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The Role of Descending Modulation in Manual Therapy and Its Analgesic Implications: A Narrative Review



Manual therapy has long been a component of physical rehabilitation programs, especially to treat those in pain. The mechanisms of manual therapy, however, are not fully understood, and it has been suggested that its pain modulatory effects are of neurophysiological origin and may be mediated by the descending modulatory circuit. Therefore, the purpose of this review is to examine the neurophysiological response to different types of manual therapy, in order to better understand the neurophysiological mechanisms behind each therapy’s analgesic effects. It is concluded that different forms of manual therapy elicit analgesic effects via different mechanisms, and nearly all therapies appear to be at least partially mediated by descending modulation. Additionally, future avenues of mechanistic research pertaining to manual therapy are discussed.
Review Article
The Role of Descending Modulation in Manual Therapy
and Its Analgesic Implications: A Narrative Review
Andrew D. Vigotsky1and Ryan P. Bruhns2
1Kinesiology Program, Arizona State University, Phoenix, AZ 85004, USA
2College of Medicine, University of Arizona, Tucson, AZ 85724, USA
Correspondence should be addressed to Andrew D. Vigotsky;
Received  July ; Revised  November ; Accepted  November 
Academic Editor: Bjorn Meyerson
Copyright ©  A. D. Vigotsky and R. P. Bruhns. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Manual therapy has long been a component of physical rehabilitation programs, especially to treat those in pain. e mechanisms
of manual therapy, however, are not fully understood, and it has been suggested that its pain modulatory eects are of
neurophysiological origin and may be mediated by the descending modulatory circuit. erefore, the purpose of this review is to
examine the neurophysiological response to dierent types of manual therapy, in order to better understand the neurophysiological
mechanisms behind each therapy’s analgesic eects. It is concluded that dierent forms of manual therapy elicit analgesic eects
via dierent mechanisms, and nearly all therapies appear to be at least partially mediated by descending modulation. Additionally,
future avenues of mechanistic research pertaining to manual therapy are discussed.
1. Introduction
Manual therapy has been a component of physical rehabilita-
tion programs since as early as  BC []. Since its inception,
many variations of manual therapy techniques have been
developed and marketed. Each year, upwards of . billion
is spent in the US on manual therapies, including chiroprac-
tic/osteopathic manipulation and massage []. Despite the
large annual nancial expenditures on manual therapies, its
mechanisms are not yet fully understood. Current research
suggests that a neurophysiological response to manual ther-
apy is responsible for clinically signicant decreases in pain
[–]. Included in the neurophysiological response is the
descending pain modulation circuit, which may be a principle
mechanism in the analgesic eect of manual therapies.
2. Descending Modulation of Pain
Melzack and Wall [] were the rst to explain the potential
mechanisms of a central pain modulatory system, wherein
the authors described the gate control theory of pain,
which simply states that nonnoxious input suppresses painful
output by inhibiting dorsal root nociceptors. Gate control is
oen triggered by touch or nonthreatening sensory input,
which activates low-threshold A𝛽bers that inhibit noci-
ceptive input from A𝛿and C aerent bers [, ]. How-
ever, another mechanism by which analgesia is induced is
through descending modulatory circuits, wherein numerous
neurotransmitters, including serotonin (-HT), vasopressin,
oxytocin, adenosine, endocannabinoids, and endogenous
opioids (EOs), have been shown to act on structures such as
the rostral ventromedial medulla (RVM) and periaqueductal
grey (PAG) in order to modulate nociceptive circuits and pain
output [–]. What is more, and important to consider, is
that the analgesic response elicited by human touch [] and
placebo [–] is also mediated by EO and endocannabi-
𝛽-endorphins are EO peptides that have not only been
shown to have a comparable analgesic eect to morphine
inhibitory control (DNIC) is the process by which aerent
noxious signals are inhibited from the peripheral nervous
system (PNS). Using a rat model, Le Bars et al. [] and
Le Bars et al. [] found that neurons were inhibited by
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Volume 2015, Article ID 292805, 11 pages
Pain Research and Treatment
noxious stimuli (a hot bath), therein coining the term DNIC.
Since then, multiple studies have suggested that EO is an
underlying mechanism of DNIC [, ], and more recently it
has been suggested that DNIC be referred to as conditioned
pain modulation (CPM), by which this mechanism will be
referred to herein []. It has been suggested that manual
therapies that are nociceptive in nature are mediated by CPM
Previous reviews have noted potential descending modu-
latory mechanisms, an endogenous opioid response, in both
physical therapy [] and physical medicine []; however,
the neurochemical response to manual therapy and its
implications for descending pain modulation, to the authors
knowledge, have not yet been thoroughly reviewed.
3. Search Methodology
In order to investigate the neurotransmitters associated with a
descending inhibitory response to manual therapy, PubMed
was searched using the following query: (“manual therapy”
OR “acupressure” OR “neural mobilization” OR “joint manip-
ulation” OR “joint mobilization” OR “massage” OR “manip-
ulative” OR “spinal manipulation”) AND (“vasopressin” OR
“naloxone” OR “glial” OR “receptors” OR “biomarkers”
OR “cannabinoid” OR “biochemical” OR “endorphin” OR
“beta-endorphin” OR “oxytocin” OR “opioid” OR “opioids”
OR “serotonin” OR “dopamine” OR “neurotransmitter” OR
“neuropeptide” OR “antinociceptive”) NOT (“labor” OR
cardiac” OR “uterus” OR “milk”) in November . All
relevant studies and reviews that were written in English were
included, with the exception of those that were retracted.
Animal studies were included, as they may provide further
measure in humans; for example, utilizing brain biopsies to
observe receptor activity. e general methods and important
ndings pertaining to descending pain modulatory systems
were described.
4. Manipulation Therapies
rough the millennia, numerous types of manipulation
been purported to cure everything from scarlet fever and
diphtheria to hearing loss []. However, perhaps the most
widely proclaimed outcome from manipulative therapy is
pain relief, which may be modulated by neurotransmitters
that act on the RVM and PAG.
4.1. Osteopathic Manipulative erapy. Degenhardt et al. []
recruited twenty male subjects: ten with low back pain
and ten without. Four osteopathic manipulative therapy
(OMT) techniques (articulatory treatment system, mus-
cle energy, so tissue technique, and Strain-Counterstrain)
were performed on areas of subjects’ “somatic dysfunc-
tion,” dened as “sites of muscle hypertonicity, tenderness,
and joint restriction” []. Blood was collected prior to
(baseline),  minutes, and  hours aer OMT. Increases
in 𝛽-endorphin and N-palmitoylethanolamide (PEA), an
endogenous analog of arachidonylethanolamide (AEA), or
anandamide, an endocannabinoid,were observed  minutes
aer treatment; at  hours, similar biomarker changes from
baseline were found. Subjects with chronic low back pain
presented greater biomarker alterations following OMT than
the control (asymptomatic) group. However, because no true
control or sham group was utilized, it is not possible to
distinguish whether these changes in biomarkers were due to
the placebo eect or something greater, as endocannabinoids
these data do show that those in pain respond dierently to
treatment than asymptomatic individuals.
In a blinded, randomized control trial, McPartland et al.
[] investigated the eects of OMT on plasma endocannabi-
noid concentrations; that is, AEA and -arachidonoylglycerol
(-AG). irty-one subjects received either an OMT treat-
sham treatment. Importantly, subjects were recruited from a
patient population of an osteopath who regularly uses OMT;
therefore, the patients most likely believe the treatment is e-
cacious. No changes were observed in -AG concentrations
in either group. In the sham group, negligible, insignicant
changes in AEA were observed (%). e OMT group
experienced a % increase (. pmol/mL) in AEA over
baseline, but this increase did not achieve statistical signif-
icance; however, this dierence may certainly be clinically
relevant, as indicated by changes in Drug Reaction Scale
(DRS) scores. ese data suggest that endocannabinoids do
4.2. Spinal Manipulation. Anumberofstudieshaveinves-
tigated the pain modulation mechanisms of spinal manip-
ulation, which, as the name implies, is specic only to
spinal articulation. e rst to do so were Vernon et al.
[], who found a small but statistical increase in plasma
𝛽-endorphin levels in the experimental group (𝑛=9)
who, following a -minute relaxation period, underwent
a procedure intended to mobilize the upper cervical spine
through “joint play maneuvers” [], during which mild
pressure is exerted dorsally on the ligamentous so tissue of
the xed segment of the neck (the subject is lying supine).
Following the introduction of pressure, a fast, low-amplitude
rotary thrust is applied that brings the joint through the
elastic barrier, producing an “audible or palpable release.”
Plasma 𝛽-endorphin levels were taken at , , +, +,
and + minutes prior to and following the intervention, and
eects were determined via an analysis of variance. Neither
the sham group (𝑛=9), which underwent the same joint
play manipulation but without the thrusting maneuver (only
mild, oscillatory pressure was exerted on the xed segment of
rotation), nor the control group (𝑛=9) experienced such
an increase in plasma 𝛽-endorphin concentration. However,
two subsequent studies demonstrated ndings contradicting
those of Vernon et al. []: Christian et al. [] and Sanders
et al. [] both failed to nd increases in plasma 𝛽-endorphin
concentrations in experimental groups with respect to sham
and control groups following spinal manipulation. Sanders et
al. [] drew blood samples , +, and + minutes prior
Pain Research and Treatment
an analysis of variance was used to examine the presence
of a dierence of plasma 𝛽-endorphin levels across all time
points. Christian et al. [] drew three  mL blood samples 
minutes apart prior to the intervention, averaged these values
as a baseline, and took mL blood samples ve and thirty
minutes following the intervention. Of note, Christian et al.
[] described a between-assay coecient of variation of %
for  pg/tube and % for  pg/tube plasma 𝛽-endorphin
assays. Relevant methodological dierences between the
investigations of Christian et al. [] and Vernon et al. []
include the division of subjects into four groups by Christian
et al. []: asymptomatic (𝑛=10)andsymptomatic(𝑛=10)
groups that received the experimental spinal manipulative
therapy (SMT) protocol and asymptomatic (𝑛=10)and
symptomatic (𝑛=10)groupsthatreceivedthesham
SMT procedure. Experimental and sham SMT procedures
employed by Christian et al. [] and Vernon et al. [] were
identical. Unlike the studies by Vernon et al. [] and Sanders
et al. [], no control group was included in that of Christian
et al. []. Methodological dierences in the Sanders et al.
[] study (which included experimental, sham, and control
groups each of 𝑛=6) from the aforementioned two include
the region of the spine considered (the lower lumbar, as
opposed to the upper cervical spine), the application of light
touch to the aected area in the sham group as opposed to
joint play of any kind, and the population sampled. Unlike
Christian et al. [] and Vernon et al. [], Sanders et al. []
recruited subjects who were “na¨
ıve to chiropractic adjustive
manipulation,” as opposed to patients from chiropractic
teaching clinics and/or students of the same chiropractic
college, which helps to eliminate the potential, previously
discussed eect of presuppositions harbored by the sample
population. Christian et al. [] attributed the outcome dis-
crepancies between their data and those of Vernon et al. []
to between-assay variation, as Vernon et al. [] reported an
% increase, which is less than the aforementioned between-
assay coecients of variation.
Recently, Plaza-Manzano et al. [] compared cervical
(𝑛=10) and thoracic manipulations (𝑛=10)toa
control group (𝑛=10) in a single-blind, randomized study
of graduate student subjects who responded to university-
placed advertisements. Cervical manipulations consisted of
a high-velocity, mid-range, and leward rotary thrust about
the C and C vertebrae of the supine subject. oracic
manipulations consisted of a high-velocity, end-range force
applied in the anteroposterior plane to T-/T- articula-
tions. Blood was collected from the cephalic vein of each
subject before, immediately aer, and two hours following the
intervention. Both cervical and thoracic groups saw decreases
in neurotensin and oxytocin, as well as increases in orexin A
plasma concentrations following respective interventions.
Multiple reviews have also investigated the pain mod-
agreed that the analgesic origins are neurophysiological in
nature, occurring through some type of descending pain
modulation circuit. is is due to observed analgesic eects
associated with SMT, including increased pain tolerance
and decreased sensitization. e exact circuit, however, is
not fully understood, and it appears that dierent types of
spinal manipulations, namely, the velocity with which and
the location at which they are performed, may elicit dierent
neurochemical responses indicative of dierent descending
pain modulation mechanisms []. For further information
on the neurophysiological eects of SMT, readers are directed
to Vernon [] and Pickar [].
4.3. Knee Joint Manipulation. Skyba et al. [] investigated
the eects of knee joint manipulation in rats on monoamine,
opioid, and type A 𝛾-aminobutyric acid (GABAA) receptors
in the spinal cord. Knee manipulations employed consisted
of the movement of the tibia on the xed femur. For a
duration of three minutes, the joint was exed and extended
across its full range of motion while the tibia was made
to translate in the anteroposterior plane. One minute was
allowed for rest between each of the three manipulation
sessions. Using a model of capsaicin-induced hyperalgesia
and the systematic introduction of GABAA,opioid,𝛼-
adrenergic, -HT1/2,-HT
inhibitors, the authors determined that the analgesic eects
of knee joint manipulation were not impacted by the spinal
Areceptors but were impacted
by the blockade of -HT1Aand 𝛼-adrenergic receptors. It
was therefore posited that descending inhibition following
knee joint manipulation may be modulated by serotonergic
and noradrenergic mechanisms. No attempt has been made
to replicate these ndings in humans.
5. Mobilization Therapies
5.1. Ankle Joint Mobilization. ere is evidence to support
that, in male, Swiss mice, ankle mobilization-induced analge-
sia is mediated by EO, endocannabinoidergic, and adenosin-
ergic pathways [–]. All of these investigations sought
to establish the eect of ankle joint mobilization (AJM) on
mechanical sensitivity in mice subjected to plantar incision
(PI) surgery, for the purpose of inducing an algesic response.
AJM was carried out in a manner consistent with Maitland
[]; this involved the rhythmic exion and extension of the
ankle joint following xation of the knee. e dosage regime
of AJM employed is the same regime delineated by Skyba et
al. [], as discussed in the previous section. In the interest of
succinctness, the convoluted methods of these investigations
and some to follow will not be described in tremendous detail.
Readers who are interested in study methodology are directed
to each respective study. Each of the studies by Martins and
others employed experimental, sham, and control groups. In
order to examine the pathways by which analgesia occurred,
Martins and others used the appropriate receptor antagonist;
for example, naloxone, an opioid receptor antagonist, to
determine the role of EO []. Mechanical sensitivity follow-
ing AJM was assessed by measuring the frequency with which
mice would withdraw the foot following the application of
pressure to its ventral surface. e withdrawal frequency out
of  pressure applications was taken as a percentage, which
constituted each mouses resultant value.
Importantly, Martins et al. [] noted that the bottleneck
in antihypersensitivity was opioid receptor availability as
opposed to opioid-containing leukocytes. Although opioid
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receptor availability may be the bottleneck in mice, this is not
in human subjects and could have large implications for
those in chronic pain or those with central sensitization,
as these individuals may have decreased opioid receptor
availability [] and therefore may not benet as much from
this technique.
Further research by Martins et al. [] investigated the
antihyperalgesic and neuroregenerative eects of AJM fol-
lowing a crush injury of the sciatic nerve in adult male Wistar
rats. Six groups were studied in order to isolate the eects of
AJM so as not to be confounded by the eects of anesthesia
and surgery. Mechanical hyperalgesia was tested in a manner
similar to the aforementioned studies by Martins and others,
and cold hyperalgesia was performed by dropping acetone
onto the mid-plantar hind paw. Histological analyses were
performed to investigate the eects of AJM on dorsal horn
glial cell activation. It was found that glial cell activation
and hyperalgesia decreased following AJM. Furthermore, the
AJM group had greater myelin sheath thickness. It is possible
that recent research has shown that those in chronic pain
exhibit greater glial cell activation []; therefore, despite
the possibility that AJM may not work well in chronic pain
patients through EO-mediated analgesia, it is possible that
chronic pain patients.
5.2. Mulligan’s Mobilization with Movement. Paungmali and
colleagues have studied Mulligan’s Mobilization with Move-
ment (MWM) in lateral epicondylalgia [, ]. Twenty-
four subjects with unilateral chronic lateral epicondylalgia
were treated with MWM on six occasions at least two days
apart. No statistical decreases in hypoalgesic eects were
seen over the treatment period []. In a follow-up study,
Paungmali et al. [] failed to antagonize the hypoalgesic
eects of MWM with naloxone, an opioid antagonist, and
concluded that MWM works through nonopioid methods.
However, as noted by Payson and Holloway [], naloxone
by itself can produce an analgesic eect due to its inhibitory
eects on inammation and ischemia; therefore, the results
of Paungmali et al. [] should be called into question.
5.3. Neural Mobilization. Neural mobilization (NM) is a type
of therapy that purports to relieve adverse neural tension,
using methods such as nerve gliding and neural stretching. A
systematic review put forth by Ellis and Hing [] highlights
the concerns of methodological quality behind claims of ther-
apeutic ecacy in randomized control trials (RCTs) aimed
at studying the clinical utility of neuromanipulative therapy,
neurodynamic therapy, or, simply, NM. is review took
into account  randomized clinical trials (represented by 
publications), gleaned from the more numerous case studies
topic. Investigative heterogeneity in the  studies resulting
from dissimilar patient populations considered a variety of
pathologies treated and dierent types of NM techniques
analyzed necessitated the use of a qualitative means of assess-
ment rather than meta-analytical means. Ellis and Hing []
reported that nine of the  studies were given, based on
the criteria of the PEDro Scale [], an internal validity
score (IVS) of  or , indicating “moderate” methodological
quality. e remaining two studies were given an IVS of ,
indicating “limited” methodological quality. None of the 
studies satised the only two classication items pertaining
to subject-therapist blinding. ough a majority of these
investigations report a positive clinical benet from the type
of NM employed, Ellis and Hing [] conclude that only
limited evidence exists to support its use. Interestingly, some
researchers (such as the next group to be discussed) assert
that this noninvasive treatment method has been “proven to
be clinically eective,” at least in the reduction of pain.
Under the hypothesis that the EO system mediates the
reversion of neuropathic pain following neurodynamic treat-
ment and an earlier study suggesting that glial cells and neural
growth factor may be involved in the analgesia associated
with neural mobilization [], Santos et al. [] studied
behavioral responses and immunochemical indication of
EOs following NM in rats with chronic constriction injury
(CCI). CCI, as described by Santos et al. [], is an induced
peripheral nerve injury wherein epineural blood ow (to
the sciatic, in this case) is occluded, but not arrested, using
chromic gut ligatures. Using male Wistar rats subjected to
NM two weeks following CCI (experimental group, 𝑛=5)
and Western blot assays of the PAG, the authors examined the
brains of the rats for 𝜇-, 𝛿-, and 𝜅-opioid receptor expression
potentially resulting from the neurodynamic intervention.
e NM protocol adopted by the investigators is as follows:
rats in the experimental group were anesthetized and placed
on their le sides such that the side aected by the CCI (the
right) could be manipulated freely; rats in the sham group
were just anaesthetized. With the right knee remaining fully
extended throughout the session, the investigators exed the
right hip to –(absolute) until the hamstrings produced
a light resistance. At this point, the right ankle was dorsi-
exed –relative to its resting position until a similar
resistance (presumably from the gastrocnemius) was detected
by the manipulator. Following the establishment of minimal
resistance in the manipulated joints, oscillations of the right
ankle, wherein the joint was dorsiexed to –repeatedly
from resting, were initiated. e oscillations were carried out
every other day for two minutes, each at  oscillations/min
with -second pauses between them. A total of  sessions
were completed. Apart from the experimental group (CCI +
NM), four other groups were considered. ese included
ıve” control, CCI only, sham, and sham + NM groups.
Researchers did not nd changes in 𝛿-or𝜇-opioid receptor
expression following the intervention; however, 𝜅-opioid
receptor expression underwent a signicant, % increase.
ese data indicate that the analgesic eects reported by those
treated with neural mobilization may be mediated by EOs
that act on 𝜅-opioid receptors, such as dynorphin A and
subtypes thereof.
6. Massage Therapies
Massage therapy is oen sought for both pleasure and ther-
apy. It has been proposed to work through the gate control
Pain Research and Treatment
theory of pain [], initially described by Melzack and Wall
[]. However, Field [] failed to note that dierent types of
massage therapy may work via dierent mechanisms and did
not dive deeply into possible mechanisms. More specically,
light or touch massages may activate low-threshold A𝛽bers,
which inhibit nociceptive input from A𝛿and C aerent bers
due to their pronociceptive nature []. erefore, a more
comprehensive review of massage therapy’s mechanisms is
6.1. Connective Tissue Massage. Connective tissue massage
is intended to both decrease pain and increase range of
motion []. In the interest of determining the mechanisms
behind the pain relief and increases in microcirculation asso-
ciated with this type of massage, Kaada and Torsteinbø []
recruited six male and six female subjects, ranging from  to
 years of age, all with a history of “myalgia and various other
in a similar investigation by the pair of authors []. irty
for each subject to rest prior to the rst of four,  mL blood
latter three were taken at , , and  minutes aer massage;
all were collected in chilled vacutainers containing . mL of
an antiproteolytic buer. e massage itself was performed by
a physiotherapist on laterally positioned, recumbent subjects.
Initially,  minutes of slow, –. in. strokes was applied to
the lumbosacral region, including T12 and subcostal strokes,
giving rise to “sharp, cutting” sensations in the subjects.
Following this,  minutes was spent treating more local
areas of pain specic to each subject using the same stroke
length and pressure as applied to the initially treated region.
Following the termination of massage treatment and an
unspecied storage time on ice (as opposed to conventional,
C storage temperatures), blood samples were centrifuged
and processed using an assay designed specically to detect
human 𝛽-endorphin (New England Nuclear 𝛽-endorphin
125I radioimmunoassay). Blood work reportedly indicated
a statistical increase in plasma 𝛽-endorphin levels follow-
ing connective tissue massage, similar to the time course
observed in acupuncture and to the magnitude observed
during exercise. ese results are indicative of a CPM
response, which modulates pain through descending inhibi-
6.2. Acupressure. Using naloxone in male and female
Sprague-Dawley rats, Trentini et al. [] suggested that
antinociceptive eects of acupressure applied to areas of low
transcutaneous resistance (< MΩ), that is, “acupoints,” are
mediated by EOs. is conclusion was derived from results
obtained from two separate groups of ve rats, one of which
was subjected to three dierent trials: () an experimental
trial in which acupressure was applied to an acupoint,
() a sham trial in which acupressure was applied to an
adjacent point of higher transcutaneous resistance, and ()
a control trial in which no acupressure was applied at all.
e other group of ve rats, however, was not subjected
to a sham trial, but rather to three trials of acupressure at
the acupoint  minutes aer intraperitoneal injection of
naloxone (. mg/kg) or a saline substitute. No indication
of exactly how many of the ve rats received naloxone
versus saline was provided by the authors. Assessments
of antinociception consisted of tail-ick latency tests in
which the distal portion of the rats’ tails was subjected to a
current-containing,tungstenwireheatedto±C. ese
assessments were performed  minutes prior,  minutes
into, and  minutes following the acupressure procedure.
Trentini et al. [] found statistical increases in tail-ick
latency during acupressure (– min) and postacupressure
(min)periodsinratsinjectedwithsaline versus those
injected with naloxone, indicating possible EO-mediated
nociception resulting from acupressure at the acupoint.
ese results are internally substantiated by the authors’
establishment of a statistically greater tail-ick latency in
experimental trials as opposed to sham and control trials,
which remained at or below baseline for the duration of the
plasma 𝛽-endorphin levels were not observed in follow-up
research in humans [] following the processing of blood
samples collected at baseline, immediately aer acupressure
treatment, and one hour aer acupressure treatment. Like
Trentini et al. [], Fassoulaki et al. [] only investigated the
eects of one experimental acupressure point with respect
to one sham acupressure point, but rather than the chosen
points being on the hind limb (as was the case in the
former), the chosen acupoint and sham point in the latter
investigation were both on the face of the human subjects.
us, the eects of acupressure applied to other parts of
the body on 𝛽-endorphin levels remain unclear. It is also
worth noting that both groups of investigators discussed here
applied experimental, sham, and control treatments on the
same groups of subjects. It was specied by Fassoulaki et
al. [] that each successive treatment for their cohort was
performed one day aer the last; however, Trentini et al. []
provided no such specication as to the time allowed between
trials in the group of rats studied. From these equivocal data,
a potential mechanism by which acupressure may produce
analgesia cannot be concluded.
6.3. Conventional Massage. Regular massage, consisting of
eeurage and other common techniques, has been well stud-
ied, but its eects are still not completely understood. Day et
al. [] were the rst to note that there is no change in plasma
𝛽-endorphin or 𝛽-lipotropin levels following a -minute
back massage. e possibility of oxytocinergic mechanisms in
massage-like stroking in rats was investigated by Agren et al.
[], who tested withdrawal latencies from a hot plate (C)
in addition to performing the Randall-Selitto test. e rats
were injected with saline, oxytocin ( mg/kg or . mg/kg),
oxytocin antagonist, or a combination of oxytocin and its
antagonist ( mg/kg). e trunk was stroked – times in
– seconds on both lateral sides, simultaneously, while
alternating between ventral and dorsal sides. Withdrawal
latency was then retested following massage; investigators
reported that the oxytocin antagonist reversed the increases
in latency of withdrawal observed in the saline group. Further
Pain Research and Treatment
research in humans (female cyclists) has also demonstrated
an oxytocin response to massage []. Participants received
a -minute Swedish massage of the neck and shoulders.
Plasma oxytocin levels were measured prior to massage
(baseline), during the massage, ve minutes following the
massage, and  minutes following the massage. A nonsta-
tistical increase (Cohen’s 𝑑 = 0.89) in plasma oxytocin
was observed ve minutes aer massage, which returned to
baseline aer  minutes. Bello et al. [] also observed an
acute increase in plasma oxytocin in healthy men following
neck, upper back, and along the spine, but this increase was
 minutes following intervention. Additionally, no changes
in arginine vasopressin were observed []. Similar ndings
were also observed by Morhenn et al. [], who compared 
minutes of Swedish massage on the upper back to rest and
found statistical increases in plasma oxytocin and statistical
decreases in 𝛽-endorphin in the massage group relative to
the control group. Importantly, a larger sample size was
incorporated here, relative to the other studies (experimental:
𝑛=65;control:𝑛=30), so the ndings of Morhenn et al.
mentioned previously.
Since then, two studies have found that massage increases
urine concentration of dopamine and serotonin [, ], sug-
gesting that massage therapy’s analgesic eects are mediated
by dopaminergic and serotonergic pathways. In addition, a
more recent review of the mechanisms of massage therapy
noted a  and % increase in serotonin and dopamine levels,
respectively [].
e longitudinal eects of massage on select cate-
cholamines and neuropeptides have also been investigated.
Hart et al. [] treated young women (mean age = ) with
anorexia nervosa with -minute massage twice per week for
ve weeks. Investigators observed a .% increase in urine
dopamine assays, while no statistical change was observed in
the control group.
Corticotropin releasing factor (CRF) acts on the locus
coeruleus and is associated with analgesic responses, possibly
due to the role of the locus coeruleus in modulating ascend-
ing and descending pain pathways []. erefore, a CRF
response to massage may have analgesic implications. Lund et
al. [] investigated the eects of  minutes of massage ther-
apy administered twice weekly for six weeks on urinary CRF
concentrations. Increases in urinary CRF concentration were
observed following the treatment period, and a nonstatistical
increase was observed one month following treatment.
In a randomized-controlled trial in women with breast
cancer, subjects received ten twenty-minute eeurage mas-
sage treatments over three to four weeks. ese treatments
were applied to either both feet and lower legs or both hands
and lower arms. e control group received the same amount
of attention but was not touched. Plasma oxytocin levels
experienced no statistical changes over the course of therapy
in either group; however, a .% decrease in oxytocin in the
massage group over the treatment period was observed [].
Recently, Tsuji et al. [] carried out a pilot study on the
eects of mother-son massage on salivary oxytocin levels in
mothers with boys with Autism Spectrum Disorder. Aer
a single -minute massage session, no changes in salivary
oxytocin concentrations were observed; however, dramatic
increases were observed in both the mother and child aer
massages were given for  minutes per day, every day, for
three months, when compared to a four-month nonmassage
period. It cannot be said for certain whether such outcomes
can be generalized to other populations.
Further longitudinal and acute work has been done by
Rapaport et al. [] and Rapaport et al. [], who investigated
the eects of a -minute massage or light touch treatment
(control) in one session and one versus two times per week,
including arginine vasopressin and oxytocin. In the acute
trial, a larger decrease in arginine vasopressin was found
relative to the touch group, but no statistical dierences
were observed for oxytocin []. In the longitudinal trial,
neuroendocrine samples were collected at  minutes and 
minute prior to the therapy sessions and at , , , , ,
and  minutes aer the end of the session. Two analyses
were performed: one that compared baseline (pre) values
to the values directly following the nal intervention and
preceding the nal intervention. e latter measure is of
particular interest, because it is indicative of longitudinal
eects. e following Cohens deect sizes are presented
relative to the touch (control) group. Following the nal
intervention, the once per week group experienced negligible
eects for oxytocin (.). e twice per week group,
following the nal intervention, noted increased levels of
oxytocin (.). Preceding the nal intervention, negligible
increases in oxytocin were noted (.) for the once per
twice per week group for oxytocin (.) following the nal
intervention [].
From the aforementioned studies, it appears clear that
oxytocin plays a role in the analgesic response following
conventional massage therapy, but the role of other neu-
ropeptides is unclear.
7. Future Research
Being that the analgesic eects of both human touch [] and
placebo [–] are mediated by an EO or endocannabinoid
response, it is imperative that a placebo control group be
utilized in research examining the neurochemical response to
manual therapy, as placebo and touch alone are confounding
variables. Future research should target therapies that have
already been shown to be eective, as to prevent the wasting
of resources investigating mechanisms that are not clinically
meaningful and should utilize both a control and sham group.
Investigators should be cautious when designing experiments
that use naloxone, as it can inhibit pain via peripheral
mechanisms; thus, it may not be appropriate to use with those
who have low back pain []. Lastly, it is imperative that
researchers be vigilant when interpreting the results of serum
levels of EO, as they may not reect levels seen in the brain or
cerebral spinal uid [].
Pain Research and Treatment
T : Neurophysiological response to manual therapy variations.
Study Subjects Control/sham Variation Findings
Degenhardt et al. [] womenandmenwith(𝑛=10)and
without (𝑛=10)lowbackpain Light touch OMT ↑𝛽-endorphins
McPartland et al. [] Osteopathic patient population
(𝑛=31)Sham manipulation OMT AEA
Vernon et al. []  healthy males
supine on a treatment table
(2) Sham group received
joint play maneuvers
SMT ↑𝛽-endorphins
Christian et al. []
 male subjects who were
chiropractic patients and students with
and without pain
Sham (joint taken to
end-range of motion) SMT →𝛽-endorphins
Sanders et al. [] malesandfemaleswithacute(<
weeks) low back pain
Sham group (𝑛=6)
received light touch at
SMT →𝛽-endorphins
Plaza-Manzano et al.
[]  graduate school students No treatment SMT
orexin A
Skyba et al. []  male Sprague-Dawley rats
(1) Vehicle w/manipulation
(2) Vehicle w/anesthesia
(3) Drugs w/anesthesia
Martins et al. []  male Swiss mice per group (1)Control
Ankle joint
mobilization EO-mediated
Martins et al. []  male Swiss mice per group (1)Control
Ankle joint
mobilization CBR-mediated
Martins et al. []  male Swiss mice per group (1)Control
Ankle joint
mobilization Adenosine-mediated
Martins et al. []  adult male Wistar rats per group
(2) Sham w/anesthesia
(3) Sham w/mobilization
(5) Crush w/anesthesia
Ankle joint
mobilization glialcellactivation
Paungmali et al. []  females and  males with lateral
(1) Placebo
(2)Control MWM No increase in tolerance
over treatment period
Paungmali et al. []  females and  males with lateral
(1) Placebo
(2)Control MWM Non-EO-mediated
Santos et al. [] Male Wistar rats
(2) Injury only
(4) Sham w/mobilization
NM Dynorphin-mediated
Kaada and Torsteinbø
tissue massage ↑𝛽-endorphins
Trentini et al. [] Male and female Sprague-Dawley rats (1)Control
(2) Placebo Acupressure EO-mediated
Fassoulaki et al. []  females and  males without
a familiarity with acupuncture
(2)Sham Acupressure →𝛽-endorphins
Day et al. []  women and  men who were
healthy and free of pain Control Conventional
Agren et al. [] – male Sprague-Dawley rats Control Conventional
massage Oxytocin-mediated
Turner et al. []  nulliparous women that cycle (1) Positive emotion
massage oxytocin
Bello et al. []  males Control Conventional
arginine vasopressin
Pain Research and Treatment
T : C o nt i n u e d .
Study Subjects Control/sham Variation Findings
Morhenn et al. []  females and  males Rest Conventional
Hernandez-Reif et al.
 women and  men with >months
low back pain Relaxation therapy Conventional
Hernandez-Reif et al.
 women with stage  or  breast
Control (medical treatment
Field et al. []Review Conventional
Hart et al. [] Nineteen women with anorexia
Control (standard
treatment only)
massage dopamine
Lund et al. []  bromyalgia patients Guided relaxation Conventional
corticotropin releasing
Billhult et al. []  women with breast cancer Attention Conventional
massage oxytocin
Tsuji et al. [ ] JapaneseboyswithAutismSpectrum
Disorder and their mothers
Control (no massage,
massage oxytocin
Rapaport et al. []  females and  males Light touch Conventional
arginine vasopressin
Rapaport et al. []  females and  males Light touch Conventional
oxytocin (acute)
oxytocin (chronic)
denotes review; denotes a conclusion inferred from naloxone or relevant antagonistic response.
8. Conclusion
Nearly all types of manual therapy have been shown to elicit
a neurophysiological response that is associated with the
descending pain modulation circuit; however, it appears that
dierent types of manual therapy work through dierent
mechanisms (Table ). For example, while massage therapy
does not. It is crucial that more higher quality research be
performed to better understand these mechanisms, as it can
lead to a better understanding of how each therapy can be
applied to drive more specic clinical research.
For some therapies, such as manipulation, a minimal
amount of force may be required for an analgesic eect [],
but whether a minimum force is required for descending
inhibition to occur does not seem to be the case, as touch and
placebo alone can trigger a descending inhibitory response.
However, this may also be treatment dependent. Being that
the gate control theory of pain states that nonnoxious stimuli
inhibit noxious stimuli, more aggressive therapies may be too
noxious to trigger a gate control response, but not noxious
enough to produce a CPM response. us, more research
is needed to shed light on these paradoxical treatment
therapy, its mechanisms are not truly understood. Under-
standing these mechanisms may help researchers and clini-
cians to choose which therapy is most appropriate for each
patient or subpopulation and may also lead to more eective
therapies in the future.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
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... 9 Numerous neurotransmitters are involved in modulating nociceptive circuits, acting on structures of the brain stem (periaqueductal gray matter and the ventromedial rostral bulb) and the spinal cord. 8,10,11 Among these neurotransmitters, beta-endorphin (BE), an endogenous opioid, has not only been shown to have a comparable analgesic effect to morphine, but also to be 18 to 33 times more potent. 11 Nevertheless, mu opioid receptors (the main binding site of BE) are expressed by somatosensory neurons in the dorsal and trigeminal root ganglia, nociceptive neurons in the dorsal horn and multiple regions of the supraspinal segment. ...
... 8,10,11 Among these neurotransmitters, beta-endorphin (BE), an endogenous opioid, has not only been shown to have a comparable analgesic effect to morphine, but also to be 18 to 33 times more potent. 11 Nevertheless, mu opioid receptors (the main binding site of BE) are expressed by somatosensory neurons in the dorsal and trigeminal root ganglia, nociceptive neurons in the dorsal horn and multiple regions of the supraspinal segment. 10 BE preferentially acts as a ligand for mu receptors, which, like other membrane receptors of the endogenous opioid system, are coupled to an inhibitory G protein and stimulate intracellular signaling cascades which normally depress neural functions and are related to the inflammatory process characteristic of pain states. ...
Full-text available
Erickson Bonifácio de Assis, Carolina Dias de Carvalho, Clarice Martins, Suellen Andrade Neuroscience and Aging Laboratory, Federal University of Paraíba, João Pessoa, PB, BrazilCorrespondence: Suellen AndradeNeuroscience and Aging Laboratory, Federal University of Paraíba, João Pessoa, 58051-900, BrazilTel +55 83 3216-713Email suellenandrade@gmail.comAbstract: A scoping review to synthesize evidence and assess articles describing the use of beta-endorphins as a pain biomarker in chronic pain patients treated with non-invasive brain stimulation techniques was systematically performed with respect to the study quality, the technique employed and the results. Independent reviewers determined if the article met the study criteria at each stage for it to be included. Content analysis was applied and summarized. The results are described in a narrative form grouped by pain condition, type of intervention, stimulation protocol, outcome measures and main results. A total of 67 of 73 references were excluded, and 6 identified studies met the inclusion criteria. The study design, sample size, stimulation type, session protocol and the main findings of each study were extracted. The studies in this scoping review ranged from unsatisfactory to good based on the adopted criteria, with no study achieving an excellent rating. There is limited evidence on the dosage of beta-endorphin in chronic pain conditions during treatment with NIBS. Based on this literature, evidence suggests that BE may not only be useful for acute and persistent pain, but also for a variety of chronic pain states in which opioids are not effective.Keywords: chronic pain, endorphin, electric stimulation, review
... Consequently, hands-on care is recommended for a range of musculoskeletal (MSK) conditions, including low back pain (LBP), neck pain, headaches, carpal tunnel syndrome and hip and knee osteoarthritis (Deyle et al., 2000;Akalin et al., 2002;MacDonald et al., 2006;Rubinstein et al., 2011;Gross et al., 2015;Cerritelli et al., 2017). A significant body of evidence demonstrates that hands-on techniques in MSK care have a particularly important role on pain modulation (Deyle et al., 2000;Bialosky et al., 2009;Vigotsky and Bruhns, 2015;Cerritelli et al., 2017;Geri et al., 2019;Sánchez-Romero et al., 2021). Therefore, the hand plays a crucial role in delivering MSK care through the sense of touch. ...
Full-text available
Touch is recognised as crucial for survival, fostering cooperative communication, accelerating recovery, reducing hospital stays, and promoting overall wellness and the therapeutic alliance. In this hypothesis and theory paper, we present an entwined model that combines touch for alignment and active inference to explain how the brain develops "priors" necessary for the health care provider to engage with the patient effectively. We appeal to active inference to explain the empirically integrative neurophysiological and behavioural mechanisms that underwrite synchronous relationships through touch. Specifically, we offer a formal framework for understanding-and explaining-the role of therapeutic touch and hands-on care in developing a therapeutic alliance and synchrony between health care providers and their patients in musculoskeletal care. We first review the crucial importance of therapeutic touch and its clinical role in facilitating the formation of a solid therapeutic alliance and in regulating allostasis. We then consider how touch is used clinically-to promote cooperative communication, demonstrate empathy, overcome uncertainty, and infer the mental states of others-through the lens of active inference. We conclude that touch plays a crucial role in achieving successful clinical outcomes and adapting previous priors to create intertwined beliefs. The ensuing framework may help healthcare providers in the field of musculoskeletal care to use hands-on care to strengthen the therapeutic alliance, minimise prediction errors (a.k.a., free energy), and thereby promote recovery from physical and psychological impairments.
... Regarding conservative, non-medical and non-dental treatments, the musculoskeletal manual approaches are noted for their impact on biological tissues. It involves a reduction in biomechanical and neurophysiological imbalances [10] responsible for pain relief, reduction in muscle activity [11] and improving function [12]. Unfortunately, despite the evidence seen in two systematic reviews that support manual therapy as producing favorable outcomes in TMD [13][14][15], the real effectiveness of different types of manual therapy in TMD remains unclear. ...
Full-text available
Background: To investigate the effectiveness of a specific manual therapy, Fascial Manipulation® (FM), in comparison with conventional treatments in temporomandibular disorders (TMD) patients using a two-arm randomized controlled trial. Methods: The study consisted of 28 patients that were divided in two groups (Group 1: Fascial Manipulation® vs. Group 2: conventional TMD treatment). The Verbal Rating Scale (VRS), RDC/TMD, electromyography (EMG) and Pression/Pain Evaluation on Masseter and Temporalis Muscle were assessed with different times. Results: In both groups, the improvement in pain was evident on the VRS scale (p < 0.0001) and pain-free opening (p < 0.001). In Group 1, the recovery of the function was faster; maximum unassisted opening T0 vs. T1 (p = 0.001). Conclusions: FM® can be used as an effective method for facial pain, being a rapid, safe and cost-effective approach to reduce pain, gain function and mouth opening that can be used prior to occlusion stabilization appliances.
... By stimulating the thick fibers, the effects of inhibitory interneurons in the substantia gelatinosa are enhanced. With the stimulation of thick fibers with manual therapy and massage, the nociceptive stimuli from the thin fibers (A delta and C) cannot pass to the spinal cord level and the pain is controlled as a result of the closure of the pathways [41]. ...
Full-text available
Fibromyalgia syndrome (FMS) is a chronic rheumatic disease in which pain is predominant and accompanied by fatigue, anxiety, depression, sleep disturbance and cognitive dysfunction. Although there are numerous pharmacological and non-pharmacological therapeutic alternatives, symptom control is frequently problematic. Manual therapy covers manipulating soft tissue and various joints using the hands. It is organized by mapping of soft tissue structures with rhythmically applied pressure to improve physical function, facilitate daily activities, promote rehabilitation procedures and decrease pain. Massage is generally accepted as an essential component of manual therapy. Stretching and mobilizations are also part of manual therapy. Although numerous beneficial effects of manual therapy and massage on the musculoskeletal system and pain have been proven, the data in FMS patients studies are inconclusive. We hypothesize that manual therapy and massage are beneficial therapeutic options for the control of symptoms of FMS patients. Furthermore, these strategies can be employed in conjunction with well-established and high-evidence therapeutic procedures. Future research should focus on establishing standardized protocols for manual therapy and massage, which is one of the major limitations. To ensure a high level of evidence, research studies with large sample sizes, long follow-up periods and methodologically complete are needed.
... Neurophysiological responses vary according to the type of therapy. The roles of endorphins, oxytocin and endocannabinoids have been advocated to explain the decrease in pain frequently described by patients [10,11]. This "massage-like effect" could be responsible for the decrease in pain noticed in the two groups and the absence of the specificity of one session. ...
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We aimed to demonstrate the antalgic effectiveness of ScenarTM (Self-Controlled Electro Neuro Adaptative Regulation) in patients experiencing low back and neck pain. Sixty patients were included and equally assigned by randomization to a Scenar-On group and to a Scenar-Off group (sham group). All patients received a 20 min application of ScenarTM on the area where they experienced pain. The pain at rest and during movement and the sensation of stiffness were assessed using a numeric rating scale at baseline, immediately after the session and 24 h after the session. The patients’ characteristics at entry were similar between groups. The pain at rest decreased after the session in both groups (from 8 (4) to 5.0 (3) in the Scenar-Off group, p = 0.0001, and from 7 (3) to 4 (4) in the Scenar-On group, p < 0.0001). The difference was not statistically significant for the groups (p = 0.22). Similar results were observed during movement, but the sensation of stiffness was not modified. Such beneficial results did not last until the next day. No undesirable major effects were noticed. Our study does not support the fact that one ScenarTM session improves low back and neck pain better than a sham session.
... Vielmehr wurden neurophysiologische Veränderungen im Zuge manual-bzw. manipulativtherapeutischer Interventionen zum primären Untersuchungsgegenstand der Wissenschaft Bialosky, et al., 2009a;Colloca, Pickar und Slosberg, 2012;Cook, 2020;Gyer, et al., 2019;Lascurain-Aguirrebeña, Newham und Critchley, 2016;Pickar, 2002;Pickar und Bolton, 2012;Potter, McCarthy und Oldham, 2005;Savva, Giakas und Efstathiou, 2014;Vigotsky und Bruhns, 2015). Im Zuge manualtherapeutischer Techniken kommt es zu einer Stimulation peripherer, regionaler, sensorischer Rezeptoren. ...
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Hintergrund: Physiotherapeut*Innen verwenden die spinale Gelenkmanipulation u.a. zur Behandlung bestimmter arthrogener Dysfunktionen. Postmanipulativ verändert sich neben dem Schmerz- und Beweglichkeitsstatus häufig das Aktivierungsmuster bestimmter Muskeln. Ziele: Detektion kurzfristiger Auswirkungen spinaler Gelenkmanipulation auf die EMG-Aktivität, Schmerz und die aktive Beweglichkeit bei erwachsenen Menschen und der Unterschied zu anderen therapeutischen Maßnahmen. Design: Systematisches Review Informationsquellen: Primäre Informationsquellen (MEDLINE, EMBASE, CINAHL, PEDro), sekundäre Informationsquellen (Open Grey, Dart-Europe, Expertenbefragungen,, ICTRP, Referenzlisten) Auswahlkriterien: Design (RCTs, randomisierte Cross-Over-Studien), Spezies (Humanstudien), Sprachen (Deutsch, Englisch), Publikationszeitraum (01/2000 – 03/2020) Studienbewertung: Evidenzklassen nach CEBM (relative Beweiskraft), PEDro-Skala (methodologische Qualität), modifizierte CIRCLe SMT (interventionsspezifische Berichterstattung) Ergebnisse: Von insgesamt 901 Treffern wurden 13 Primärarbeiten mit akkumuliert 443 Proband*Innen zur Bearbeitung dieser systematischen Übersichtsarbeit inkludiert. Die vorliegende Arbeit konnte keine generalisierbare Aussage über die kurzfristigen Auswirkungen spinaler Gelenkmanipulation auf die EMG-Aktivität, Schmerzen und die aktive Beweglichkeit bei erwachsenen Menschen liefern, indizierte aber schwache Evidenz für jeden Ergebnisparameter. Das detektierte postmanipulative Aktivierungsverhalten der Muskulatur konnte sowohl exzitatorisch als auch inhibitorisch sein. Mittels Subgruppenanalysen wurde ein potentieller Einfluss der Krankheitsbilder auf die postmanipulative EMG-Aktivität eruiert. Es gibt moderate Evidenz dafür, dass eine lumbale Rotationsmanipulation bei Patient*Innen mit nichtspezifischen Rückenschmerzen zu einer signifikanten Reduktion der EMG-Aktivität der paravertebralen Muskulatur während des Haltens in voller Rumpfflexion und der Extensionsbewegung aus der vollen Flexion führt. Ebenso besteht moderate Evidenz dafür, dass eine lumbopelvine Rotationsmanipulation der betroffenen Seite bei Patient*Innen mit einem Patellofemoralen Schmerzsyndrom zu einem signifikanten An-stieg der EMG-Aktivität des M. gluteus medius führt. Schwache Evidenz besteht da-für, dass segmentspezifische Manipulationen im Bezug auf die EMG-Aktivität und Schmerzen keinen Benefit im Vergleich zu global ausgeführten Techniken bringen. Unklar bleibt, ob eine spinale Gelenkmanipulation kurzfristig signifikante Benefits im Vergleich zu Placebo-, Pseudoplacebo- oder anderen therapeutischen Kontrollinterventionen im Bezug auf die EMG-Aktivität, Schmerzen und die aktive Beweglichkeit bei erwachsenen Menschen bietet. Limitationen: Die methodologische Qualität über die Studien hinweg lag bei 5,77/10 Punkten und war mäßig. Das Risiko für Performance Bias über die Studien hinweg war sehr hoch. Das Risiko für Spectrum bzw. Detection Bias war moderat. Das Risiko der Verzerrungen aufgrund der interventionsspezifischen Berichterstattung über die Studien hinweg wurde als gering angesehen. Die individuellen Primär-arbeiten waren hinsichtlich der wichtigsten Studienmerkmale heterogen. Schlussfolgerungen: Die spinale Gelenkmanipulation soll allenfalls supportiv zur überwiegend aktiven Behandlung von veränderten muskulären Aktivierungsmustern, Schmerzen und Bewegungseinschränkungen eingesetzt werden. Die spinale Gelenkmanipulation eignet sich, um Patient*Innen bereits innerhalb einer Therapieeinheit die Adaptabilität des neuromuskuloskelettalen Systems bzw. die Modifikationsmöglichkeit für Symptome und Bewegung zu visualisieren. Somit kann weitere passive, assistive oder idealerweise aktive Bewegung fazilitiert werden. Registrationsnummer: PROSPERO - CRD42020160690 Stichworte: Spinale Gelenkmanipulation, EMG, Schmerz, aktive Beweglichkeit
... Therefore, pain intensity is decreased [41]. Another possible mechanism of analgesia is induced by plummeting modulatory circuits in which various neurotransmitters-including serotonin (5-HT), oxytocin, adenosine, endocannabinoids, vasopressin, and endogenous opioids (EOs)have been demonstrated to act on structures such as the rostral ventromedial medulla (RVM) and periaqueductal grey (PAG) to modify nociceptive circuits and pain output [42,43]. Intensive massage and manipulation can cause a significant release of endogenous opiates (inhibitory neurotransmitters) and suppress profound pain [44]. ...
Purpose Multiple sclerosis (MS) causes a range of different symptoms. Patients with MS (PwMS) have looked for alternative therapies to control their MS progress and treat their symptoms. Non-invasive therapeutic approaches such as massage can have benefits to mitigate some of these symptoms. However, there is no rigorous review of massage effectiveness for PwMS. The present systematic review aims to examine the effectiveness of different massage approaches on common MS symptoms, including fatigue, pain, anxiety, depression, and spasticity. Materials and Methods A systematic search of related trials was conducted in electronic databases including Cochrane Library, PubMed, Scopus, Web of Science, and Google Scholar, using search terms related to Multiple Sclerosis and massage therapy. The PEDro scale was used to evaluate the methodological quality of reviewed studies. Results A total of 12 studies met the inclusion criteria. We rated 5 studies as fair and 7 studies as good. Fatigue was improved by different massage styles, such as reflexology, nonspecific therapeutic massage, and Swedish massage. Pain, anxiety, and depression were effectively improved by reflexology techniques. Spasticity was reduced by Swedish massage and reflexology techniques. Conclusions Different massage approaches effectively improved MS symptoms such as fatigue, pain, anxiety, depression, and spasticity. • Implications for rehabilitation • The present review results indicate that massage may have beneficial effects on motor and non-motor symptoms in MS. • Massage could be considered a complementary and alternative treatment combined with conventional medicine in people with MS. • Pain and fatigue are best improved by Swedish massage, while anxiety and depression are effectively improved by reflexology.
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The article presents an analytical review of the literature on the application of the principles of evidence-based medicine in modern healthcare. It is noted that in some areas of medicine, scientifically based standards of treatment significantly fall behind the general trends. Complementary medicine, including osteopathy, is an important healthcare resource, the use of which is officially recognized in 94 countries around the world. However, despite certain achievements in the treatment and prevention of many chronic diseases, there are scientific articles that criticize its effectiveness. Therefore, the relevance of obtaining new, strictly evidence-based data on the impact of osteopathy on health is beyond doubt. For osteopathy, as for other types of complementary medicine, a new paradigm of evidence-based clinical research is probably needed. Three types of the organism response to treatment — instant, fast and delayed — are identified.
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The main focus for development of adenosine targets as analgesics to date has been A1Rs due to its antinociceptive profile in various preclinical pain models. The usefulness of systemic A1R agonists may be limited by other effects (cardiovascular, motor), but enhanced selectivity for pain might occur with partial agonists, potent and highly selective agonists, or allosteric modulators. A2AR agonists exhibit some peripheral pronociceptive effects, but also act on immune cells to suppress inflammation and on spinal glia to suppress pain signalling and may be useful for inflammatory and neuropathic pain. A2BR agonists exhibit peripheral proinflammatory effects on immune cells, but also spinal antinociceptive effects similar to A2AR agonists. A3Rs are now demonstrated to produce antinociception in several preclinical neuropathic pain models, with mechanistic actions on glial cells, and may be useful for neuropathic pain. Endogenous adenosine levels can be augmented by inhibition of metabolism (via adenosine kinase) or increased generation (via nucleotidases), and these approaches have implications for pain. Endogenous adenosine contributes to antinociception by several pharmacological agents, herbal remedies, acupuncture, transcutaneous electrical nerve stimulation, exercise, joint mobilization, and water immersion via spinal and/or peripheral effects, such that this system appears to constitute a major pain regulatory system. Finally, caffeine inhibits A1-, A2A- and A3Rs with similar potency, and dietary caffeine intake will need attention in trials of: (a) agonists and/or modulators acting at these receptors, (b) some pharmacological and herbal analgesics, and (c) manipulations that enhance endogenous adenosine levels, all of which are inhibited by caffeine and/or A1R antagonists in preclinical studies. All adenosine receptors have effects on spinal glial cells in regulating nociception, and gender differences in the involvement of such cells in chronic neuropathic pain indicate gender may also need attention in preclinical and human trials evaluating efficacy of adenosine-based analgesics.
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Seven male children with autism spectrum disorder (ASD), aged 8-12 years, attending special education classrooms for ASD and disabled children, were assigned to receive touch therapy. Their mothers were instructed to provide gentle touch in the massage style of the International Liddle Kidz Association. The mothers gave massages to their child for 20 min every day over a period of 3 months, followed by no massage for 4 months. To assess the biological effects of such touch therapy, saliva was collected before and 20 min after a single session of massage for 20 min from the children and mothers every 3 weeks during the massage period and every 4 weeks during the non-massage period, when they visited a community meeting room. Salivary oxytocin levels were measured using an enzyme immunoassay kit. During the period of massage therapy, the children and mothers exhibited higher oxytocin concentrations compared to those during the non-massage period. The changes in oxytocin levels before and after a single massage session were not significantly changed in children and mothers. The results suggested that the ASD children (massage receivers) and their mothers (massage givers) show touch therapy-dependent changes in salivary oxytocin concentrations.
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Background Although neuroimaging techniques have provided insights into the function of brain regions involved in Trigeminal Neuropathic Pain (TNP) in humans, there is little understanding of the molecular mechanisms affected during the course of this disorder. Understanding these processes is crucial to determine the systems involved in the development and persistence of TNP. Findings In this study, we examined the regional μ-opioid receptor (μOR) availability in vivo (non-displaceable binding potential BPND) of TNP patients with positron emission tomography (PET) using the μOR selective radioligand [11C]carfentanil. Four TNP patients and eight gender and age-matched healthy controls were examined with PET. Patients with TNP showed reduced μOR BPND in the left nucleus accumbens (NAc), an area known to be involved in pain modulation and reward/aversive behaviors. In addition, the μOR BPND in the NAc was negatively correlated with the McGill sensory and total pain ratings in the TNP patients. Conclusions Our findings give preliminary evidence that the clinical pain in TNP patients can be related to alterations in the endogenous μ-opioid system, rather than only to the peripheral pathology. The decreased availability of μORs found in TNP patients, and its inverse relationship to clinical pain levels, provide insights into the central mechanisms related to this condition. The results also expand our understanding about the impact of chronic pain on the limbic system.
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Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and levels of circulating proinflammatory cytokines, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
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Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A3 adenosine receptor (A3AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A3AR agonist. These effects were prevented by blockade of spinal and supraspinal A3AR, lost in A3AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A3AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A3AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain. Published by Oxford University Press on behalf of the Guarantors of Brain 2014. This work is written by US Government employees and is in the public domain in the US.
In this review, massage therapy has been shown to have beneficial effects on varying conditions including prenatal depression, preterm infants, full-term infants, autism, skin conditions, pain syndromes including arthritis and fibromyalgia, hypertension, autoimmune conditions including asthma and multiple sclerosis, immune conditions including HIV and breast cancer and aging problems including Parkinson's and dementia. Although many of the studies have involved comparisons between massage therapy and standard treatment control groups, several have compared different forms of massage (e.g. Swedish versus Thai massage), and different active therapies such as massage versus exercise. Typically, the massage therapy groups have experienced more positive effects than the control or comparison groups. This may relate to the massage therapy providing more stimulation of pressure receptors, in turn enhancing vagal activity and reducing cortisol levels. Some of the researchers have assessed physical, physiological and biochemical effects, although most have relied exclusively on self-report measures. Despite these methodological problems and the dearth of research from the U.S., the massage therapy profession has grown significantly and massage therapy is increasingly practiced in traditional medical settings, highlighting the need for more rigorous research.
Placebo analgesia has become a well-studied phenomenon that encompasses psychology, physiology and pharmacology. In this chapter we explore the complex interactions between these disciplines in order to argue that the placebo response is more than a simple change in perception but is a cognitive style driven by prior expectations. The expectation of treatment effect is shaped by prior information and prior experience which our brain uses to predict future events. In the case of placebo analgesia the prediction of pain relief overrules the actual feeling of pain leading to a decrease in pain sensation. This altered sensation can be attributed to personality traits, altered error monitoring processes, changes in anticipatory responses to pain and activation of the endogenous opioid system. In conclusion we discuss how altered sensory processing by descending pain modulation may play a part in placebo analgesia and how the loss of the brains prefrontal regions can make it impossible to have a placebo response.
Moderate pressure massage has contributed to many positive effects including increased weight gain in preterm infants, reduced pain in different syndromes including fibromyalgia and rheumatoid arthritis, enhanced attentiveness, reduced depression and enhanced immune function (increased natural killer cells and natural killer cell activity).Surprisingly, these recent studies have not been reviewed, highlighting the need for the current review. When moderate and light pressure massage have been compared in laboratory studies, moderate pressure massage reduced depression, anxiety and heart rate, and it altered EEG patterns, as in a relaxation response. Moderate pressure massage has also led to increased vagal activity and decreased cortisol levels. Functional magnetic resonance imaging data have suggested that moderate pressure massage was represented in several brain regions including the amygdala, the hypothalamus and the anterior cingulate cortex, all areas involved in stress and emotion regulation. Further research is needed to identify underlying neurophysiological and biochemical mechanisms associated with moderate pressure massage.
The effect of electro-acupuncture in the treatment of naloxone precipitated morphine withdrawal in mice was studied. Thirty minutes of acupuncture was enough to suppress withdrawal behaviors by more than 60%. Concomitant to the decrease of withdrawal behavior, there was a significant increase of brain beta-endorphin level in the acupunctured animals. Plasma beta-endorphin level of the treated and untreated group was not significantly different.