obtained
threshold outcomes and all continuous outcomes de-
with the TSA-II Neurosensory Analyzer.
pended on the distribution of the data and whether any
In addition to the baseline current and thermal thresh-
of the values were censored. Values were considered
old measurements, we also investigated how the pain censored when the maximum possible pain threshold
tolerance thresholds were affected by local anesthetic. values were not reached, i.e., the maximum possible
The methodology to evaluate the sensitivity to different pain threshold values in these volunteers were a func-
local anesthetics using the Neurometer has been de- tion of the limits of the Neurometer device (maximum
scribed in previous studies.17,26 Briefly, the volar surface output is 20 mA) and not a physical limitation. That is,
of the nondominant forearm of the volunteer was di- the actual pain threshold values were not known be-
vided into three areas, each measuring approximately cause the values were truncated or “right censored” at
2 ⫻ 4 cm. One area functioned as control; the second 20 mA. Outcomes that were normally distributed were
area was covered with a 6-mm-thick layer of 4% liposo- compared with unpaired, two-sided t tests. If the values
mal lidocaine (ELA-Max; Ferndale laboratories, Ferndale, were skewed, the Mann–Whitney rank sum test was
MI), which was wiped clean after 60 min. In a previous used for comparing the groups. If some of the data were
study,26 the average onset time for this formulation of censored, we used Kaplan–Meier survival curves and log
lidocaine was 7 min; the application time of 60 min in rank tests. P ⬍ 0.05 was considered statistically
this study should therefore be sufficient to provide cu- significant.
taneous anesthesia. In the third area, we injected 2 ml
lidocaine, 1.0%, subcutaneously and allowed an onset
time of at least 5 min. Results
Pain tolerance threshold values were determined at Demographic and morphometric characteristics of the
frequencies of 2,000, 250, and 5 Hz as described above red-haired and dark-haired volunteers were similar (table
for all three areas. Subjects were blinded to the pain 1). Baseline thresholds for the dominant and nondomi-
tolerance threshold values generated for each area. Pain nant arms were also similar; values from each arm were
tolerance thresholds of areas tested for local anesthetic thus averaged. None of the baseline responses to elec-
sensitivity were found to have a censored outcome, i.e., trical stimulation (Neurometer; current perception, pain
many volunteers reached maximum pain tolerance perception, or pain tolerance thresholds) differed signif-
thresholds and could go no higher. icantly between the two groups (table 1).

Anesthesiology, V 102, No 3, Mar 2005

512 LIEM ET AL.

Table 2. Thermal Perception, Pain Perception, and Pain pared with the finger test sites, this difference is consis-
Tolerance Thresholds tent with the difference observed in other studies when
Red Hair Dark Hair P Value different test sites were used.26,27 This merely seems to
indicate that the absolute range of the threshold mea-
Cold sensory perception 30.7 (30.3–31.0) 30.5 (29.9–31.2) 0.596
threshold, °C surements depends on the location of a particular test
Cold pain perception 22.6 (15.1–26.1) 12.6 (0.0–20.0) 0.004 site. The highest values for each threshold were ob-
threshold, °C
Cold pain tolerance 6.0 (0.0–9.7) 0.0 (0.0–2.0) 0.001 tained with electrical stimulation at 2,000 Hz, and the
threshold, °C
Heat sensory perception 33.8 (33.5–34.0) 33.5 (33.4–33.8) 0.015 lowest values were obtained with 5-Hz stimulation, con-
threshold, °C sistent with previous observations.26 Nonetheless, we
Heat pain perception 41.4 (39.7–43.1) 42.4 (41.3–44.6) 0.059
threshold, °C were unable to detect any differences in baseline sen-
Heat pain tolerance 46.3 (45.7–47.5) 47.7 (46.6–48.7) 0.009 sory, pain perception, or pain tolerance thresholds in
threshold, °C
response to electrical stimuli between women with red
Data are presented as median (interquartile range). Comparisons are made or dark hair.
with Mann–Whitney rank sum tests.
Baseline heat pain perception and heat pain tolerance
threshold values in this study corresponded well to
In contrast, baseline threshold responses to thermal those reported in previous studies.16,18,24 We found that
stimuli were different between the groups: Redheads redheads were significantly more sensitive to cold pain
were more sensitive to cold pain, both in terms of cold perception, cold pain tolerance, and heat pain tolerance.
pain perception and cold pain tolerance (table 2). Al- Heat pain perception threshold was also lower, but not
though the difference in heat pain perception between significantly so, in redheads. In contrast to the pain
the two groups did not reach statistical significance, tolerance thresholds, the heat sensory perception
redheads had a lower threshold for heat pain tolerance threshold was actually higher in redheads.
(table 2). Interestingly, our baseline responses to thermal stimuli
Liposomal lidocaine was slightly, but not significantly,
contrast with those reported by Mogil et al.,9 in which
less effective in redheads (table 3). In contrast, subcuta-
no group differences were reported in ischemic pain
neous lidocaine was significantly less effective in red-
perception thresholds, ischemic pain tolerance thresh-
heads than in subjects with dark hair: Median survival
olds, or thermal pain intensity ratings as a function of
thresholds for pain tolerance (table 3) were lower in
hair color.9 Methodologic differences are a possible ex-
red-haired than in dark-haired volunteers (fig. 1).
planation: In the study of Mogil et al., a series of suprath-
reshold thermal stimuli consisting of 10 heat pulses at
Discussion 52°C were applied, and the subjects rated the intensity
of each pulse on a scale of 0 –100. The ratings were then
The range of the baseline current perception, pain combined to obtain a score for thermal pain intensity.
perception and pain tolerance thresholds in this study Despite the fact that such scales have fixed endpoints, a
was consistent with those reported in earlier studies limitation in the use of this and other such scales is the
using test sites on the fingers27 or the volar surface of the fact that these endpoints are entirely based on a subject’s
forearm.26 Although we measured considerably lower previous subjective experiences. The use of rating scales
pain tolerance thresholds on the forearm test sites com- possibly leads to a more variable measurement range
compared with the determination of specific threshold
Table 3. Effect of Topical and Subcutaneous Lidocaine on Pain
values.
Tolerance Thresholds (mA)
We therefore observed differences between the hair
Red Hair Dark Hair P Value color groups in baseline thermal sensitivity, but not in
Control
baseline electrical pain. That responses differed with
2,000 Hz 5.5 (4.5–6.5) 6.0 (4.5–7.5) 0.187 electrical and thermal stimuli is perhaps unsurprising: It
250 Hz 2.8 (2.4–3.2) 2.8 (1.6–4.0) 0.292 is well established that sensitivity to one type of pain
5 Hz 2.0 (1.5–2.4) 2.1 (1.5–2.8) 0.708
poorly predicts sensitivity to other types of pain as var-
Liposomal lidocaine
2,000 Hz 7.5 (5.5–8.5) 9.0 (6.5–11.5) 0.460 ious mechanisms underlie different types of pain.28 An
250 Hz 3.6 (3.2–6.0) 5.0 (3.2–6.0) 0.114 alternative explanation is that electrical stimulation by-
5 Hz 3.2 (2.8–4.0) 4.5 (3.2–5.0) 0.106 passes peripheral transduction mechanism whereas ther-
Subcutaneous
lidocaine
mal stimulation does not. The observed differences in
2,000 Hz 11.0 (8.5–16.5) ⬎ 20 (14.5 to ⬎ 20) 0.005 thermal thresholds could therefore also be due to differ-
250 Hz 5.0 (4.0–9.0) 11.6 (8.0–13.0) 0.003 ences in peripheral transduction rather than (central)
5 Hz 6.3 (3.2–10.2) 8.5 (7.0–14.2) 0.013 processing of pain signals beyond the nociceptors. De-
Data are presented as median survival threshold (95% confidence interval). spite the fact that the differences in thermal thresholds
Comparisons are made with log rank tests. were statistically significant, the clinical significance re-

Anesthesiology, V 102, No 3, Mar 2005

REDUCED LOCAL ANESTHESIA EFFICACY IN REDHEADS 513

Fig. 1. Pain tolerance thresholds to

2,000-, 250-, or 5-Hz stimulation on the
forearm of volunteers with dark hair
(dark, solid lines) or red hair (pale,
dashed lines). Three areas of the arm
were tested: an untreated control area, an
area treated with 4% liposomal lidocaine,
and an area injected with 1 ml lidocaine,
1%. Data were plotted as Kaplan–Meier
survival curves, and the curves were com-
pared with log rank tests. The y-axis rep-
resents the fraction of the study popula-
tion still able to reach a particular
threshold. The curves for the two groups
were significantly different for all three
frequencies on the area treated subcuta-
neously with lidocaine.

mains unclear because the absolute temperature differ- study by Mogil et al.,9 women with two variant MC1R
ences between the two groups were quite small. alleles displayed significantly greater analgesia in re-
The pain threshold changes to liposomal lidocaine in sponse to the ␬ opioid pentazocine compared to those
this study were comparable to those found in previous with one or zero variant MC1R variant alleles. The au-
studies,26,29 but despite a trend toward higher threshold thors suggested that involvement of MC1Rs in analgesia
values in the red-haired group, none of the comparisons could be mediated through MC1Rs expressed in brain
between the two groups reached statistical significance glial cells11 and the neurons of the periaqueductal
for liposomal lidocaine. Our most striking finding, gray,34 a brain area that critically modulates nocicep-
though, was that redheads were resistant to anesthesia tion.35 Another possibility is that dysfunctional periph-
produced by subcutaneous lidocaine as measured by the eral MC1R mutations produce compensatory up-regula-
pain perception and tolerance thresholds. This outcome tion of central melanocortins that in turn increase
is consistent with the anecdotal observations that baseline pain sensitivity via stimulation of melanocor-
prompted our study and makes red hair a distinct phe- tin-4 receptors. Numerous other explanations might be
notype associated with local anesthetic sensitivity. How- postulated, and currently available information does not
ever, without a dose–response relation, it remains un- provide the basis for identifying a specific mechanism by
clear whether this represents absolute failure of local which MC1R mutations might influence pain sensitivity
anesthetic action or merely a shift of the dose–response or anesthetic requirement. Whether resistance to local
curve to the right.30 That is, redheads may simply re- anesthesia is therefore due to central up-regulation of
quire more local anesthetic but ultimately obtain ade- melanocortin receptor ligands or some other mechanism
quate analgesia. remains unknown.
Local anesthetics such as lidocaine prevent transmis- It is well established that women are more sensitive to
sion of nerve impulses by inhibiting passage of sodium painful stimuli and require more analgesic medication
ions through ion-selective sodium channels in nerve than men.13–15 To reduce variability, we restricted this
membranes.31–33 However, the peripheral nervous sys- study and a previous one in redheads to women.7 Mogil
tem is not a known site of MC1R expression.6 Therefore, et al.9 found significant effects of the MC1R genotype on
there is no known direct association between MC1R pentazocine analgesia, but this effect only emerged in
function and peripheral local anesthetic action. In the women, which suggests that the effects of MC1R dys-

Anesthesiology, V 102, No 3, Mar 2005

514 LIEM ET AL.

function might be sex specific. Whether our results can 8. Xing Y, Sonner JM, Eger EI, II, Cascio M, Sessler DI: Mice with a melano-
cortin 1 receptor mutation have a slightly greater MAC than control mice.
be extrapolated to men thus remains unknown. ANESTHESIOLOGY 2004; 101:544 – 6
Another limitation of our study is that we did not 9. Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV, Lariviere WR,
Groce MK, Wallace MR, Kaplan L, Staud R, Ness TJ, Glover TL, Stankova M,
perform DNA analysis on our volunteers. However, DNA Mayorov A, Hruby VJ, Grisel JE, Fillingim RB: The melanocortin-1 receptor gene
analysis in our previous study7 confirmed that all of the mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl
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red-haired volunteers carried at least one variant MC1R 10. Chhajlani V: Distribution of cDNA for melanocortin receptor subtypes in
allele and that 9 of 10 carried two such alleles, which is human tissues. Biochem Mol Biol Int 1996; 38:73– 80
11. Wikberg JE: Melanocortin receptors: Perspectives for novel drugs. Eur
consistent with previous reports.1–3,36 In contrast, 5 of J Pharmacol 1999; 375:295–310
10 dark-haired volunteers carried a single mutant allele, 12. Vrinten DH, Gispen WH, Groen GJ, Adan RA: Antagonism of the melano-
cortin system reduces cold and mechanical allodynia in mononeuropathic rats.
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Therefore, it is reasonable to assume that virtually all our 13. Fillingham R, Ness T: Sex-related hormonal influences on pain and anal-
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pain models reveal no sex differences in pentazocine analgesia in humans.
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we cannot fully rule out bias on the part of the investi- 17. Sarton E, Olofsen E, Romberg R, den Hartigh J, Kest B, Nieuwenhuijs D,
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GA: Ischemic but not thermal pain sensitivity varies across the menstrual cycle.
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readings. It therefore seems unlikely that bias was the 20. Raj P, Chado HN, Angst M, Heavner J, Dotson R, Brandstater ME, Johnson
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Somerville J, Wallace M, Panchal S: Painless electrodiagnostic current perception
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