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

Abstract

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.

Full text

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; avigotsk@asu.edu
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-
noids.
𝛽-endorphins are EO peptides that have not only been
shown to have a comparable analgesic eect to morphine
[],butaretotimesmorepotent[].Diusenoxious
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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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
insightintomechanismsthatmaynotbeethicaltodirectly
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
therapieshavebeendevelopedandadvocated,andhave
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
areimplicatedinplacebo-inducedanalgesia[],though
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-
ment(biodynamicosteopathyinthecranialeld)ora
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
playaroleintheanalgesiceectofOMT.
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
thecervicalspinewhiletheheadandneckunderwentpassive
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
toandfollowingtheinterventionand,likeVernonetal.[],

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-
ulatingmechanismsofspinalmanipulation[,]and
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
1A,-HT
2A,and-HT
3receptor
inhibitors, the authors determined that the analgesic eects
of knee joint manipulation were not impacted by the spinal
blockadeofopioidorGABA
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 mouse’s resultant value.
Importantly, Martins et al. [] noted that the bottleneck
in antihypersensitivity was opioid receptor availability as
opposed to opioid-containing leukocytes. Although opioid

Pain Research and Treatment
receptor availability may be the bottleneck in mice, this is not
necessarilytrueforhumans.esedatashouldbereplicated
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
thattheseoutcomesarerelatedandareofrelevance,being
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
glialcellinhibitionwouldproducefavorableoutcomesfor
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
andothernonblindedtrialsllingthepoolofliteratureonthe
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
“na¨
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
[,].Deepermassages,however,mayelicitaCPMresponse
due to their pronociceptive nature []. erefore, a more
comprehensive review of massage therapy’s mechanisms is
warranted.
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
typesofpain.”Ofnote,thesamevolunteercohortwasstudied
in a similar investigation by the pair of authors []. irty
minutesonabedina“thermoregulated”roomwasallowed
for each subject to rest prior to the rst of four,  mL blood
samplesbeingtakenfromthe(median)cubitalvein.e
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-
tion.
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
assessment.
DespitethendingsofTrentinietal.[],changesin
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
minutesofmassageappliedtotheshoulders,upperarms,
neck, upper back, and along the spine, but this increase was
similartothatobservedinthe“reading”controlatbothand
 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.
[]maybemorereliableandrobustwhencomparedtothose
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,
forveweeks,onanumberofneuroendocrinemeasures,
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
anotherthatcomparedbaseline(pre)valuestothevalues
preceding the nal intervention. e latter measure is of
particular interest, because it is indicative of longitudinal
eects. e following Cohen’s 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
weekmassagegroup.Alargeeectwasobservedinthe
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
↑PEA
McPartland et al. [] Osteopathic patient population
(𝑛=31)Sham manipulation OMT ↑AEA
Vernon et al. []  healthy males
(1)Controlgrouplaid
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
L/L–S
SMT →𝛽-endorphins
Plaza-Manzano et al.
[]  graduate school students No treatment SMT
↑orexin A
↓neurotensin
↓oxytocin
Skyba et al. []  male Sprague-Dawley rats
(1) Vehicle w/manipulation
(2) Vehicle w/anesthesia
(3) Drugs w/anesthesia
Knee
manipulation
Serotonin-mediated
Norepinephrine-
mediated
Non-GABA-mediated
Martins et al. []  male Swiss mice per group (1)Control
(2)Sham
Ankle joint
mobilization EO-mediated†
Martins et al. []  male Swiss mice per group (1)Control
(2)Sham
Ankle joint
mobilization CBR-mediated†
Martins et al. []  male Swiss mice per group (1)Control
(2)Sham
Ankle joint
mobilization Adenosine-mediated†
Martins et al. []  adult male Wistar rats per group
(1)Sham
(2) Sham w/anesthesia
(3) Sham w/mobilization
(4)Crush
(5) Crush w/anesthesia
Ankle joint
mobilization ↓glialcellactivation
Paungmali et al. []  females and  males with lateral
epicondylalgia
(1) Placebo
(2)Control MWM No increase in tolerance
over treatment period
Paungmali et al. []  females and  males with lateral
epicondylalgia
(1) Placebo
(2)Control MWM Non-EO-mediated†
Santos et al. [] Male Wistar rats
(1)Control
(2) Injury only
(3)Sham
(4) Sham w/mobilization
NM Dynorphin-mediated
Kaada and Torsteinbø
[]
maleandfemalesubjectswith
ahistoryofmyalgia
Connective
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
(1)Control
(2)Sham Acupressure →𝛽-endorphins
Day et al. []  women and  men who were
healthy and free of pain Control Conventional
massage
→𝛽-endorphins
→𝛽-lipotropins
Agren et al. [] – male Sprague-Dawley rats Control Conventional
massage Oxytocin-mediated†
Turner et al. []  nulliparous women that cycle (1) Positive emotion
(2)Negativeemotion
Conventional
massage ↑oxytocin
Bello et al. []  males Control Conventional
massage
↑oxytocin
→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
massage
↑oxytocin
↓𝛽-endorphins
Hernandez-Reif et al.
[]
 women and  men with >months
low back pain Relaxation therapy Conventional
massage
↑dopamine
↑serotonin
Hernandez-Reif et al.
[]
 women with stage  or  breast
cancer
Control (medical treatment
only)
Conventional
massage
↑dopamine
↑serotonin
Field et al. []∗Review Conventional
massage
↑dopamine
↑serotonin
Hart et al. [] Nineteen women with anorexia
nervosa
Control (standard
treatment only)
Conventional
massage ↑dopamine
Lund et al. []  bromyalgia patients Guided relaxation Conventional
massage
↑corticotropin releasing
factor
Billhult et al. []  women with breast cancer Attention Conventional
massage ↑oxytocin
Tsuji et al. [   ] JapaneseboyswithAutismSpectrum
Disorder and their mothers
Control (no massage,
crossover)
Conventional
massage ↑oxytocin
Rapaport et al. []  females and  males Light touch Conventional
massage
→oxytocin
↓arginine vasopressin
Rapaport et al. []  females and  males Light touch Conventional
massage
↑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
appearstoelicitanoxytocinresponse,spinalmanipulation
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
outcomes.
Despitethelargepopularityandlonghistoryofmanual
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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