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Background Vaso-occlusive pain crises (VOCs) are the “hallmark” of sickle-cell disease (SCD) and can lead to sympathetic nervous system dysfunction. Increased sympathetic nervous system activation during VOCs and/or pain can result in vasoconstriction, which may increase the risk for subsequent VOCs and pain. Hypnosis is a neuromodulatory intervention that may attenuate vascular and pain responsiveness. Due to the lack of laboratory-controlled pain studies in patients with SCD and healthy controls, the specific effects of hypnosis on acute pain-associated vascular responses are unknown. The current study assessed the effects of hypnosis on peripheral blood flow, pain threshold, tolerance, and intensity in adults with and without SCD. Subjects and methods Fourteen patients with SCD and 14 healthy controls were included. Participants underwent three laboratory pain tasks before and during a 30-minute hypnosis session. Peripheral blood flow, pain threshold, tolerance, and intensity before and during hypnosis were examined. Results A single 30-minute hypnosis session decreased pain intensity by a moderate amount in patients with SCD. Pain threshold and tolerance increased following hypnosis in the control group, but not in patients with SCD. Patients with SCD exhibited lower baseline peripheral blood flow and a greater increase in blood flow following hypnosis than controls. Conclusion Given that peripheral vasoconstriction plays a role in the development of VOC, current findings provide support for further laboratory and clinical investigations of the effects of cognitive–behavioral neuromodulatory interventions on pain responses and peripheral vascular flow in patients with SCD. Current results suggest that hypnosis may increase peripheral vasodilation during both the anticipation and experience of pain in patients with SCD. These findings indicate a need for further examination of the effects of hypnosis on pain and vascular responses utilizing a randomized controlled trial design. Further evidence may help determine unique effects of hypnosis and potential benefits of integrating cognitive–behavioral neuromodulatory interventions into SCD treatment.
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The effect of hypnosis on pain and peripheral
blood ow in sickle-cell disease: a pilot study
Ravi R Bhatt1
Sarah R Martin1
Subhadra Evans2
Kirsten Lung1
Thomas D Coates3,4
Lonnie K Zeltzer1
Jennie C Tsao1
1UCLA Pediatric Pain and Palliative
Care Program, Division of
Hematology-Oncology, Department
of Pediatrics, David Geffen School
of Medicine at UCLA, Los Angeles,
CA, USA; 2School of Psychology,
Deakin University, Geelong, VIC,
Australia; 3Department of Pediatrics,
Keck School of Medicine, University
of Southern California, 4Children’s
Center for Cancer and Blood
Diseases, Children’s Hospital Los
Angeles, Los Angeles, CA, USA
Background: Vaso-occlusive pain crises (VOCs) are the “hallmark” of sickle-cell disease (SCD)
and can lead to sympathetic nervous system dysfunction. Increased sympathetic nervous system
activation during VOCs and/or pain can result in vasoconstriction, which may increase the risk
for subsequent VOCs and pain. Hypnosis is a neuromodulatory intervention that may attenuate
vascular and pain responsiveness. Due to the lack of laboratory-controlled pain studies in patients
with SCD and healthy controls, the specific effects of hypnosis on acute pain-associated vascular
responses are unknown. The current study assessed the effects of hypnosis on peripheral blood
flow, pain threshold, tolerance, and intensity in adults with and without SCD.
Subjects and methods: Fourteen patients with SCD and 14 healthy controls were included.
Participants underwent three laboratory pain tasks before and during a 30-minute hypnosis ses-
sion. Peripheral blood flow, pain threshold, tolerance, and intensity before and during hypnosis
were examined.
Results: A single 30-minute hypnosis session decreased pain intensity by a moderate amount
in patients with SCD. Pain threshold and tolerance increased following hypnosis in the control
group, but not in patients with SCD. Patients with SCD exhibited lower baseline peripheral
blood flow and a greater increase in blood flow following hypnosis than controls.
Conclusion: Given that peripheral vasoconstriction plays a role in the development of VOC,
current findings provide support for further laboratory and clinical investigations of the effects
of cognitive–behavioral neuromodulatory interventions on pain responses and peripheral vas-
cular flow in patients with SCD. Current results suggest that hypnosis may increase peripheral
vasodilation during both the anticipation and experience of pain in patients with SCD. These
findings indicate a need for further examination of the effects of hypnosis on pain and vascular
responses utilizing a randomized controlled trial design. Further evidence may help determine
unique effects of hypnosis and potential benefits of integrating cognitive–behavioral neuro-
modulatory interventions into SCD treatment.
Keywords: sickle-cell disease, pain, hypnosis, blood
Sickle-cell disease (SCD) affects up to 100,000 Americans at a rate of one of every
500 African-American births.1 Vaso-occlusive pain crises (VOCs) are considered the
“hallmark” of SCD. VOCs occur frequently and may lead to development of chronic
pain, such that 30% of sampled patients with SCD have reported pain nearly every
day.1 It has been proposed that continuous allostatic stress load (eg, recurring VOCs)
can initiate a cascade of physiological changes in patients who experience recurrent
pain.2 Enhanced sympathetic nervous system activation, parasympathetic nervous
Correspondence: Ravi R Bhatt
UCLA Pediatric Pain and Palliative Care
Program, Department of Pediatrics,
David Geffen School of Medicine at
UCLA, 10833 Le Conte Ave – MDCC
22-464, Los Angeles, CA 90095, USA
Journal name: Journal of Pain Research
Article Designation: ORIGINAL RESEARCH
Year: 2017
Volume: 10
Running head verso: Bhatt et al
Running head recto: Hypnosis on pain and blood flow in SCD
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system withdrawal, and subsequent peripheral vaso-occlusion
in individuals with SCD3 result in hypoxic tissue damage,
which if recurrent may ultimately lead to changes to the
peripheral and central nervous systems. Indeed, transgenic
sickle mice exhibit hyperalgesia and neuronal hypersensitiv-
ity and individuals with SCD show hypersensitivity (lower
pain thresholds) to thermal stimuli,4 providing support for the
hypothesis that changes in peripheral and central neuronal
sensory signaling may lead to changes in pain responsive-
ness.5,6 If this hypothesis is validated, SCD patients with
frequent7 VOCs may be at higher risk for the development
of altered pain-response mechanisms and thus at higher risk
for the development of chronic pain. Therefore, examination
of interventions that may address factors associated with the
initiation of VOCs (eg, stress, pain, peripheral blood flow)
is needed.
Neuromodulatory interventions target cortical pain
modulation and have been shown to have a favorable effect
on central and peripheral physiological processes related to
the experience of acute and chronic pain;8,9 however, limited
data exist on the effect of neuromodulatory interventions on
mechanisms underlying VOCs (ie, microvascular stress/pain
responses) in patients with SCD. Engagement in hypnosis,
a cognitive-based neuromodulatory intervention, has been
associated with decreases in acute and chronic pain.8 Specifi-
cally, engagement in hypnosis is associated with changes in
central neuromodulatory and autonomic processes.9–13
Despite limited studies in SCD samples, preliminary
evidence suggests that hypnosis may be a promising inter-
vention to mitigate pain and the acute-stress response. One
study described patients with SCD reporting less pain overall
as well as during VOCs following a hypnosis intervention.14
A case study of a longitudinal hypnosis intervention in two
adolescents with SCD reported that the adolescents had a
feeling of overall warmth and a flushed appearance, presumed
to be associated with peripheral vasodilation.15 Other studies
reported preliminary evidence of hypnosis-induced vasodila-
tation in healthy controls and other pain conditions.14,15 These
results suggest that hypnosis may be a beneficial cognitive–
behavioral intervention for individuals with SCD. While
prior studies have shown promise for hypnosis as a clinical
tool for pain control in SCD, the mechanisms underlying the
effects of hypnosis on acute pain in this population remain
unknown. Because the clinical setting provides significant
variability in pain experiences, context, and responses, a
study of mechanisms of the effects of hypnosis on acute
pain in patients with SCD is best studied in the controlled
setting of a psychophysiological pain laboratory. Inclusion
of a comparison non-SCD control group can further provide
evidence on responses that may be unique to patients with
SCD. Therefore, the objective of the current study was to
assess the effects of hypnosis on acute experimental pain
responses and the corresponding responses in microvascu-
lature in adults with and without SCD.
Specic aims and hypotheses
The first aim of this pilot study was to assess whether base-
line pain responses (ie, pain threshold, tolerance, intensity)
and peripheral blood flow differed across patients with SCD
and race-matched healthy controls. The second aim was to
examine the effect of a brief hypnotic intervention on acute
experimental pain responsiveness during a thermal pain task,
as assessed by pain threshold, tolerance, and intensity. The
third aim was to determine the effects of hypnosis on changes
in peripheral blood flow during anticipation of the pain task
and during the pain task itself. Finally, the fourth aim was
to determine if the effect of hypnosis on pain responses and
blood flow differed across groups.
We hypothesized that patients with SCD would have
lower peripheral blood flow at baseline and demonstrate lower
pain thresholds and tolerance and higher pain intensity. We
hypothesized that in both groups, pain threshold and toler-
ance would increase and pain intensity would decrease after
hypnosis. We also hypothesized that peripheral blood-flow
amplitude would increase in both groups during the anticipa-
tion and experience of the pain tasks following the hypnosis
intervention. Finally, due to already present vasoconstriction
and reduced blood flow, we hypothesized that patients with
SCD would experience more benefit from hypnosis and thus
exhibit a greater change in blood flow following hypnosis. In
addition, we expected that patients with SCD would demon-
strate a greater increase in pain threshold and tolerance and
decrease in pain intensity following hypnosis compared to
healthy controls.
Subjects and methods
All procedures and methods of the current study were
approved by the Medical Institutional Review Board of the
University of California – Los Angeles. This trial is registered
with (NCT02620488).
Participants with SCD (n=14, eleven females, mean age 34
years, SD 12.88) and without SCD (n=14, eleven females,
mean age 37.23 years, SD 17.34) were recruited from vari-
ous locations in the greater Los Angeles area, including the
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Hypnosis on pain and blood ow in SCD
Cayenne Wellness Center and Children’s Foundation, and
various community SCD meetings in Los Angeles. Inclusion
criteria for the participants with SCD were a confirmed diag-
nosis of SS hemoglobin, SC hemoglobin, or S-thalassemia
hemoglobin. Inclusion criteria for the control population
were healthy individuals (ie, no chronic illness diagnosis)
whose race matched that of the SC patients. Exclusion criteria
included any neurologic disorder that affected sensation, skin
abnormalities/abrasions over the site of stimulus application,
and any acute or chronic illness that may have impaired
safety or lab performance. All participants were screened
via telephone to determine eligibility. We know of only one
study looking at changes in peripheral blood flow in disease
populations,16 and various studies investigating peripheral
blood flow following hypnotic suggestions.14,17
We chose our sample size to assess feasibility of the cur-
rent protocol and to see if there was any effect on a clinically
meaningful outcome that has been specifically implicated
in the genesis of VOCs, and our sample comparable to past
studies looking at hypnosis and peripheral blood flow.
All procedures were approved by the Institutional Review
Board of the University of California, Los Angeles and were
conducted at the Pediatric Pain and Palliative Care Program
Laboratory. The experimenter and the participant were seated
in the same room. The participant first provided written con-
sent and completed questionnaires. Next, a pulse-oximetry
transducer was placed on the participant’s left thumb to assess
peripheral blood flow. The participant sat quietly for 3 min-
utes, during which baseline peripheral blood-flow data were
collected. Following the baseline period, the experimenter
verbally announced, “In a minute, pain task 1 will begin”,
which marked the start of the pain-anticipation period that
lasted approximately 1 minute. The first set of pain tasks
(referred to pre-hypnosis tasks) were then conducted and
pain threshold and tolerance assessed. This was followed by
a 3-minute recovery, or washout period, and then followed
by assessing pain intensity. After the three pain tasks had
been completed, a psychologist trained in medical hypnosis
was then brought into the room to engage the participant in
a 30-minute hypnosis session. After the psychologist had
delivered hypnotic suggestions for analgesia (referred to as
post-hypnosis), the three pain tasks were readministered in
the same order as before hypnosis (with a 3-minute washout
period following assessment of pain threshold). During the
second pain task, the participant was receiving booster sugges-
tions from the psychologist. The anticipation period before the
application of the pain stimulus was investigated because it is
known that the anticipation of pain has influence over activity
in the somatosensory cortex, and thus can influence the pain
experience itself and corresponding physiological responses.18
A summary of the study phases is depicted in Figure 1. At
the end of the laboratory session, the psychologist conducted
a brief exit interview and confirmed that the participant was
fully alert and able to function cognitively before leaving the
premises. Compensation was then provided.
Peripheral blood ow
Peripheral blood flow and the heat signal from the neurosen-
sory analyzer were collected continuously throughout the study
using the BioPac MP150 system and AcqKnowledge software
(version 3.9.0) so that the timing of all of the measurements
was synchronized. Continuous readings for SpO2, pulse rate,
and pulse waveform were monitored using the pulse-oximetry
transducer placed on the left thumb at 1,000 Hz. The average
blood-flow amplitude – defined by the distance from trough
to peak on photoplethysmography – during each study phase
was used for analyses. Blood-flow data were then normalized
so that parametric statistical tests could be performed, and thus
no unit is reported, as they were normalized.
Laboratory pain responsiveness
All nociceptive stimulation was applied using a TSA-II
neurosensory analyzer (Medoc Advanced Medical Systems,
Baseline Anticipation
AnticipationPain intensity
Washout Hypnosis Repeat
Pain threshold Pain tolerance
Figure 1 Summary of study phases before and after hypnosis.
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Bhatt et al
Ramat Yishai, Israel). The TSA-II consists of a “thermode”
(30×30 mm) starting at a temperature of 32°C and reaching
a maximum temperature of 52°C to prevent tissue damage.
The thermode was placed on the participant’s right forearm
(brachioradialis muscle) just below the joint cavity and was
moved down 25.4 mm after each ramp was delivered. Each
participant was administered a set of pain tasks twice: before
and after hypnotic analgesia suggestions. Each set of pain
tasks consisted of three pain tasks (ie, assessment of pain
threshold, pain tolerance, and pain intensity; see Figure 1
for illustration of study procedure). This procedure was
established in a previous study.19
Pain threshold and tolerance
The pain-threshold and -tolerance tasks consisted of six
heat ramps. Once the ramp started, temperature rose 1°C
per second. During the first three ramps, participants indi-
cated when they first perceived the stimulus to be painful,
which was considered their pain threshold. During the
last three ramps, participants indicated when they could
no longer tolerate the pain (ie, pain tolerance). Then, the
threshold and tolerance ratings were averaged across all
six trials (three threshold and three tolerance trials), and
this value was used as the target temperature administered
during the third task.
Pain intensity
The third task consisted of two heat ramps delivered at the
aforementioned target temperature. Once the thermode
reached this temperature, the participant was asked to rate
his/her pain intensity on a 0–100 numeric rating scale (ie,
0 = no pain, 100 = worst pain possible). This value was clas-
sified as pain intensity.
Hypnosis intervention
After administration of the first set of pain tasks, the psy-
chologist greeted the patient. The participant was informed
about the facts and myths about medical hypnosis and was
provided an opportunity to ask questions. The hypnosis pro-
cedure was divided into five phases: 1) relaxation induction
to induce a narrowed focus of attention, 2) intensification
of the focused attention and involvement in imagery using
a “favorite place” suggestion, 3) pre-pain-task analgesic
suggestions for personally derived analgesic imagery, 4) pre-
and within-task blood-flow suggestions targeting improved
peripheral vasodilatation through imagery related to warming
and water flow, and 5) posttask posthypnotic suggestions for
continued comfort with an alert mind.
Relaxation induction
After the introduction, the participant was encouraged to sit in
a relaxed, comfortable position with eyes closed, if so desired.
The participant was then invited to experience relaxation
imagery, involving relaxation throughout the body with such
suggestions as “Allowing all the muscles in the shoulders to
let go, relaxing, feeling the support of the chair, sinking into
the chair… letting all the tension drain out of the shoulders”.
A deepening elevator exercise was then used, where the par-
ticipant was instructed to imagine going down in an elevator
and relaxing more deeply with each floor. This was followed
by instructions to imagine a favorite place, a place that evokes
feelings of relaxation and ease. The participant was invited to
experience the sights, smells, and textures of this favorite place,
eg, “… You inhale and smell all the delicious smells of your
favorite place. Perhaps it’s a beach, or a mountaintop. Somewhere
you’ve felt warm and safe and serene and content before. You
reach down and feel the ground. Is it sand slipping through the
fingers, or the coolness of new-grown grass? Let’s stay here, in
this place, for a few moments, while you soak in the sensations.
Hypnotic analgesia – suggestion 1
Next, consistent with the study by Jensen,20 analgesia sug-
gestions were offered in which the participant was invited to
imagine his or her own personal pain analgesia. Suggestions
were offered for this personal analgesia to be experienced as
a favorite color, a cooling balm, a pill, or any other way the
subject desired. Feelings of relief and comfort were encour-
aged immediately following use of the analgesia.
Hypnotic analgesia and vasodilatory imagery –
suggestion 2
The pain tasks were then administered a second time, while
the hypnotherapist continued to support the participant in the
experience of relief and comfort, eg, “… perhaps imagining
feelings of relief throughout the arm, the arm feeling more
and more comfortable as the medicine spreads”. During the
pain task, the psychologist continued to provide booster sup-
port to enhance the effects hypnotic analgesia further, eg, “…
Now imagine the area of the arm experiencing heat, imagine
it being completely surrounded… or completely filled… with
a sensation of relief… a pleasant sensation of comfort … you
might like to picture feelings of relief spreading down the arm.
Noticing how naturally, how easily, you are able to make the
arm feel different and much more pleasant… even decreasing
sensations from that area; as if it were disappearing”.
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Hypnosis on pain and blood ow in SCD
Posthypnotic period
After the pain tasks had been completed, the psychologist
invited the participant to experience warm-bath imagery,
designed to evoke vasodilatory sensations for a 5- to 7-minute
posttask recovery period. Instructions included: “This bath,
just the right kind of warmth. The water soothing muscles,
opening the body, to relax. Such a calm, pleasant feeling. The
warm water like liquid therapy, melting away troubles, wash-
ing away cares, allowing the body to relax into an even deeper
state of well-being”. The participant was then provided with
sufficient time to return to their normal state. A countdown
from 10 to 1 was used, with 1 being a state of full awareness
and alertness. The full script for the hypnosis procedure is
included in the Supplementary Material.
Data analysis
Shapiro–Wilk tests of normality were conducted on the
primary-outcome variables (blood flow, pain threshold, pain
tolerance, pain intensity) to determine appropriate statistical
tests. Natural log transformations were conducted to normal-
ize abnormal pain-responsiveness data, but the data were
resistant to transformation. As such, appropriate parametric
(ie, paired- or independent-sample t-tests) and nonparametric
(ie, Wilcoxon signed-rank and Mann–Whitney U-tests) mean-
difference tests were used for analyses that included normal
and abnormal variables, respectively. Independent-sample
t-tests were utilized to determine if baseline levels differed
across groups. Paired-sample mean-difference tests were
conducted to determine if there was a significant change in
laboratory pain responses and blood-flow amplitude following
hypnosis. To compare the effect of hypnosis on blood-flow
amplitude across groups, the change in amplitude following
hypnosis was determined by subtracting the mean amplitude
during hypnosis from the amplitude value during each post-
hypnosis task. Independent-sample t-tests were then used to
compare change in blood-flow amplitude across groups. All
significance testing was conducted at α=0.05. Parametric test-
ing used Cohen’s d as the effect size (small = 0.2, medium =
0.5, large = 0.8).19 Nonparametric testing used Pearson’s r as
the effect size (small = 0.1, medium = 0.3, large = 0.5).20 All
analyses were conducted in RStudio (version 3.2.1).
Preliminary results
The sample consisted of 14 total patients with SCD (eleven
females, mean age 34 years, SD 12.88) and 14 healthy controls
(eleven females, mean age 37.23 years, SD 17.34). Age was
not associated with baseline pain threshold (r=–0.16, p=0.58;
r=–0.48, p=0.09) or pain tolerance (r=–0.47, p=0.09; r=0.11,
p=0.7) in the SCD and control groups, respectively. Age was
associated with baseline peripheral blood flow in patients with
SCD (r=0.69, p=0.019), but not in controls (r=0.32, p=0.31).
Aim 1: baseline pain threshold, tolerance,
self-reported pain intensity, and blood
An independent-sample t-test revealed that there was no
difference in baseline pain threshold (t25.96=–0.07, d=0.03;
p=0.94), tolerance (t25.82=-0.25, d=0.09; p=0.81), or inten-
sity (t25.38=–0.75, d=0.29; p=0.457). The same test revealed
controls had higher peripheral blood flow during baseline
than patients with SCD (t21.17=2.54, d=1.01; p=0.019), but
there were no group differences during hypnosis (t19.14=1.61,
d=0.672; p=0.12). No other differences between groups were
found across tasks in blood flow. Means of each task across
groups are reported in Table 1.
Aim 2: effects of hypnosis on pain
threshold, tolerance, and self-reported
pain intensity
Paired t-tests and Wilcoxon signed-rank tests were conducted
within groups to determine the effect of hypnosis on controls
and patients with SCD for each task. Results revealed that
Table 1 Laboratory pain sensitivity and peripheral blood ow
during each phase of the study
Pain Controls (n=14) SCD (n=14)
SD Mean
Pre-hypnosis pain threshold 43.56 3.95 43.86 3.93
Pre-hypnosis pain tolerance 47.12 2.83 47.39 2.57
Pre-hypnosis pain intensity 31.68 22.44 38.64 26.27
Post-hypnosis pain threshold 45.9 3.81 44.45 3.71
Post-hypnosis pain tolerance 48.48 1.98 47.7 3
Post-hypnosis pain intensity 18.57 18.26 33.46 28.23
Blood ow Controls (n=13) SCD (n=11)
Mean SD Mean SD
Baseline** 0.82 0.07 0.76 0.05
Pre-hypnosis anticipation 1 0.81 0.08 0.76 0.05
Pre-hypnosis pain task 1 0.82 0.05 0.77 0.05
Pre-hypnosis anticipation 2 0.81 0.09 0.76 0.08
Pre-hypnosis pain task 2* 0.81 0.06 0.75 0.08
Hypnosis 0.8 0.05 0.76 0.06
Post-hypnosis anticipation 1* 0.79 0.06 0.82 0.05
Post-hypnosis pain task 1 0.79 0.05 0.79 0.07
Post-hypnosis anticipation 2 0.77 0.09 0.82 0.09
Post-hypnosis pain task 2 0.78 0.08 0.79 0.07
Note: *p<0.05; **p<0.01. Units for blood ow are normalized and thus arbitrary units.
Abbreviation: SCD, sickle-cell disease.
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post-hypnosis pain threshold (median 46.3) was higher than
pre-hypnosis threshold (median 44.1) in the control group
(Z=–2.542, r=0.68; p=0.011), but pre- and post-hypnosis pain
threshold (median 43.8 and 45.5, respectively) did not differ in
the SCD group (Z=–0.722, r=0.21; p=0.43). Similarly, results
revealed that pain tolerance significantly increased following
hypnosis in the control group (t13=2.49, d=0.67; p=0.027),
but not in the SCD group (Z=–0.0408, r=0.097; p=0.72).
Finally, post-hypnosis pain-intensity ratings (median 18.75)
were lower than pre-hypnosis ratings (median 26.25) in the
control group (Z=–2.275, r=–0.55; p=0.041). Post-hypnosis
pain-intensity ratings decreased in the SCD group, as indi-
cated by a moderate effect size, but did not reach statistical
significance (t13=–1.825, d=–0.49; p=0.091).
Aim 3: effects of hypnosis on peripheral
blood-ow responsiveness
A paired-sample t-test revealed that in the SCD group,
anticipation-period peripheral blood-flow amplitude was
significantly higher following hypnosis (t10=5.722, d=1.73;
p=0.0002). In the control group, there was no change between
pre- and post-hypnosis anticipation-period peripheral blood
flow (t12=–0.0207, d=0.06, p=0.84). There were no other
pre- and post-hypnosis differences in each task for either
group. See Table 2.
Aim 4: effect of hypnosis across groups
An independent-sample t-test across groups revealed that the
increases in blood-flow amplitude during post-hypnosis pain
task 1 – anticipation, pain task 1 (trending toward signifi-
cance, moderate effect size), and pain task 2 – anticipation
period (trending toward significance, moderate effect size)
were larger in the SCD group compared to controls (t=3.152,
d=1.242, p=0.004; t=1.704, d=0.68, p=0.1; t=1.403, d=0.56,
p=0.18). Change in blood-flow amplitude during the pain-
intensity task was similar across groups (Table 3).
The current pilot study assessed the effects of a brief hypnosis
session on acute experimental pain responses and peripheral
blood flow in adults with and without SCD. Overall, following
hypnosis, pain threshold and tolerance increased and pain
intensity decreased in the control group, and in the SCD
group peripheral blood flow increased to levels comparable
to controls. Pain-threshold and tolerance levels did not change
following hypnosis in patients with SCD, but a moderate
effect size showed decreased pain intensity in this group.
Acute-pain responsiveness
Examination of baseline pain responsiveness revealed that
there were no differences between controls and adults with
SCD in respect to pain threshold, tolerance, or intensity. We
found that following hypnosis, pain threshold and tolerance
significantly increased and pain intensity decreased in the
control group. Pain-threshold and tolerance levels did not
change following hypnosis in patients with SCD. There was
a trend toward decreased pain intensity in the SCD group,
and although this decrease was not statistically significant,
there was a moderate effect in the hypothesized direction.
Of note, based on previously published clinically significant
benchmarks for change in pain intensity, the mean decrease
in pain intensity in the control group reflected a minimally
Table 2 Effects of hypnosis ow on peripheral blood ow responsiveness
Control SCD
t p d t p d
Pre-hypnosis anticipation period –0.207 0.84 0.06 5.722 0.0002 1.73
Pre-hypnosis pain task –0.01 0.99 0.003 –0.587 0.57 0.18
Post-hypnosis anticipation period 0.187 0.85 0.05 1.294 0.23 0.39
Post-hypnosis pain task 0.255 0.8 0.07 0.719 0.49 0.22
Abbreviation: SCD, sickle-cell disease.
Table 3 Effect of hypnosis on peripheral blood ow
Change in blood-ow amplitude
Post-hypnosis period Control (n=13) SCD (n=11) t p d
Mean SD Mean SD
Pre-hypnosis anticipation period –0.01 0.068 0.06 0.042 –3.152 0.004 1.242
Pre-hypnosis pain task –0.01 0.049 0.02 0.035 –1.704 0.103 0.679
Post-hypnosis anticipation period –0.01 0.088 0.03 0.067 –1.403 0.175 0.561
Post-hypnosis pain task –0.01 0.026 0 0.076 –0.251 0.806 0.11
Abbreviation: SCD, sickle-cell disease.
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Hypnosis on pain and blood ow in SCD
important change,23 whereas the SCD group did not reach this
threshold.24 This pilot study may have had insufficient power
to detect a significant effect, and there was limited variability
in pain scores across each group. Future work may benefit
from including a larger sample size to examine the clinically
significant effects of hypnosis on pain outcomes.
Another explanation for the lack of reduction in pain
thresholds and tolerance in the SCD group may be the
presence of central sensitization resulting in persistent or
chronic pain. Persistent pain often experienced by individuals
with SCD2 may result in altered pain perception set points.
Modulation of neuronal activation thresholds have also
been observed via TRPV1 channels, which may translate to
changes in pain sensitivity to thermal stimuli21 and changes
in the central gain of the somatosensory system.22 However,
if patients with SCD are exposed to background chronic pain,
they may use a different reference point to indicate acute-pain
responses than those who do not have this experience with
chronic pain. Pain thresholds may be set higher in patients
with SCD compared to controls, because of either past experi-
ences with significant pain during VOCs or because of under-
lying chronic pain and altered pain perception. Therefore, the
limited dose of treatment (ie, a single, brief hypnosis session)
may have not been sufficient to alter acute-pain thresholds
and tolerance in the face of altered peripheral and central
pain-modulation systems secondary to pain history or the
development of chronic pain. Future studies would benefit
from assessing pain history and the presence of chronic pain
to determine how these may affect acute-pain responsiveness.
Mechanisms of acute pain and chronic pain in patients with
SCD warrant further study.
Peripheral blood ow
Although pain responses in the SCD group did differ sig-
nificantly following hypnosis, the single hypnosis session
did have a significant effect on peripheral blood flow in
anticipation of and in response to pain stimulation in the
SCD group. At baseline, patients with SCD had significantly
lower blood flow than controls, but these levels increased to
levels comparable to the control group during post-hypnosis
tasks, erasing the group differences found at baseline. A
change in blood flow with hypnosis was not seen in the
control group. Hypnosis may produce analgesia by engaging
descending inhibitory pathways from the brain and increas-
ing regional blood flow.23 In the current study, we expected
blood flow in both groups to increase with hypnosis, but
blood flow increased only in the SCD group. In this study,
we demonstrated that hypnosis was beneficial in improving
peripheral blood flow in anticipation of pain stimulation in
patients with SCD.
The current findings provide further support that patients
with SCD exhibit peripheral vascular system dysfunction.24
Our results indicate that a single brief hypnosis session may
activate top-down neuromodulatory mechanisms in patients
with SCD that result in increased vasodilation and peripheral
blood flow to a degree comparable to that of healthy controls.
Longitudinal research utilizing multiple hypnosis sessions
and continuous monitoring of blood flow in a larger sample is
warranted to examine the efficacy of hypnosis on blood flow
over time. Of interest is that peripheral blood flow increased
with hypnosis in anticipation of the pain event in SCD
patients, even without changes in reported pain responses.
Exploration of effects of hypnosis on pathways, such as the
autonomic nervous system (ANS), that can impact peripheral
blood flow but may not reach conscious awareness in patients
with SCD warrant further study.
Possible mechanisms
Considering possible mechanisms from a central perspective,
alterations in brain connectivity in inhibitory pain-control
networks have been observed during hypnosis.25,26 Specifi-
cally, increased connectivity between the ipsilateral insula
and bilateral dorsolateral prefrontal cortex has been observed
during hypnosis in healthy individuals who were highly
hypnotizable.25 In addition, decreased fractional amplitude
of low-frequency fluctuation in the dorsal anterior cingulate
cortex was observed in individuals who were highly hypnotiz-
able, a finding that may represent decreased attention to the
external environment during hypnosis25 and thus decreased
pain perception and responsiveness. Results from these
studies provide more evidence to support the concept that
hypnosis affects pain-modulatory systems, engages top-down
neuromodulatory pain circuits, and helps filter out external
stressors that may be contributing to allostatic stress load (ie,
pain and anticipation of pain). In the current study, although
no significant changes were observed in behavioral responses,
the increase in blood flow despite exposure to stress (ie, a
pain stimulus) may demonstrate this central pain-modulatory
In our sample, patients with SCD had lower baseline
peripheral blood flow compared to healthy controls, which is
consistent with other literature showing evidence of allostatic
load and ANS dysfunction in patients with SCD.27 In the cur-
rent study, following a single session of hypnosis, patients
with SCD exhibited increased peripheral blood flow in antici-
pation of and during pain tasks. This finding suggests that a
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Bhatt et al
single session of hypnosis may affect peripheral vascular pain
responses modulated by the ANS. Given that ANS-modulated
peripheral vasoconstriction with stress or pain may increase
likelihood for vaso-occlusion and VOCs,28–32 further examina-
tion of ANS mechanisms and neuromodulatory treatments
aimed at addressing pain-related autonomic regulation (eg,
hypnosis) is warranted.
Additional research is needed to understand the underly-
ing mechanisms of the effects of hypnosis in patients with
SCD. Specifically, future studies should examine neurally
mediated systems, such as the ANS (eg, heart-rate vari-
ability and electrodermal activity), and central supraspinal
parameters (eg, brain imaging) to advance our understanding
of treatment effects and SCD pain-related pathophysiology
from a multisystem perspective. Tailoring neuromodulatory
interventions for the specific needs of patients with SCD
has the potential to improve treatment and patient outcomes.
Limitations in the study should be noted. First, the small
sample of this pilot study limited statistical power, and
findings may not generalize to larger samples or broader
populations. In addition, this pilot study did not include a
treatment-control condition, which limits our ability to assess
the success or unique effects of hypnosis. Future work should
include a treatment-control condition (eg, diaphragmatic
breathing, distraction) within a randomized controlled trial to
examine and confirm the specific effects of hypnosis. Future
studies may also compare hypnosis to other evidence-based
interventions, such as biofeedback, cognitive–behavioral
therapy, or therapeutic yoga.33 The current study did not
examine the effects of hypnosis on clinical pain outcomes
either, including the frequency and/or severity of VOCs, and
future work would benefit from assessing these outcomes
through longitudinal methodology. Further, it is possible that
more than a single hypnosis session is needed to affect change
in perception and behavioral responses to acute pain, and the
examination of the effects of multiple hypnosis sessions on
pain outcomes is warranted.
In the current study, baseline peripheral blood flow was
related to age in patients with SCD. This finding is not surpris-
ing, since we would expect that as individuals age they are
more prone to microvascular pathologies,34 which may impair
vascular function. Therefore, potential previous vascular dam-
age in our adult sample may have influenced baseline data and
treatment effects. Sampling of adolescents within a specific
age range in future studies may help control for potential
effects of microvascular damage on blood-flow outcomes.
It is also important to note that only thermal sensory
testing was applied in the current study, and may not be
generalizable to all types of pain, as thermal pain has dif-
ferent underlying molecular mechanisms compared to other
types of pain.35 Additional covariates that may influence
ANS responsiveness and blood flow not included in the
current analyses (eg, pain history, SCD genotype, history of
VOCs, heart disease, anxiety, depression, smoking history,
and medication use) may have had an impact on the current
findings and should be assessed in future work. In addition,
the current study did not assess hypnotizability, which has
been shown to be associated with the effect of hypnosis on
autonomic response10 and vaso-occlusion.36 The inclusion of
qualitative post-hypnosis interviews in future work may help
further explore participants’ experiences and the effect of
hypnosis. Additionally, investigating the anticipation period
to unpainful stimuli would help address differences and
similarities in physiological responses. To help diminish the
effect of confounding variables, counterbalancing hypnotic
and nonhypnotic conditions may also help better isolate the
effect of hypnosis. Finally, the investigator and clinician in
the current study were not blinded to the patient condition,
which may have introduced bias. Future work will aim to
blind the investigator in the room or place the investigator
in a different room to collect psychophysiological measures.
This study demonstrated that the amount of peripheral blood
flow in anticipation of pain in adults with SCD increased
following a single, 30-minute hypnosis session. There was
a trend toward decreased perceived pain in SCD patients as
well. Given that peripheral vasoconstriction and blood flow
likely play a role in the development of VOCs, these findings
provide initial support for further study of mechanisms and
effects of neuromodulatory interventions in pain management
for patients with SCD. Collectively, our results suggest that
patients with SCD may need targeted treatment that addresses
both central and peripheral neurovascular processes. Future
work will determine if engagement in hypnotherapy affects
long-term pain and VOC outcomes in patients with SCD,
as well as examine pathways through which these effects
take place.
Author contributions
RRB was the primary author of manuscript and conducted
statistical analyses and interpretation of data. SRM was the
secondary author of the manuscript, interpreted data, and
provided expertise regarding sickle-cell disease. SE was
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Hypnosis on pain and blood ow in SCD
the lead developer of the hypnosis protocol and conducted
the hypnosis procedure with participants. KL assisted with
development of laboratory assessment and conducted labora-
tory assessments with participants. TDC provided expertise
regarding clinical aspects of sickle-cell disease. LKZ assisted
with development of the overall study protocol and provided
clinical expertise regarding the use of hypnosis for pain. JCT
provided expertise on laboratory pain assessment and was the
lead developer of the laboratory pain protocol. All authors
contributed toward data analysis, drafting and revising the
paper and agree to be accountable for all aspects of the work.
This research was supported by the National Heart, Lung,
and Blood Institute (1U54HL117718 to TDC and LKZ).
The abstract of this paper was presented at the 2016 American
Society of Hematology meeting as a poster with interim find-
ings. The authors report no conflicts of interest in this work.
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Bhatt et al
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... Psychosocial therapies Cognitive behavioral therapy Improved belief in ability to control pain, and decreased next-day pain intensity following completion of a session in children with SCD [144][145][146][147] Guided imagery Effective in reducing pain frequency and intensity in children with SCD 148 Audio-visual relaxation Reduced composite pain scores in patients with SCD 149 Hypnosis Decreased pain intensity and improved pain threshold in patients with SCD 150 Virtual reality Reduced VOC pain intensity with no reported side effects in patients with SCD 151 Physical therapies Yoga 30-minute yoga session provided greater reduction in pain levels when compared to control in patients with SCD 155 Acupuncture Attenuated inflammatory microenvironment and decreased hyperalgesia in sickle mice, also effective in reducing pain in patients with SCD 156,157 Massage therapy Improved measures of pain, depression, and anxiety in children with SCD 158 Dietary supplementation Mouse sickle diet Decreased chronic hyperalgesia in sickle mice increasing levels of serotonin in the spinal cord 137 Omega-3 fatty acid Significantly decreased opioid use and pain related school absences in pediatric sickle patients. Nonsignificant reduction of 45% in frequency of pain crises 163 Curcumin and CoQ10 Decreased inflammation and microglial activation leading to reduction in hyperalgesia in sickle mice. ...
... 149 A 30minute hypnosis session was also shown to decrease pain intensity and improve pain threshold in patients with SCD. 150 A more recent development is the use of immersive virtual reality as a way to alleviate pain. In a study of 30 pediatric patients at the University of California San Francisco Benioff Children's Hospital, the use of virtual reality in patients admitted with VOC pain crisis decreased pain intensity with no reported side-effects. ...
Pain is a major comorbidity of sickle cell disease (SCD). Patients with SCD may suffer from both acute and chronic pain. Acute pain is caused by recurrent and unpredictable episodes of vaso-occlusive crises (VOC), whereas the exact etiology of chronic pain is still unknown. Opioids are the mainstay for pain treatment, but the opioid epidemic has significantly altered access to prescription opioids and has brought concerns over their long-term use into the forefront, which have negatively impacted the treatment of sickle pain. Opioids remain potent analgesics but growing opioid-phobia has led to the realization of an unmet need to develop non-opioid therapies that can provide relief for severe sickle pain. This realization has contributed to the approval of 3 different drugs by the Food and Drug Administration (FDA) for the treatment of SCD, particularly to reduce VOC and/or have an impact on the pathobiology of SCD. In this review, we outline the challenges and need for validation of side-effects of opioids and provide an update on the development of mechanism-based translational therapies, specifically targeting pain in SCD.
... Psychological interventions are effective in controlling and even abolishing persistent pain 24 . Techniques such as hypnotism and mindfulness have been successfully used to modulate pain in sickle cell disease (SCD) and other conditions [25][26][27] . Success of these interventions led us to hypothesize that psychosocial enhancement could be an alternate strategy to treat chronic pain. ...
... Besides elevating mood, 5-HT and DA are also involved in modulating nociceptive stimuli via the descending pain pathway 37 . Enhanced levels of these neurotransmitters could therefore elevate mood and increase pain threshold, thus potentially reducing intensity and duration of pain [25][26][27] . ...
Full-text available
Treatment of severe chronic and acute pain in sickle cell disease (SCD) remains challenging due to the interdependence of pain and psychosocial modulation. We examined whether modulation of the descending pain pathway through an enriched diet and companionship could alleviate pain in transgenic sickle mice. Mechanical and thermal hyperalgesia were reduced significantly with enriched diet and/or companionship. Upon withdrawal of both conditions, analgesic effects observed prior to withdrawal were diminished. Serotonin (5-hydroxytryptamine, 5-HT) was found to be increased in the spinal cords of mice provided both treatments. Additionally, 5-HT production improved at the rostral ventromedial medulla and 5-HT accumulated at the dorsal horn of the spinal cord of sickle mice, suggesting the involvement of the descending pain pathway in the analgesic response. Modulation of 5-HT and its effect on hyperalgesia was also investigated through pharmaceutical approaches. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, showed a similar anti-nociceptive effect as the combination of diet and companionship. Depletion of 5-HT through p-chlorophenylalanine attenuated the anti-hyperalgesic effect of enriched diet and companionship. More significantly, improved diet and companionship enhanced the efficacy of a sub-optimal dose of morphine for analgesia in sickle mice. These findings offer the potential to reduce opioid use without pharmacological interventions to develop effective pain management strategies.
... HypnothérapieL'hypnose ericksonienne prend racine dans l'approche comportementaliste de JohnWatson et dans l'approche centrée sur le patient de Carl Rogers. Elle se définit comme une « expérience relationnelle basée sur la suggestion mettant en jeu des mécanismes prendre en charge des douleurs aiguës et chroniques et leurs anticipations négatives(147). ...
L’hématologie pédiatrique est une spécialité médicale prenant en charge des patients de 0 à 18 ans, atteints de maladies malignes comme la leucémie aigüe ou de maladies non-malignes comme la drépanocytose, et traités par diverses thérapeutiques. L’adhésion thérapeutique constituée par l’adhésion médicamenteuse et non-médicamenteuse, c’est-à-dire l’adhésion aux thérapeutiques non-médicamenteuses, aux recommandations diététiques, aux rendez-vous médicaux et d’imagerie. L’adhésion thérapeutique est influencée par de nombreux facteurs et est non-optimale, en hématologie pédiatrique comme pour d’autres spécialités médicales. Toutefois, ses enjeux individuels et collectifs sont importants; c’est pourquoi il est essentiel d’améliorer cette adhésion. Actuellement, plusieurs interventions existent, mais elles sont rares en hématologie pédiatrique. La problématique de ce travail est la suivante : Alors que l’adhésion thérapeutique en hématologie pédiatrique a des enjeux importants, comment se fait-elle qu’elle soit non-optimale ? Pour cela deux études ont été menées. Elles ont utilisé la méthodologie qualitative en explorant les représentations et les vécus vis-à-vis de l’adhésion thérapeutique. La première étude a été menée auprès d’aidants et de professionnels de santé d’enfants ayant eu une allogreffe de cellules souches hématopoïétiques. Les résultats montrent d’une part que l’adhésion médicamenteuse et non-médicamenteuse semble influencer par des facteurs similaires. D’autre part, l’entité familiale a toute sa place dans la prise en charge et l’adhésion médicamenteuse et non-médicamenteuse. En plus de la sortie d’hospitalisation, l’adolescence et les maladies non-malignes sont exprimées par les professionnels de santé comme des facteurs majeurs de non-adhésion lors d’une allo-greffe. Pour comprendre l’adhésion thérapeutique là où elle semble plus problématique, la seconde étude de ce travail est menée auprès de patients adolescents et adultes atteints de drépanocytose hors allogreffe, d’aidants et de professionnels de santé. Les résultats de cette étude ont montré qu’au moment de l’adolescence a lieu une « double transition », la « transition d’état du patient » et la transition de soins pédiatrie-adulte. Cette « double transition » fait de l’adolescence un moment particulièrement « à risque » de rupture de soins, nécessitant donc une intervention d’amélioration de l’adhésion thérapeutique. Les résultats de cette étude ont montré que cette intervention doit être multifactorielle et centrée sur le patient, en intégrant les aidants. Pour répondre à ce besoin, l’étude interventionnelle DREPADO est proposée. Il s’agit d’un programme de transition en plusieurs axes, éducatif, psychologique et social, intégré à un essai clinique contrôlé randomisé. Ce programme de transition est comparé à la prise en charge habituelle du patient. L’objectif principal de cet essai clinique est d’améliorer l’état de santé des adolescents atteints de drépanocytose dans les deux années qui suivent leur transfert en secteur adulte (mesuré sur le nombre d’hospitalisation pour complication de la maladie). Actuellement DREPADO est mis en œuvre en France métropolitaine et DOM-TOM (début octobre 2020 : 4 centres ouverts et 22 patients inclus). Ce travail de thèse a permis de mieux comprendre la problématique de l’adhésion thérapeutique en hématologie pédiatrique et de proposer une étude interventionnelle adaptée.
... Existing evidence related to the efficacy of hypnosis as a nonpharmacological intervention to address the pain and symptoms often associated with chronic disease management is mixed [34][35][36]. Heterohypnosis alone or followed by self-hypnosis treatment may benefit some individuals with chronic pain of various etiologies. ...
Full-text available
Sickle cell disease (SCD) is characterized by recurrent painful vasoocclusive crises. Current evidence focuses on the frequency of acute pain crises resulting in emergency department use and nonplanned inpatient hospital admissions; yet few studies focus on pain sequelae outside the healthcare system or how individuals self-manage their chronic SCD-related pain. This study investigated the feasibility of a biobehavioral intervention as an adjunct nonpharmacological therapy to assist in the self-management of chronic pain. A randomized, controlled clinical trial of hypnosis was conducted in outpatients with SCD (n = 31). Patient-reported outcomes (PROs) administered at baseline, five, and twelve weeks from both groups included pain frequency, intensity, and quality (Pain Impact Scale (PIQ) and Numerical Rating Scales); anxiety (State-Trait Anxiety Inventory), coping strategies (Coping Strategies Scale), sleep (Pittsburgh Sleep Quality Index (PSQI)), and depression (Beck Depression Inventory (BDI)). The same PROs were collected at weeks seventeen and twenty-four from the control group after the crossover. No significant group by time interaction effects were found in any of the PROs based on the repeated-measures mixed models. The PIQ and PSQI scores decreased over time in both groups. Post hoc pairwise comparisons with the Bonferroni adjustment indicated that the mean PIQ score at baseline decreased significantly by week 12 (p = 0.01) in the hypnosis group. There were no significant changes across time before and after the crossover in any of the PROs in the control group. As suggested by these findings, pain impact and sleep in individuals with SCD may be improved through guided mind-body and self-care approaches such as hypnosis.
... This results in peripheral and central sensitization resulting in chronic pain refractory to classical therapy. Therefore, recently, attention has focused on perception-based components of pain because of their ability to reduce pain through nonpharmacological behavioral techniques, such as imagery, mindfulness and relaxation training, hypnosis and cognitive behavioral therapy (23). ...
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Los pacientes con enfermedad de células falciformes (ECF), también denominada drepanocítica, sufren un dolor intenso que suele comenzar durante la infancia y aumenta su gravedad a lo largo de la vida, lo que lleva a la hospitalización y a una mala calidad de vida a lo largo de los años. Una característica única de la ECF son las crisis vaso-oclusivas (CVO), caracterizadas por episodios recurrentes e impredecibles de dolor agudo. La obstrucción microvascular durante una CVO provoca una disminución del suministro de oxígeno a la periferia y una lesión por isquemia y posterior reperfusión, inflamación, estrés oxidativo y disfunción endotelial, todo lo cual puede perpetuar un microambiente nocivo que provoca dolor. Por otro lado, además de los dolores agudos episódicos, los pacientes con ECF también padecen dolor crónico, definido como dolor casi diario durante un periodo de 6 meses, asociado a trastornos psicosociales. Pueden deberse a lesiones crónicas como úlceras cutáneas, necrosis avascular ósea o infartos en diversos órganos. Asimismo, la sensibilización central parece estar directamente involucrada en la cronicidad del dolor y existe un componente de dolor neuropático claramente infradiagnosticado e infratratado. El tratamiento actual del dolor moderado a intenso en la ECF se basa principalmente en la administración de los opioides, vía oral, de liberación rápida ambulatoria o en forma de analgesia controlada por el paciente vía intravenosa intrahospitalaria. Sin embargo, el uso de opioides a largo plazo está asociado con múltiples efectos secundarios. Esta revisión presenta los últimos avances en la comprensión de la fisiopatología del dolor en la ECF y se describen los mecanismos subyacentes que pueden ayudar a desarrollar nuevas estrategias terapéuticas y/o preventivas para mejorar el dolor en la ECF.
... 106 These and other modalities, such as transcutaneous electrical nerve stimulation (TENS), heat, cold and vibration, relaxation, distraction, massage, music, guided imagery, self-hypnosis, self-motivation, acupuncture and biofeedback have been used in controlling pain in SCD; however, there are no controlled clinical studies to support their use. 10,105,[107][108][109][110] Possible targets of pain treatment of SCD and future possibility. Many pharmacological treatments targeting one or more of the mechanisms that contribute to the pain relief or the disease process of SCD are being explored in clinical trials. ...
Objectives The hallmark of sickle cell disease (SCD) is acute and chronic pain, and the pain dominates the clinical characteristics of SCD patients. Although pharmacological treatments of SCD targeting the disease mechanisms have been improved, many SCD patients suffer from pain. To overcome the pain of the disease, there have been renewed requirements to understand the novel molecular mechanisms of the pain in SCD. Methods We concisely summarized the molecular mechanisms of SCD-related acute and chronic pain, focusing on potential drug targets to treat pain. Results Acute pain of SCD is caused by vaso-occulusive crisis (VOC), impaired oxygen supply or infarction-reperfusion tissue injuries. In VOC, inflammatory cytokines include tryptase activate nociceptors and transient receptor potential vanilloid type 1. In tissue injury, the secondary inflammatory response is triggered and causes further tissue injuries. Tissue injury generates cytokines and pain mediators including bradykinin, and they activate nociceptive afferent nerves and trigger pain. The main causes of chronic pain are from extended hyperalgesia after a VOC and central sensitization. Neuropathic pain could be due to central or peripheral nerve injury, and protein kinase C might be associated with the pain. In central sensitization, neuroplasticity in the brain and the activation of glial cells may be related with the pain. Discussion In this review, we summarized the molecular mechanisms of SCD-related acute and chronic pain. The novel treatments targeting the disease mechanisms would interrupt complications of SCD and reduce the pain of the SCD patients.
... The fact that humans may each have characteristic autonomic vascular reactivity likely contributes to the clinical variability in VOC frequency and is probably also important in other diseases. Furthermore, recent pilot studies have shown that cognitive-based therapies can modulate peripheral vasoconstriction in SCD [68] and might offer a new approach for VOC prevention. ...
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Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.
Sickle cell disease (SCD) is a genetic disorder characterized by hemolysis, end-organ damage, inflammation, and pain. Recurrent and unpredictable episodes of acute pain due to vaso-occlusive crises are a unique feature of SCD. Many patients also develop lifelong chronic pain. Opioids are the primary method of pain treatment in SCD; however, continued use is associated with several adverse effects. Integrative approaches to treating pain in SCD are increasingly being explored to prevent the side effects associated with opioids. In this review, we highlight the mechanisms of pain in SCD and describe mechanism-based integrative approaches for treating pain.
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Purpose of review: Sickle cell disease (SCD) is a hematological disorder which leads to serious complications in multiple organ systems. While significant research has addressed many of the effects of acute pain episodes and end-organ damage connected to this disease, little has approached the chronic pain state associated with this condition. Recent findings: Associated chronic pain represents a significant detractor from the quality of life experienced by these patients, affecting over half of those with SCD on more days than not. Current treatment typically is centered upon preventing and responding to acute vasoocclusive crises, presumably because this is the most common reason for hospitalization in these patients. The lack of management of chronic pain symptoms leaves many with SCD in a state of suffering. In this review, the treatment methodologies of SCD patients are examined including alternative treatments, both pharmaceutical and non-pharmaceutical, as well as procedural approaches specifically aimed at reducing chronic pain in these patients.
Pain and vaso-occlusive crises (VOC) are hallmark complications of sickle cell disease (SCD) and result in significant physical and psychosocial impairment. The variability in SCD pain frequency and triggers for the transition from steady state to VOC are not well understood. This paper summarizes the harmful physiological effects of pain and emotional stressors on autonomically-mediated vascular function in individuals with SCD and the effects of a cognitive, neuromodulatory intervention (i.e. hypnosis) on microvascular blood flow. We reviewed recent studies from the authors' vascular physiology laboratory that assessed microvascular responses to laboratory stressors in individuals with SCD. Results indicate that participants with SCD exhibit marked neurally mediated vascular reactivity in response to pain, pain-related fear, and mental stress. Further, pilot study results show that engagement in hypnosis may attenuate harmful microvascular responses to pain. The collective results demonstrate that autonomically-mediated vascular responses to pain and mental stress represent an important SCD intervention target. This ongoing work provides physiological justification for the inclusion of cognitive, neuromodulatory and complementary treatments in SCD disease management and may inform the development of targeted, integrative interventions that prevent the enhancement of autonomic vascular dysfunction in SCD.
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Peripheral inflammation causes mechanical pain behavior and increased action potential firing. However, most studies examine inflammatory pain at acute, rather than chronic time points, despite the greater burden of chronic pain on patient populations, especially aged individuals. Furthermore, there is disagreement in the field about whether primary afferents contribute to chronic pain. Therefore, we sought to evaluate the contribution of nociceptor activity to the generation of pain behaviors during the acute and chronic phases of inflammation in both young and aged mice. We found that both young (2 months old) and aged (>18 months old) mice exhibited prominent pain behaviors during both acute (2 day) and chronic (8 week) inflammation. However, young mice exhibited greater behavioral sensitization to mechanical stimuli than their aged counterparts. Teased fiber recordings in young animals revealed a twofold mechanical sensitization in C fibers during acute inflammation, but an unexpected twofold reduction in firing during chronic inflammation. Responsiveness to capsaicin and mechanical responsiveness of A-mechanonociceptor (AM) fibers were also reduced chronically. Importantly, this lack of sensitization in afferent firing during chronic inflammation occurred even as these inflamed mice exhibited continued behavioral sensitization. Interestingly, C fibers from inflamed aged animals showed no change in mechanical firing compared with controls during either the acute or chronic inflammatory phases, despite strong behavioral sensitization to mechanical stimuli at these time points. These results reveal the following two important findings: (1) nociceptor sensitization to mechanical stimulation depends on age and the chronicity of injury; and (2) maintenance of chronic inflammatory pain does not rely on enhanced peripheral drive.
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Nous proposons de discuter des études comportementales, électrophysiologiques et de neuroimagerie investiguant l’hypnose comme un processus de conscience ou comme un outil pour moduler les réponses cérébrales au repos ou lors de stimulations douloureuses. Différentes études ont mis en évidence une modification de l’activité cérébrale au niveau des réseaux interne (conscience de soi) et externe (conscience de l’environnement). Par ailleurs, les mécanismes cérébraux qui sous-tendent la modulation de la perception de la douleur sous-hypnose comprennent des régions telles les cortex cingulaire antérieur et frontal, les ganglions de la base et le thalamus. Combinée à une anesthésie locale et une sédation consciente chez les patients subissant une chirurgie, l’hypnose est également associée à une amélioration péri- et postopératoire du confort des patients et des chirurgiens. Enfin, l’hypnose peut être considérée comme un outil utile pour créer des symptômes de conversion et de dissociation chez des sujets sains, ce qui permet de mieux caractériser ces troubles en mimant des observations cliniques similaires.
INTRODUCTION: Sickle cell disease is an inherited blood disorder characterized by vaso-occlusive crises (VOC). HbS in red blood cells (RBC) polymerizes rapidly after it releases oxygen to tissues, causing RBC to become rigid. Anything that decreases flow in the microvasculature increases the chance that this flexible-to-rigid transformation occurs causing the rigid blood cell to lodge in the microvasculature, therefore increasing the chance of vaso-occlusion and the risk of VOC. Although hypoxia and stress are known risk factors for crises, the exact mechanism that initiates VOC events is not well known. We have previously shown that transient hypoxia causes parasympathetic withdrawal and sighs cause vasoconstriction more frequently in SCD subjects than in normal controls. Pain is the hallmark of SCD and is a consequence of VOC but has not been considered as a possible trigger of vasoconstriction that may lead to VOC. OBJECTIVES: To determine if heat induced pain causes decrease in peripheral blood flow (PBF) in SCD. METHODS: 30 SCD and 30 control subjects (healthy and sickle cell traits) were recruited at Children's Hospital Los Angeles (CHLA). Quasi-periodic pulses of pain were induced on the right forearm using TSA-II neuro analyzer heating thermode. We implemented a technique using cross correlation analysis to detect changes in complex microvascular flow signals measured bilaterally on the hands, using laser-Doppler flowmeter (LDF), Peripheral Arterial Tonometer (PAT) and photo-plethysmography (PPG). We also measured the average drop from baseline in the microvascular flow during the heat pain. Data were analyzed using one- and two- sample Student t-test. RESULTS: Data on 53 subjects were analyzed. There was a significant correlation between heat pain pulses and PBF responses, as well as a significant drop in blood flow in all study participants (PPG signal, both p<0.001), indicating that heat pain pulses lead to vasoconstriction. Males had higher correlation (p<0.005) and stronger vasoconstriction (p<0.05) during heat stimuli compared to females. Other Signals (LDF and PAT) had a similar pattern but were less significant. The vasoconstriction response consisted of two components, the first one occurred prior to administration of the painful stimulus indicating that anxiety or anticipation of pain causes significant vasoconstriction. Application of the painful stimulus causes further vasoconstriction. CONCLUSIONS: The findings demonstrate a significant decrease in PBF in both SCD and controls in response to heat pain and possibly to pain anticipation. The decrease in PBF could play a critical role in the genesis of VOC in SCD by markedly prolonging microvascular transit time, increasing the likelihood of red cell entrapment when sickle red cells transform from flexible to rigid. Furthermore, the potent vasoconstriction response to pain in SCD means that pain resulting from VOC could potentially trigger a cascade effect in which vasoconstriction could lead to even more serious VOC. Since regional blood flow is regulated by the autonomic nervous system (ANS), which has been described to be dysfunctional in SCD, our study calls attention to the ANS as a factor in the genesis of crisis in this disorder. Disclosures No relevant conflicts of interest to declare.
Hypnosis has proven clinical utility, yet changes in brain activity underlying the hypnotic state have not yet been fully identified. Previous research suggests that hypnosis is associated with decreased default mode network (DMN) activity and that high hypnotizability is associated with greater functional connectivity between the executive control network (ECN) and the salience network (SN). We used functional magnetic resonance imaging to investigate activity and functional connectivity among these three networks in hypnosis. We selected 57 of 545 healthy subjects with very high or low hypnotizability using two hypnotizability scales. All subjects underwent four conditions in the scanner: rest, memory retrieval, and two different hypnosis experiences guided by standard pre-recorded instructions in counterbalanced order. Seeds for the ECN, SN, and DMN were left and right dorsolateral prefrontal cortex, dorsal anterior cingulate cortex (dACC), and posterior cingulate cortex (PCC), respectively. During hypnosis there was reduced activity in the dACC, increased functional connectivity between the dorsolateral prefrontal cortex (DLPFC;ECN) and the insula in the SN, and reduced connectivity between the ECN (DLPFC) and the DMN (PCC). These changes in neural activity underlie the focused attention, enhanced somatic and emotional control, and lack of self-consciousness that characterizes hypnosis.
Sickle cell disease (SCD), a hemoglobinopathy, causes sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. A vast majority of SCD patients experience pain on a chronic basis, and many turn to opioids to provide limited relief. The side effects that come with chronic opioid use push for research into understanding the specific mechanisms of SCD-associated chronic pain. Current advances in SCD-associated pain have focused on alterations in the pain pathway including nociceptor sensitization and endogenous pain inducers. This article reviews the underlying pathophysiology of SCD, potential pain mechanisms, current treatments and their mechanism of action, and future directions of SCD-associated pain management. The information provided could help propel research in SCD-associated chronic pain and uncover novel treatment options for clinicians.
Abstract Evidence supports the efficacy of hypnotic treatments, but there remain many unresolved questions regarding how hypnosis produces its beneficial effects. Most theoretical models focus more or less on biological, psychological, and social factors. This scoping review summarizes the empirical findings regarding the associations between specific factors in each of these domains and response to hypnosis. The findings indicate that (a) no single factor appears primary, (b) different factors may contribute more or less to outcomes in different subsets of individuals or for different conditions, and (c) comprehensive models of hypnosis that incorporate factors from all 3 domains may ultimately prove to be more useful than more restrictive models that focus on just 1 or a very few factors.
Sickle cell disease is an inherited hemoglobinopathy caused by a single amino acid substitution in the β chain of hemoglobin that causes the hemoglobin to polymerize in the deoxy state. The resulting rigid, sickle-shaped red cells obstruct blood flow causing hemolytic anemia, tissue damage, and premature death. Hemolysis is continual. However, acute exacerbations of sickling called vaso-occlusive crises (VOC) resulting in severe pain occur, often requiring hospitalization. Blood rheology, adhesion of cellular elements of blood to vascular endothelium, inflammation, and activation of coagulation decrease microvascular flow and increase likelihood of VOC. What triggers the transition from steady state to VOC is unknown. This review discusses the interaction of blood rheological factors and the role that autonomic nervous system (ANS) induced vasoconstriction may have in triggering crisis as well as the mechanism of ANS dysfunction in SCD.
Improvements in survival for children with sickle cell disease (SCD) during the last 30 years have been well established. Whether similar improvements for adults with the disease have occurred is unknown. We investigated mortality rates for children and adults with SCD. We used the National Center for Health Statistics multiple-cause-of-death files to examine age at death and calculate mortality rates from 1979 to 2005. We examined trends in mortality rates using negative binomial regression, and we examined age at death using t-tests and linear regression. We identified 16,654 sickle cell-related deaths. Mean age at death was significantly different for males (33.4 years, 95% confidence interval [CI] 33.0, 33.7) than for females (36.9 years, 95% CI 36.5, 37.4). In a regression model controlling for gender, the mean age at death increased by 0.36 years for each year of the study. The median age at death in 2005 was 42 years for females and 38 years for males. The overall mortality rate increased 0.7% (<0.001) each year during the time period studied. The adult (>19 years of age) mortality rate increased by 1% (<0.001) each year during the time period studied. The pediatric mortality rate decreased by 3% (<0.001) each year during the time period studied. These data confirm prior findings of a significant decrease in mortality for children with SCD. The mortality rate for adults appears to have increased during the same time period. It seems unlikely that this increase is due merely to an influx of younger patients surviving to adulthood and may reflect a lack of access to high-quality care for adults with SCD.