MYOFASCIAL PAIN-UPDATE IN DIAGNOSIS

AND TREATMENT 1047-9651/97 $0.00 + .2O

REFERRED PAIN
Clinical Significance, Pathophysiology,
and Treatment

Leonardo Vecchiet, MD, a n d Maria Adele Giamberardino, M D

REFERRED PAIN IN CLINICAL PRACTICE

The term referred pain is classically used to indicate pain perceived in regions
of the body other than the one whose stimulation caused the pain, that is, the
structure in which the primary algogenic pathology takes place.19
This kind of pain is extremely frequent in the clinical setting; in fact, pain
in somatic parietal areas of the body (at the cutaneous, subcutaneous, and
muscular level) may not only be a result of algogenic processes directly involv-
ing the painful areas (such as direct traumas or local inflammatory states)35but
may also be the result of algogenic processes in distant structures, either somatic
(other muscles, joints, ligaments, bones, etc) or visceral (referred pain from
somatic or visceral structure^).^, 8r 33, 37, 40 Whether the pain is referred from
somatic or visceral structures, it can be fundamentally divided into two types:
referred pain without kyperalgesia (also called segmental pain) and referred pain with
kyperalgesia (also called true parietal pain), that is without or with a condition of
somatic tissue hypersensitivity, in terms of increased reactivity to painful stimuli,
and also often of a decreased pain threshold to stimuli of various natures
(mechanical, electrical, etc) (Fig. I).",27

Clinical Examination of the Patient with Referred Pain

One of the first challenges for the clinical practitioner dealing with painful
conditions in patients is to establish whether the pain is primary or referred.
The first step in this respect is a careful evaluation of the clinical history. If the

From the hstitute of Medical Pathophysiology, G. D'Annunzio University of Chieti,

Chieti, Italy
~ ~ ~ p p ~ ~ ~ ~ p

PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA

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VOLUME 8. NUMBER 1 FEBRUARY 1997 119
120 VECCHIET & GIAMBERARDINO

without Hyperalgesia Somatic Structures

(muscle, joint, bone, etc)

/
with Hyperalgesia \ Visceral Structures
Figure 1. Classification of referred pain.

pain is primary, that is, the site of the symptom coincides with the primary
algogenic focus, the clinical history often reveals the occurrence of events de-
termining local damage to the painful tissues, such as local mechanical traumas
or microtraumas (muscle sprains, strains, or contusions), or contact with irritant/
algogenic substances.30,34 In the case of referred pain, the clinical history may
reveal traumatic events involving somatic areas situated far from the painful
area (e.g., for pain at quadriceps level, a past trauma to the knee joint) or point
out episodes indicative of a visceral disease (e.g., an episode of malaise, sense
of epigastric oppression with marked neurovegetative signs, indicative of true
visceral pain).31In the latter case, the involved viscus may be identified by
bearing in mind the neuromeric connections of viscera to different somatic
districts."
The second, basic step in the evaluation of the patient's algogenic condition
is physical examination of the painful area. One crucial element with this respect
is the detection of h y p e r a l g e ~ i a . ~
44 ~At
, ~ a~ ,first approach, this can be achieved
simply by applying an additional stimulus to the affected area manually, for
example by means of local digital pressure.36This simple maneuver is able to
reveal hypersensitivity (pain for mild pressure) or normal sensitivity (no pain
but only the sensation of pressure).32If no hypersensitivity is present, then the
pain complained of by the patient in that area is undoubtedly a referred pain
without hyperalge~ia.~~ If hypersensitivity is detected, the pain can be either
primary or referred with hyperalge~ia.~'
Inspection of the painful area can help to distinguish between the two. In
the case of primary pain, it may reveal the presence of alterations like reddening,
swelling, or hematic extravasation, which are not normally evident in the case
of referred pain with hyperalge~ia.~~
Further steps in the examination of the painful area involve use of both
clinical and instrumental procedures for hyperalgesia detection, which are selec-
tive per each parietal tissue (skin, subcutaneous tissue, muscle).", 39, a,43, lM

The clinical procedures for hyperalgesia detection are the dermopraphic

procedure and Head's technique for the skin:] the pinch palpation for the
subc~tis,3',~~ and the digital pressure for the muscle.3643 The instrumental proce-
dures include threshold evaluation via: (1) for skin, von Frey's hairs,2O Fischer's
algometer over a skinfold: thermal algometer,2O 22 electrical stimulation via
,(2) for subcutis, pinch algometerl" and electri-
SurfaCeelectrodeSR,14.33,34,37-39.41,42.
cal stimulation via needle electrodes8,14, 33, 37-42;(3) for muscle, Fischer's
algometer4, and electrical stimulation via needle electrodes (refer also to refer-
ences8,14, 33, 34, 3742 for detailed description of both clinical and instrumental
procedures).
In areas of primary pain, the results of the combined clinical and instrumental
examination usually
 REFERRED PAIN 121

(1) in skin, prevalence of the ischemic phase of dermographism and hyper-

sensitivity to Head's maneuver,3I lowering in pain threshold to mechani-
cal (von Frey's hairs and Fischer's algometer),hMthermal," and electrical
~timulation~~
(2) in subcutis, hypersensitivity to pinch decrease in pain
threshold to mechanical (pinch algometer)," and electrical stimula-
tion39, 40
(3) in muscle, hypersensitivity to digital pressure3643 and decrease in pain
threshold to mechanical (Fischer's algometer)" and electrical s t i r n ~ l i . ~ ~ , ~
In areas of referred pain with hyperalgesia, the hyperalgesic involvement tends
to be more pronounced at the muscular level than at the cutaneous/subcutane-
ous level.", 12, 14, 27 Furthermore, specific trophic changes in parietal tissues are
also detectable; these consist of an increase in thickness of the subcutis and a
decrease in thickness and section area of rn~scle.~, 42 The increased thickness of
subcutis is easily detectable by clinical means by pinching of folds of tissue and
putting finger pressure on the tissue." This latter maneuver either does not
leave any fovea or leaves fovea for a very short time (3 seconds for a pressure
of 2 kg, Fischer's unpublished observation, 1995). In fact, this tissue thickening
does not present the characteristics of edema, in which the fovea lasts longer
and hyperalgesia is a b ~ e n t . ~
The formation of edema can be attributed to the increase in liquid interstitial
pressure and not to solid tissue pressure exerted on the points of contact of the
cells, fibers, collagen, and intercellular gel.17 The phenomenon can be evaluated
quantitatively by measuring the capacity of the tissue to accept physiologic
solution from outside. A high correlation is normally found between the increase
in thickness and consistency of the subcutis and the increase in the resistance to
the introduction of the physiologic solution (refer to reference 8).
The increased thickness of the subcutis and decreased thickness and section
area of the muscle can be evaluated also (and precisely quantified) instrumen-
tally (ultrasonographies)." 26, 37
One typical characteristic of both sensory (hyperalgesia) and trophic
changes in areas of referred pain is that they persist for a long time, outlasting
not only the spontaneous painful symptomatology but sometimes also the pres-
ence of the primary algogenic focus that has generated them.", 12, 14, 31, 3 T h e s e
changes are, in fact, typically detectable in the referred zones of the patients in
the pain-free interval, and residual hyperalgesia can be found in some cases
even years after the primary focus has been e~tinguished.~~ This is what happens,
for example, in patients who have suffered from renal colics due to calculosis
and then have eliminated the stone spontaneously through the urine; hyperalge-
sia is still detectable in the oblique musculature ipsilateral to the previously
affected urinary tract in most cases years after the stone has passed away.33

Clinical Examples of Referred Pain

Referred Pain from Joints

The pain of osteoarthrosis of the knee is deep, fairly well localized, and of
varying intensity, often well tolerated but sometimes less so, and in some cases
even making walking difficult. It spreads up to the lower part of the thigh and
down as far as the middle of the calf? The skin appears pale and hypothermic
to the touch in an area covering the anterior surface of the knee, at the borders
of which telangiectasias can often be observed? The underlying subcutis appears
122 VECCHIET & GIAMBERARDINO

tender and thickened at pincer palpation; finger pressure against the bone
produces pain and leaves fovea briefly or not at all, and the skeletal muscles
connected to the joint are tender and tense.8 When the disease is longlasting,
enlargement of the knee may occur. This enlargement becomes even more
evident due to thinning of the thigh muscle^.^ The pain may be caused by
mechanical activation of receptors as occurs, for instance, during arthroscopy or
sudden effusions. It can also be caused by rupture of subchondral vessels,
intracavital bleeding, and detachment of fragments of cartilage. All these condi-
tions can induce synovial inflammation and release of algogenic substances that
pass from the synovia to the surrounding adipose and fibrous tissues, which are
rich in chemoreceptors3(also refer to reference 8).
Starting from the aforementioned clinical and experimental data, research
was carried out by our group to determine if there was a relationship between
the intra-articular algogenic condition and the referred tenderness and trophic
changes in the superficial structures in patients suffering from painful os-
teoarthrosis of one knee. The skin, subcutaneous tissue, and skeletal muscle
therefore were examined!

Skin
An interruption of dermographism was observed in the skin overlying the
vastus medialis muscle 3 to 4 cm from the articular rima of the affected knee.9
In the same area, the pain threshold to electrical stimulation was slightly lower
than on the opposite side.&

Subcutaneous Tissue
The subcutaneous tissue underlying the aforementioned skin area proved
to be hypersensitive and turgid (thicker) at clinical maneuvers for detection of
hyperalgesia and trophic change^.^
The pain threshold to electrical stimulation of the tissue was significantly
lower on the affected side than on the contralateral side. In contrast, the thick-
ness of the tissue measured by echographic scans was significantly greater in
the affected knee than in the unaffected knee.&

Muscle
The pain threshold to electrical stimulation of the vastus medialis was
significantly lower on the affected side than on the opposite side.', The section
area of the muscle and the density of the interfibrillar tissue, examined by
echographic scans, were lower and higher, respectively, on the affected side
than on the unaffected side.8 In the vastus medialis muscle of healthy subjects
in standing position, no electromyographic activity was found at rest, whereas
in subjects with osteoarthrosis of the knee an intense activity was seen, which
increased on straightening the trunk.'
Disappearance of Pain. To establish a relationship between pain and sensi-
tive-trophic changes, the latter were tested before and after a reversible anesthe-
tic block of the kneecap. A return to normal values was seen in several indexes,
such as the pain threshold of all three tissues, the electrical activity at rest of the
muscle, and the capacity of the subcutaneous tissue to take in liquids from
outside. A decrease in tissue thickness was observed also!
In conclusion, in patients affected with osteoarthrosis of the knee, sensitive-
trophic changes are present in the parietal tissues of the referred painful area.
 REFERRED PAIN 123

These changes are likely to depend on the activity of the intra-articular algogenic
focus because the suppression of the latter by anesthetic block eliminates or
reduces them considerably.

Referred Pain from Muscles

Myofascial pain syndromes are a typical example of referred pain from mus-
c l e ~ These
? ~ syndromes are defined as a clinical picture of pain and autonomic
phenomena referred from active myofascial trigger points with associated dys-
function, where a trigger point is a focus of hyperirritability in a muscle or its
fascia that causes pain at rest or motion in a target area, according to a pattern
of spatial distribution that is specific for the muscle.30,34, 43
This area is called of reference or of radiation depending on whether or not it
is anatomically continuous with the site of the trigger point (TrP).It is included
usually in the same dermatome, myotome, or scceroiome but, sometimes, ex-
tends to parts of other neurologically unrelated segments. An active TrP is
always painful; it is located in a hardened palpable band, prevents complete
lengthening of the muscle, usually produces referred or radiated pain when
directly compressed, mediates a local twitch response of muscle fibers when
appropriately stimulated, and often produces specific neurovegetative phenom-
ena in a target area.%43 A TrP is called latent when it is clinically silent with
respect to spontaneous pain but has all the other characteristics of active TrPs.
Thus pain in a somatic area may be the result of the presence of a TrP in distant
muscles (referred pain from muscles).34
Specific sensory changes are detected at both TrP and target level (area of
referral)?9 In particular, at the level of the TrP there is a considerable lowering
in pain threshold (as measured via electrical stimulation) not only, as expected,
in the muscular tissue, but also in the overlying cutaneous and subcutaneous
t i ~ s u e s ?At
~ ,target
~ ~ level (area of pain referral) of active TrPs, the same sensory
alterations are found, although of a lesser extent with respect to those of active
T ~ P sIn. ~particular,
~ the hyperalgesia is most pronounced in the muscle, less so
in the subcutis, and minimal in the skin. The extent of the threshold decrease in
the area of pain referral is a function of the degree of TrP hyperirritability, with
a greater extent of hyperalgesia (and progressively greater extent of superficial
parietal tissue involvement)." In the case of latent trigger points, the sensory
changes at target level consist mainly of muscular hyperalgesia, with sensory
normality of skin and s u b ~ u t i s . ~ ~

Referred Pain from Viscera

Visceral pain is a dominant symptom in the clinical setting. In fact, pain is
the most important sensory experience that can be evoked in viscera." 27 Pain
in the course of a visceral disease usually has a temporal evolution, and the
characteristics of the symptom differ over the various phases.41The classification
of visceral pain derived from the classic studies of Lewis, Lunedei and Galletti,
Hansen and Schliack, as well as Wolff (refer to reference 27), distinguishes true
visceral pain from referred pain with hyperalgesia and referred pain without
hyperalgesia.
True visceral pain is usually perceived during the initial episode, or initial
phases of the very first episode of a painful visceral disease. The pain is usually
felt in the same site regardless of the viscus in question (i.e., along the midline
of the chest or abdomen, mainly in the lowest sternal area and the epigastric
region).27,31 The symptom is generally perceived as a deep, dull, vague, and
124 VECCHIET & GIAMBERARDINO

poorly defined sensation; in most cases, it cannot even be clearly described,

being a sense of discomfort, malaise, or oppression rather than real pain.32It can
vary from slight to maximal intensity, and is characteristically associated with
marked autonomic phenomena, such as pallor, profuse sweating, nausea, vom-
iting, changes in blood pressure and heart rate, disturbances of the alvus, and
dysthermia.'l~~~ Strong emotional reactions are very often present and consist of
anxiety, anguish, and sometimes even a sense of impending death." In some
cases, true visceral pain may manifest exclusively through vegetative and emo-
tional reactions accompanied by metaesthesia (i.e., an intermediate sensation
between pain and dis~omfort)?~ Another important feature is that additional
stimuli, when applied to the parietal structures of the area where the sensation is
perceived, do not increase the pain.31Over time, the symptom can be continuous,
subcontinuous, undulating, or accessional (colics). Its duration is always limited,
varying from a few minutes to a few hours, after which it either ceases or
becomes superficial (i.e., referred to a parietal somatic area).31
Referred pain from viscera. Referral (or superficialization) is one of the funda-
mental features of visceral pain.12When a visceral algogenic process either recurs
or becomes particularly intense and prolonged, the sensation is no longer felt in
a common site irrespective of the viscus of origin. Instead, it tends to be
perceived in superficial somatic structures (i.e., skin, subcutaneous tissue and
muscle) of areas that differ according to the viscus and that are often remote
from the primary source of the algogenic impulse^.^,^^ Furthermore, the sensation
becomes sharper, qualitatively more similar to pain of somatic origin, much
better defined and localized, and is no longer accompanied by marked auto-
nomic phenomena.27As for referred pain from somatic structures, referred pain
from viscera may manifest in the classic two modalities: (1) without hyperalge-
sia, and (2) with hyperalge~ia.~~ The first is felt in wide areas of the parietal
metameres that relate to the viscus in question (i.e., areas supported by the same
spinal segments as the viscus). It may extend also to adjoining metameres. The
second, by far the more frequent, appears in areas that are metamerically
connected to the affected viscus, but its extent is more limited with respect to
that of "referred pain without hyperalgesia." Hyperalgesia is most often con-
fined to the muscular tissue where it is often accompanied by a condition of
sustained c o n t r a c t i ~ n . ~ ~
Two subtypes of referred pain with hyperalgesia have been distinguished
(refer to reference 11):
1. Referred pain with hyperalgesia in a selected area, that is, in a fixed
position for each internal organ (i.e., in the xiphoid region for the lowest
third of the esophagus, submammary position for the pleura, at the
epigastral level for the peritoneum); and
2. epicritic referred pain with hyperalgesia, which is localized in a parietal
region above the site of the affected organ. For example, except for pleura
covering the diaphragmatic center, which projects to C4 and sometimes
to C3-5 metameres, the pain is perceived in the area above that in which
friction murmurs are recorded in pleurisy.
Extension of the referral area of pain from a viscus (with or without
hyperalgesia) is linked to the duration of visceral stimulation." In other words,
a prolonged or repeated visceral stimulation or both results in enlargement of
the area. A clinical example is irritable bowel syndrome; many such patients
report extension, during the course of their disease, of the abdominal area from
which the pain is experienced. The experimental counterpart of this phenome-
non was clearly provided by Ness and co~orkers,2~ who examined responses to
 REFERRED PAIN 125

repeated colorectal distension in normal, healthy young adults. Distension of a

25-cm tract of sigrnoid colon produced sensations that were perceived in the
pelvic area (i.e., low abdomen), perineum, and upper lumbar area. The first
distension (60 mm Hg for 30 seconds) was not regarded as painful by the
subjects, whereas 10 consecutive distensions 5 minutes apart produced signifi-
cant enlargements in the referral areas of the sensation that became pain of an
aching quality by the tenth distension.
Another important phenomenon is linked to the referral of pain from
viscera. If somatic tissues in a metamere related to the viscus in question are
already the site of an algogenic process (e.g., because of a myofascial trigger
point), then referred pain from the involved viscus is preferentially felt in
that area."
Both sensory and trophic changes are generally found in the parietal tissues
of areas with true parietal pain of visceral origin, as already described in the
general section on Referred Pain in Clinical Practice. They can involve the three
parietal tissues but are generally far more pronounced in the muscle.27
Myocardial infarction is one of the most typical examples of visceral pain in
the clinical setting.18,27 During the first phase, true visceral pain is perceived in
the lowest sternal and/or epigastric areas and sometimes also in the interscapu-
lar region. The symptom has only a vague localization and an oppressive or
constrictive quality, is often of high intensity, and is generally accompanied by
pallor, profuse sweating, nausea, and vomiting. An associated, strong alarm
reaction frequently occurs in the patient, sometimes with a feeling of impending
death. In this phase, additional stimuli applied to the area of pain do not
increase the symptom. After a period varying from 10 minutes to several hours,
the pain reaches the parietal structures and assumes the characteristics of deep
somatic pain. It becomes sharper in quality and tends to be located in the
thoracic region, either anteriorly or posteriorly, and very often extends to the
upper limbs, especially the left one (referred pain).
Less frequent sites of pain referral are the jaw and neck. At this stage, the
accompanyi~gneurovegetative signs are scarce; and the pain symptom is simi-
lar to that provoked experimentally by injecting hypertonic saline directly into
skeletal muscle. In patients not treated with morphine, the duration of referred
pain is longer than that of true visceral pain (i.e., 30 minutes to 12 hours).
Muscular hyperalgesia accompanies the symptom and often outlasts its duration,
so additional stimuli exerted on the area of referral increase the pain. Hyperalge-
sia mainly involves the pectoralis major and muscles of the interscapula; regcon
and forearm. The trapezius and deltoid muscles are less frequently involved. In
a minor percentage of cases, pain is also referred to the skin, within the derma-
tomes C8-T1 (i.e., on the ulnar side of the arm and forearm) and hyperalgesia is
found at the same level.", 27, 31
Another example of referred pain from viscera is represented by biliay
colic^.^^ These occur frequently as a consequence of biliary calculosis but may
also be the result of dysfunctional pathology of the gallbladder.31As for all other
viscera, an episode of biliary colic usually begins with poorly localized pain in
the midepigastrium, is very intense, and generally accompanied by anorexia,
nausea, and vomiting. As time passes in the course of the first episode or,
subsequently, in other episodes, the sensation starts to become referred to
somatic areas, anteriorly in the right upper abdominal quadrant and posteriorly
in the right scapular and subscapular regions. The symptom is accompanied by
sensory and trophic changes in the area of pain referral, particularly, decreased
pain threshold mostly in the muscle (but often also in skin and subcutis) at the
level of the cystic point with respect to the contralateral point, increased thick-
126 VECCHIET & GIAMBERARDINO

ness of the subcutaneous and decreased thickness of the muscle (unpub-

lished observation), which long outlast the pain itself. The sensory and trophic
changes are strictly related to the algogenic potential of the visceral disease; the
changes are, in fact, significant only when the pathology has been algogenic (no
significant changes, for example, were found in the case of asymptomatic biliary
calculosis, but significant changes were detected in the case of painful gallblad-
der dysfunction) (unpublished observation). Furthermore, the extent of both
sensory and trophic changes proves to be related to the extent of the spontaneous
painful symptomatology, that is, a greater threshold lowering (especially in the
muscle), and subcutaneous tissue thickness increases are observed when a
greater number of colics has been experienced by the patient^.^"

EXPERIMENTAL REFERRED PAIN

Before addressing the pathophysiologic issue of referred pain, it is im-

portant to describe some experimental models of the condition because these
have helped to clarify some aspects of basic mechanisms.

Experimental Referred Pain from Somatic Structures

One of the first and most frequently employed methods of inducing muscu-
lar pain experimentally has been the injection of hypertonic saline solution of
different concentrations into the tissue. As early as the 1930s, Kellgren (1937-
1938) and Lewis (1938)37injected 0.1-0.3 mL of 6% hypertonic saline into a
variety of skeletal muscles through locally anesthetized skin. In this way, they
were able to describe the clinical features of the symptom with special regard
to the spatial distribution and spread of the pain from the stimulated site to
adjacent and/or distant areas (referred pain). In particular, their observation led
them to conclude that injection of a given site of muscle tissue induces pain
over a definite area and that the distribution for a given muscle is constant and
similar in different individuals. Further studies by the same researchers evi-
denced that the induced muscular pain is also associated with cutaneous hyper-
algesia, tenderness, reflex muscle spasm and, not infrequently, sympathetic
hypera~tivity.~~ The same technique of muscle stimulation was subsequently
employed by other researchers (Maison, 1939; Inman and Saunders, 1944; Mac-
Arthur and Alstead, 1953; Procacci et al, 1961; Wolff et al, 1961).37The overall
experience led to basic general agreement concerning the clinical features of the
referred muscle pain induced. The symptom is deep, fairly well discriminated
and of medium degree of spatial localization, arises a few seconds to 1 minute
after the injection, lasts a few minutes, and is generally less severe than that felt
in the stimulated site. Furthermore, the symptom is perceived within the muscle
and bone structures (myotomes and sclerotomes) included in the same meta-
mere(s) as the injected muscle, sometimes extending to adjacent metameres, and
is accompanied by paresthetic sensations and almost constantly by a sense of
heaviness and functional impairment of the limb and at times also by cramp-
like and tingling sensations.
Because the injection of hypertonic saline was able to induce not only local
muscle pain but also pain distant from the injection site, it seemed very useful
in studies regarding the referred pain zone. Most subsequent research using the
method was performed by the Florentine School, where it was particularly
directed towards the study of changes taking place in the cutaneous tissue of
 REFERRED PAIN 127

the referred area using the dermographic procedure, Head's technique, and
measurement of skin impedan~e.~' Less attention was paid, however, to the
quantification of sensory changes in the subcutaneous and muscular tissue of
the referred area. In order to have a complete picture of the algosensitive
modifications of the three parietal tissues (skin, subcutaneous tissue, and muscle)
in the referred pain area, in one of the previous studies by our group, pain
thresholds to electrical stimulation were measured differentially in the three
tissues in the area of referred pain from an experimentally induced muscular
algogenic focus.38
Healthy volunteers underwent injection of 1 mL of 20% hypertonic saline
into the brachioradialis muscle. Following injection, all of them felt a pain whose
characteristics were those of deep somatic pain in an area extending from the
injection site up to the elbow and down to the base of the thumb, sometimes
accompanied by tingling in the same area, as well as neurovegetative signs,
namely pallor, sweating, and vertigo.
Clinical observation of the three parietal tissues in the painful zone showed:
(1) a 7 x 6 cm hyperalgesic area concentric to the injection site in the skin;
(2) a 5 x 4 cm hyperalgesic and turgid area, also concentric to the injection
site in the subcutaneous tissue;
(3) a hyperalgesic area, including the metameric field of the brachioradialis
from the elbow down to the base of the thumb in the muscle.
In the hyperalgesic areas, pain thresholds to electrical stimulation under-
went:
(1) in the skin, a highly significant decrease for up to 15 minutes in the
whole area and up to 45 minutes in the center (P<0.01);
(2) in the subcutaneous tissue, a highly significant decrease for up to 25
minutes in the whole area and up to 55 minutes in the center (P<0.01);
(3) in the muscle, a highly significant decrease for up to 24 hours in the
whole area (P<0.01).
A group of control subjects also underwent injection of 1 mL hypertonic
saline in the brachioradialis muscle followed by clinical and instrumental verifi-
cation of the development of hyperalgesic areas in the skin, subcutaneous tissue,
and muscle. About 30 minutes after injection, the pain focus in the muscle was
suppressed by means of a 1mL injection of 2% carbocaine. After saline injection,
pain thresholds in the three tissues were significantly lower than basal values
but, after carbocaine injection, thresholds immediately returned to normal, not
only in the muscle (i.e., the tissue injected with the anesthetic) but also in the
skin and subcutaneous tissue. This experiment clearly showed the cause-effect
relationship between the primary muscular algogenic focus and the sensory
changes in the three parietal tissues of the referred pain area. The sensory
changes are not, however, the only objective finding in the area of referred pain
from hypertonic solution. In a separate set of experiments performed using the
same technique of injection in healthy volunteers, subcutaneous tissue thickness
in the area of referred pain was monitored via echographic scans before (basal
values) and after the injection, at regular intervals of time.26A significant tissue
thickening was found from the 15th to the 36th hour.
In subsequent studies, the technique of hypertonic saline injection was used
to explore the possible relationship between the algogenic potential of the
muscle focus (in terms of intensity and duration of spontaneously perceived
pain) and the extent and duration of both sensory and trophic changes in the
128 VECCHIET & GIAMBERARDINO

area of referred pain. To induce muscle foci of different algogenic potential,

saline solutions of different concentrations were used (i.e., hypotonic solution,
10% and 20% saline solution).37Saline isotonic solution, which is not algogenic,
was also used as control. The study was conducted on the vastus lateralis
muscle of the same subjects and the different injections were performed in a
random order with an interval of at least 3 weeks from each other.
Following physiologic saline solution injection, no pain was felt whereas
after hypertonic and hypotonic saline all the subjects felt a deep, moderately
diffused, cramp-like or burning pain extending from the middle third of the
anterolateral region of the thigh to the upper margin of the kneecap for 10%
hypertonic and hypotonic solutions, and from the coxofemoral joint to below
the kneecap for 20% hypertonic solution. The duration and maximum intensity
of the symptom varied according to the solution used (from maximal to minimal
in the following order for: 20% hypertonic, 10% hypertonic, hypotonic). After
physiologic solution, no sensory and trophic changes were detected in the whole
area explored. After the algogenic solutions, both sensory and trophic changes
were found, whose extent and duration proved to be a function of the extent
and duration of spontaneous pain perceived. In particular, a direct correlation
was found between:
(1) the maximum intensitv of the pain perceived and the maximum de-
crease in pain threshofd, highlyLsigniiicantfor the skin and the muscle
IP<O.OOlk
(2) the maximum intensity of pain and the duration of hyperalgesia (i.e., of
a pain threshold decrease of over 20% of basal values), highly significant
for the muscle (P<0.001);
(3) the duration of pain and the maximal decrease in pain threshold, sig-
nificant for the skin (P<0.03) and the subcutaneous tissue (P<0.05) and
highly significant for the muscle (P<0.001);
(4) the duration of pain and the duration of hyperalgesia, significant for the
muscle (P<0.05).
A direct linear correlation was also found between:
(1) the maximal intensity of pain and the maximal thickening of the tissue,
highly significant (P<0.003);
(2) the maximal intensity of pain and the duration of the thickening in the
tissue, highly significant (P<0.003);
(3) the duration of pain and the maximal thickening of the tissue, highly
significant (P<0.001);
(4) the duration of pain and the duration of the thickening in the tissue,
highly significant (P<0.001).
In conclusion, the results of the experimental induction of an algogenic
focus in the skeletal muscle show clearly that pain in deep somatic structures is
not only localized in the site of the lesion (algogenic stimulation) but also tends
to be referred to distant areas where hyperalgesia and trophic changes in
tissue are detected, whose extent and duration are strictly dependent upon the
algogenic potential of the deep focus.

Experimental Referred Pain from Viscera

The characteristics of the referred hyperalgesia from urinary stones have

been reproduced in animals (rats) with artificial stones formed in the upper
 REFERRED PAIN 129

third of one ureter by injection of dental cement under general anesthesia.I5

Stone-implanted animals develop hypersensitivity of the ipsilateral obliquus
extemus (the same muscle involved in humans with urinary colic^),'^^^ as shown
by a decrease in the vocalization threshold to electrical muscle stimulation. This
hypersensitivity appears on the first day after stone implantation and although
particularly pronounced during the first 3 to 4 days, usually lasts for over
a week.'"
Along with the muscle hyperalgesia, and as shown by long-term nonstop
videotape recordings, stone-implanted animals also show complex behavioral
episodes, similar in nature to the writhing behavior characteristic of noxious
visceral stimulation in animal^.'^,'^ These are never manifested in sham-operated
rats or rats subjected to nonalgogenic ureteric interventions.12The episodes vary
in frequency and duration. Their number and duration decrease significantly
and linearly in time after the operation and are mostly observable during the
first 3 days. Number, duration, and complexity of the episodes are significantly
reduced in a dose-dependent fashion by chronic treatment with morphine.15
All these observations together strongly support the notion that this behav-
ior is an index of perceived visceral pain and thus the behavioral equivalent of
urinary colics in humans.
These visceral episodes show a precise and constant relationship with re-
ferred muscular hyperalgesia. In fact, a significant direct linear correlation exists
between the number of episodes and the extent of the decrease of ipsilateral
muscle threshold, so that hyperalgesia is more accentuated in rats displaying a
high number of visceral episodes than in those with a smaller number.15Further-
more, the hyperalgesia ii still detectable 1 week after stone implantation, even
in rats, who at autopsy, prove to have expelled the stone spontane~usly.'~
Therefore, this animal model of referred lumbar muscle hyperalgesia from
artificial calculosis closely resembles the condition of referred lumbar muscle
hyperalgesia observed in humans with urinary colic.
As in patients, the phenomenon is mainly localized to muscle of the lumbar
region ipsilateral to the affected urinary tract; appears at an early stage with
respect to the start of the activity of the visceral focus; is accentuated by
repetition of painful visceral episodes; and tends to persist for a long time,
outlasting the duration of direct pain from the viscus and the presence of the
visceral focus in the urinary tract.33
Electrophysiologic experiments (spinal cord recordings of the activity of
single dorsal horn neurones) in this animal model have shown a significant
contribution by central mechanisms to the genesis of the referred phenomenon.13
In rats with referred muscle hyperalgesia with respect to controls, in fact, results
showed: (1) a significantly higher percentage of neurons displaying a receptive
field in the hyperalgesic muscle, (2) a significantly higher percentage of neurons
with muscle input displaying spontaneous activity, (3) a significantly higher
frequency of discharge of spontaneously active neurons with muscle input, and
(4) a significantly higher percentage of neurons with input from the hyperalgesic
muscle with a low mechanical threshold of activation. All these findings were
proportional to the number of visceral episodes shown by the animals before
spinal cord recordings and to the extent of the muscle threshold decrease
detected behaviorally.
The results of this study can be interpreted in terms of a condition of central
sensitization, probably triggered by the visceral algogenic focus, which amplifies
and facilitates messages from the referred somatic area, thus, accounting for the
hyperalgesia.
130 VECCHIET & GIAMBERARDINO

PATHOPHYSIOLOGY OF REFERRED PAIN

Referred Pain Without Hyperalgesia

An initial, simple model for interpreting referred pain without hyperalgesia

was based on the idea of viscerosomatic convergence occurring in primary
afferent fibers, with multiple peripheral branches innervating both the site of
the primary algogenic focus (viscus, deep somatic structure, etc) and the area of
referred pain. The number of fibers with these characteristics, however, is ex-
tremely limited; therefore, it is not reasonable that the peripheral branching of
axons can account for such a dominant phenomenon as referred pain, which
occurs in algogenic pathologies involving so many somatic/visceral d ~ r n a i n s . ~
The convergence of afferent fibers coming from both the site of the primary
algogenic focus and the area of pain referral upon the same neurons at central
level is, in contrast, more adequate to account for the pathophysiology of
referred pain without hyperalgesia?,45 In fact, this kind of convergence is well
documented at several levels in the central nervous system (CNS) (spinal cord,
brain stem, thalamus, cortex45);one very explanatory example is represented by
viscerosomatic convergence, which is the rule throughout the CNS (there are
virtually no afferent fibers exclusively concerned with visceral domains)?, 45
According to the convergence-projection theory, the message from the site of
the primary algogenic focus would be interpreted by higher brain centers as
coming from the area of pain referral. This, in the case of referred pain from
viscera, is because of the mnemonic traces of previous experiences of somatic
pain (more frequent than experiences of direct visceral pain)27(Fig. 2).

Figure 2. Referred pain without hyperalgesia. Schematic representation of the "conver-

gence-projection" theory in the case of referred pain from viscera to muscle.
 REFERRED PAIN 131

Referred Pain with Hyperalgesia

Interpreting "referred pain with hyperalgesia" or "true parietal pain" is

more complex than interpreting simple referred pain, and the convergence-
projection mechanism alone is inadequate to account for hyperalge~ia.~' TWO
main theories, which are not mutually exclusive, have been proposed. The first
is known as "convergence-facilitation"23;the abnormal input from the site of the
primary algogenic focus would produce an "irritable focus" in the relative
spinal cord segment, thus facilitating messages from somatic structures. In other
words, thanks to the convergence of fibers from the primary focus and the area
of referral onto the same neurons and the increased input from the primary
focus, the central effect of the normal input from the area of referral is amplified.
This produces a more intensely painful sensation than normal when algogenic
stimuli are applied onto the somatic receptive field (i.e., secondary hyperalgesia)
(Fig. 3).= According to this theory, referred pain with hyperalgesia is caused
mainly by central mechanisms. Some experimental evidence has been provided
for this theory, as already described in the previous section on experimental
referred pain from viscera.
The second theory postulates that algogenic conditions develop in the
periphery (i.e., the referred area), with subsequent excitation of pain receptors,
because of several reflexes (in the case of referred pain from viscera, viscerocuta-
neous and visceromuscular reflexes) that are triggered by the afferent barrage
from the primary algogenic focus.2,27 Therefore, referred pain with hyperalgesia
would be produced by activation of a reflex arc, the afferent branch of which is
represented by sensory afferent fibers from the site of the primary focus, whereas

Viscus
\

Figure 3. Referred pain with hyperalgesia. Schematic representation of the "convergence-

facilitation" theory in the case of referred pain from viscera to muscle.
 132 VECCHIET & GIAMBERARDINO

the efferent branch differs for superficial and deep somatic tissues. According
to some authors: hyperalgesia and related phenomena at skin level are induced
i by sympathetic efferents, because an experimental, local anesthetic block of the
sympathetic ganglia led to disappearance or marked decrease in referred pain,
hyperalgesia, and dermographic skin alterations! In contrast, hyperalgesia in
muscle is caused by somatic efferents in this view.I7,31 These are responsible for
a sustained contraction that, in turn, sensitizes muscular nociceptors and be-
comes a new source of pain (Fig. 4). The muscle contraction that occurs subse-
quent to noxious visceral stimulation, for instance, was illustrated in a classic
experiment by McLellan and Goodell in 1942.24Upon electrical stimulation of
the pelvis and ureter in patients, muscles of the abdominal wall on the stimu-
lated side remained contracted and began to ache 30 minutes later. The ache
increased over the following 6 hours, with tenderness persisting even the next
dav. It must be noted. however. that sustained contraction is not alwavs docu-
mlnted in cases of referred hheralgesia, although it is a frequentJfinding.
Therefore, local sensitization of nociceptors via a reflex arc may contribute in
some cases, but it certainly is not the sole mechanism.27

TREATMENT OF REFERRED PAIN

The first and correct approach to treatment of referred pain is, of course,
the identification of the source of the symptom.32
In the case of referred pain of visceral origin, treatment varies according to
the nature of the visceral algogenic pathology.'" Thus, for instance, referred pain

Ascendent pathway
4

Figure 4. Referred pain with hyperalgesia. Schematic representation of the "reflex arc
theory" in the case of referred pain from viscera to muscle.
 REFERRED PAIN 133

from urinary colics from calculosis will respond to administration of spasmolyt-

ics, nonsteroidal anti-inflammatories or, preferably, the two in c~mbination,'~
whereas referred pain due to ischemic heart disease will cease after administra-
tion of drugs active on coronary circ~lation.~~ Referred pain from a somatic
structure, such as a joint, will cease or improve upon treatment of the joint
disease that has provoked it (e.g., intra-articular infiltration of anti-inflammator-
i e ~ )Referred
.~ pain from myofascial trigger points will respond to treatment of
the latter with the well-known techniques of trigger point inactivation (stretch
and spray, postisometric relaxation, ischemic compression, trigger point injec-
tion, etc)? 21,30 or to correction of factors that promote the trigger point formation
(like lower limb length discrepancy, via heel-lift or dynamic insole).29
If the primary focus originating referred pain is not identifiable, then re-
ferred pain can only be approached directly. All kinds of referred pain are, of
course, sensitive to general analgesic treatments: major analgesics, nonsteroidal
anti-inflammatories, psychoactive drugs, alone or in various combinations.1° 36
The distinction between referred pain without and with hyperalgesia becomes
important when we are to apply local treatment^.^^

Referred Pain Without Hyperalgesia

There is generally no advantage in treating an area of segmental pain

locally. Referred pain without hyperalgesia, in fact, is not influenced at all by,
for instance, local injection of anesthetic substance^.",^',^^ Referred pain without
hyperalgesia can thus only be treated effectively either by acting on the primary
source of the symptom or by applying measures intended to alleviate pain in
general, as already said.

Referred Pain with Hyperalgesia

This responds to local treatment of the painful area in the same way as
primary somatic pain, that is, injection of local anesthetics preferably into the
muscular tissue36(or, sometimes, also other local measures like transcutaneous
electrical nerve stimulation (TENS).46 In our experience, the technique of anesthe-
tic injection is the most effective. Most often in the area of referred pain with
hyperalgesia a point of maximum tenderness can be identified which has the
characteristics of a TrP.30In this case, the injection is preferentially performed at
that level with a procedure identical to the one classically used for TrP injection
in areas of primary pain.5 In some circumstances, however, no specific point of
focal tenderness can be located and a whole area, of variable extension, can be
diffusely and more or less uniformly tender.36In this case, the best results
are, in our experience, obtained with multiple ( 2 4 ) intramuscular injections of
anesthetics performed in sequence in the course of a single session at points of
regular distances apart within the tender area. The total amount of anesthetic
used for all the injections is equivalent to that which would normally be used
for a single TrP injection. One particular effect that may occur in the case of
referred pain from viscera is that, upon annulling the referred pain component
by injecting the painful somatic area, the true visceral pain component may
come back. In other words, if a patient with pain in muscle structures of the
left arm due to myocardial ischemia undergoes injection of these hyperalgesic
structures, he or she may then have a return of pain in the epigastric region
accompanied by marked neurovegetative signs and emotional reactions.",31
134 VECCHIET & GIAMBERARDINO

SUMMARY

Referred pain that is perceived in somatic parietal areas other than the site
of the primary source of pain is very frequent in clinic as a result of algogenic
pathologies in deep somatic structures or viscera (referred pain from somatic
and visceral structures). Two types of referred pain are normally distinguished
on the basis of the absence or presence of accompanying deep and/or superficial
parietal hyperalgesia: (1) referred pain without hyperalgesia; and (2) referred
pain with hyperalgesia. These two forms of pain are probably sustained by
different pathophysiologic mechanisms: the first is easily accounted for by the
phenomenon of convergence-projection. The second can be explained on the
basis of both central (convergence-facilitation theory) and peripheral (theory of
the reflex arc) mechanisms, as some experimental evidence (on experimental
models of referred pain) exists to support both mechanisms.
The optimal therapy for referred pain is treatment of the source of the
symptom; this implies identification of the site of the primary disease, which
may not be easy in all circumstances. If the primary algogenic focus cannot be
identified, treatment is only symptomatic, either with generally administered
analgesic drugs or with local measures (such as injection of anesthetics in the
painful area). Local treatment, however, is only effective in the case of referred
pain with hyperalgesia.

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Leonardo Vecchiet, MD
via Colle Marino, 108
G5100 Pescara
Italy