muscle pain: understanding the...

Muscle Pain: Understanding the Mechanisms

Siegfried Mense l Robert D. GerwinEditors

Muscle Pain: Understandingthe Mechanisms

EditorsProf. Dr. Siegfried MenseUniversitat HeidelbergMedizinische Fakultat Mannheim CBTM,NeuroanatomieLudolf-Krehl-Str. 13-17, R. C61468167 [email protected]

Dr. Robert D. GerwinAssociate Professor of NeurologyJohns Hopkins UniversityBaltimoreMaryland 21287USAPain and Rehabilitation Medicine7830 Old Georgetown RoadSuite C-15Bethesda, [email protected]

ISBN 978-3-540-85020-5 e-ISBN 978-3-540-85021-2DOI 10.1007/978-3-540-85021-2Springer Heidelberg Dordrecht London New York

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Foreword

This edition of the companion volumes Muscle Pain: Understanding the Mechan-isms and Muscle Pain: Diagnosis and Treatment is essential reading for those

interested in clinical approaches to acute and chronic pain conditions involving

muscle tissues and in the mechanisms underlying these conditions. The volumes

cover a very important topic in pain medicine, since muscle pain is very common

and can often be difficult to diagnose and treat effectively. Furthermore, chronic

pain involving muscle and other components of the musculoskeletal system

increases with age, such that it is a common complaint of those of us who are

middle-aged or older. Indeed, as changing population demographics in “wester-

nized” countries result in higher proportions of the population living longer and

being middle-aged and elderly, chronic muscle pain will likely become even more

of a health problem.

In the case of acute muscle pain, this can often be very intense, and in the short

term can limit or modify the use of components of the musculoskeletal system

associated with the sensitive muscle. Chronic muscle pain can also be intense, as

well as unpleasant and disabling, and it is in many cases the over-riding symptom of

most musculoskeletal disorders that are associated with long-term deleterious

changes in musculoskeletal function. This can present a challenge both to the

patient who has to live with the condition and to the clinician called upon to assist

the patient, not only because of the physical or biomechanical impediment but also

because of the presence of chronic pain reflecting persistent alterations in the

peripheral muscle tissues and/or central nervous system. Chronic pain is now

recognized as a multidimensional experience encompassing cognitive, emotional

and motivational aspects as well as the sensory or perceptual dimension. Thus, as

the editors of this work note in their preface, it can distort the patient’s life,

including work, family and social relationships, and can change the patient’s

perception of himself or herself from being an effective and independent human

being to one who is ineffective and dependent. These features apply especially to

patients with chronic muscle pain, and the range and impact of most musculoskele-

tal disorders and the pain that they manifest dictate that clinicians need to have a

v

good knowledge base about pain and adopt a broad biopsychosocial perspective in

order to provide effective management of the patient. These companion volumes

provide this knowledge base and perspective.

Although the etiology and pathogenesis of several muscle pain conditions are

still unclear, recent advances have been made in understanding muscle pain

mechanisms and in the management of the conditions. The chapters in these

books collectively provide up-to-date details of these mechanisms and management

approaches. The anatomy and neurophysiology relevant to muscle pain is covered

in Muscle Pain: Understanding the Mechanisms. It offers a solid basic science

underpinning for the more clinically oriented second volume, Muscle Pain: Diag-nosis and Treatment, which outlines present knowledge of etiologic and pathophys-iologic processes, and which also deals with current approaches to the management

of the various conditions manifesting muscle pain.

Like its predecessor, these companion volumes should prove to be an invaluable

resource not only to clinical practitioners wanting to have a basic understanding of

pain mechanisms and clinical approaches currently available to diagnose and

manage muscle pain problems, but also to basic and clinical pain scientists who

are interested in an up-to-date and comprehensive review of the diagnostic and

management approaches to muscle pain.

Toronto Barry J. Sessle

vi Foreword

Preface

Disorders of the musculoskeletal system are the leading causes of disability in

western societies. Musculoskeletal pain syndromes can be divided into two broad

categories: (1) myalgias, which include the major condition of myofascial pain

syndromes, as well as inflammatory and other myosites, and (2) articular disorders,

which include all of the arthritides. Fibromyalgia has long been considered a

chronic musculoskeletal pain syndrome, but recent research supports categorizing

fibromyalgia as a widespread chronic pain syndrome. Ergonomic and postural and

other structural dysfunctions, including pain associated with the hypermobility

syndromes, can bridge these two categories, although they tend to fall more into

the myalgic group of disorders.

A problem for the practitioner trying to understand a patient’s pain is that pain is

a subjective sensation that is colored by the patient’s personal life experience, and

ethnic and cultural background. Chronic pain is not simply a sensation, but a global

experience that involves suffering and a distortion of the patient’s role in all phases

of life, including family, work and social relationships, and can change the patient’s

self perception of him- or herself from being an independent, effective human

being, to being a dependent, ineffective person. Communication is particularly

difficult with chronic pain patients, because chronic pain is such a personal experi-

ence of global suffering, rather than a simple sensation like touch. There is a

definite effect of gender on pain perception. Therefore, when examining muscles

in patients for painful conditions, the greater sensitivity of women to painful stimuli

has to be taken into account.

Pain from muscle and skin is subjectively and objectively distinct. Muscle pain

is described as aching and cramping, diffuse and poorly localized, whereas cutane-

ous pain is described as sharp and pricking, and precisely localized. Cutaneous pain

is usually not referred to other body regions, while muscle pain is commonly

referred to other deep somatic structures like tendons and fascia or other muscles,

and viscera (viscerosomatic pain syndromes). Objective differences between

muscle and cutaneous pain exist in the processing of neuronal information at the

vii

spinal and brainstem level and continue up to the brain, where nociceptive activity

from skin and muscle terminates in different regions. Some of the established pain

terms used in this book are defined in chapter 1 of the volume “Muscle Pain:

Understanding the Mechanisms”.

Heidelberg/Mannheim S. Mense

Bethesda R.D. Gerwin

viii Preface

Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Siegfried Mense and Robert D. Gerwin

2 Functional Anatomy of Muscle: Muscle, Nociceptors

and Afferent Fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Siegfried Mense

3 Peripheral Mechanisms of Muscle Pain: Response Behavior

of Muscle Nociceptors and Factors Eliciting Local

Muscle Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Siegfried Mense

4 Central Nervous Mechanisms of Muscle Pain: Ascending

Pathways, Central Sensitization, and Pain-Modulating Systems . . . . . . 105

Siegfried Mense

5 Referral of Musculoskeletal Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

Thomas Graven-Nielsen and Siegfried Mense

6 Increased Muscle Tone as a Cause of Muscle Pain . . . . . . . . . . . . . . . . . . . . 207

Siegfried Mense and Alfonse T. Masi

7 Reorganized Motor Control Due to Muscle Pain . . . . . . . . . . . . . . . . . . . . . . 251

Thomas Graven-Nielsen and Lars Arendt-Nielsen

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

ix

Contents to

Muscle Pain: Diagnosis and Treatment

1 Introduction


Part I Myofascial Pain Syndrome

2 Myofascial Pain Syndrome

Robert D. Gerwin

3 Morphology of Myofascial Trigger Points: What Does

a Trigger Point Look Like?

Siegfried Mense

Part II Fibromyalgia Syndrome

4 Fibromyalgia Syndrome: Clinical Aspects and Management

Emma Guymer and Geoffrey Littlejohn

5 Gender, Genetics, and Other Risk Factors Increasing

Vulnerability to Fibromyalgia

Geoffrey O. Littlejohn

Part III Other Muscle Pain Syndromes

6 Low Back Pain of Muscular Origin

Robert D. Gerwin

xi

7 Masticatory Muscle Pain

S. Palla and M. Farella

8 Inflammatory Myopathies

Ingrid E. Lundberg and Li Alemo Munters

9 Whiplash Injury, Muscle Pain and Motor Dysfunction

Jan Dommerholt

10 Brain Imaging of Muscle Pain

Sandra Kamping and Herta Flor

Glossary

Index

xii

Contributors

Lars Arendt-Nielsen Center for Sensory-Motor Interaction, Department of Health

Science and Technology, Aalborg University Fredrik Bajers Vej 7, Bld. D3 DK-

9220 Aalborg E, Denmark, [email protected]

Robert D. Gerwin Associate Professor of Neurology, Johns Hopkins University,

Baltimore, Maryland 21287, USA; Pain and Rehabilitation Medicine, 7830

Old Georgetown Road, Suite C-15, Bethesda, MD 20814-2432, USA, gerwin@

painpoints.com

Thomas Graven-Nielsen Center for Sensory-Motor Interaction (SMI), Laboratory

for Musculoskeletal Pain and Motor Control, Department of Health Science and

Technology, Aalborg University, Fredrik Bajers Vej 7D-3, DK-9220 Aalborg E,

Denmark, [email protected]

Alfonse T. Masi University of Illinois at Chicago, Dept. Epidemiology and

Biostatistics, 1603 W. Taylor Street, (MC 923), Chicago, Il 60612-4394, USA,

[email protected]

Siegfried Mense Institut fur Anatomie, Universitat Heidelberg, Medizinische

Fakultat Mannheim, CBTM, Ludolf-Krehl-Str. 13-17, R. C614, 68167 Mannheim,

Germany, [email protected]

xiii

Chapter 1

Introduction


Contents

1.1 Subjective Nature of Pain Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.2 Established Pain Terms (partly after Merskey

and Bogduk 1994; Loeser and Treede 2008) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.2.1 General Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.2.2 Increased Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1.2.3 Decreased Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1.3 Established, But Often Ill-Defined, Pain Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1.3.1 Contracture (in the Physiological Sense) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1.3.2 Muscle Spasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1.3.3 Muscle Stiffness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.3.4 Muscle Tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.3.5 Projected Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.3.6 Referred Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.3.7 Spread of Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1.4 General Aspects of Pain and Nociceptor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1.5 Muscle Pain Versus Skin Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1.5.1 Subjective Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

1.5.2 Objective Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

1.6 Descending Pain-Modulating Influences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

1.7 Transition from Acute to Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

1.8 Interactions Between Psychosocial and Somatic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

S. Mense (*)

Universit€at Heidelberg, Mediz. Fakult€at Mannheim CBTM, Neuroanatomie, Ludolf-Krehl-Str.

13-17, R. C614, 68167, Mannheim, Germany

e-mail: [email protected]

R.D. Gerwin

Associate Professor of Neurology, Johns Hopkins University, Baltimore, Maryland 21287, USA;

Pain and Rehabilitation Medicine, 7830 Old Georgetown Road, Suite C-15, Bethesda, MD 20814-

2432, USA


S. Mense and R.D. Gerwin (eds.), Muscle Pain: Understanding the Mechanisms,DOI 10.1007/978-3-540-85021-2_1, # Springer-Verlag Berlin Heidelberg 2010

1

Abstract The introduction presents the terms and concepts that underlie the

chapters that follow. Many complex and unique terms have arisen in the field of

muscle pain; they must be clearly understood when studying this phenomenon. For

example, there is a difference between nociception, the activation of the neural

matrix that responds specifically to noxious stimuli, and the sensation of pain that is

subjective and of chronic pain in particular that evokes an affective and emotional

response reflected in activation of specific areas of the brain. The terms associated

with nociception are defined, and the mechanisms of transduction and transmission

of nociceptive impulses through the nervous system cranially to activate the cortex

resulting in the perception of pain are introduced. The differences between acute

and chronic pain, and the unique features of muscle pain in contrast to cutaneous

pain, are addressed in the introduction. Peripheral and central sensitization is of

great importance in the transition from acute to chronic pain. The principles that

underlie sensistization that results in increased intensity of pain, and in the spread of

pain sensation spatially and temporally, summarized in the term referred pain, are

introduced in this section. Muscle pain is associated with muscle hardness (specifi-

cally in myofascial pain syndrome) that is associated with muscle hardness. Muscle

contracture, muscle spasm, cramp and stiffness are differentiated in the introduc-

tion. The mechanisms that underlie contracture, important in such conditions as

myofascial pain syndrome, are explained. Finally, it is recognized that nociception

does not simply follow a direct ascending path from peripheral stimulation to

activation of the dorsal horn neuron and then thalamic and cortical neurons. The

introduction lays the groundwork for the later discussion in the text of descending

pain modulation mechanisms that are essential to understanding the sensation that

we finally call pain.

1.1 Subjective Nature of Pain Terms

There is no objective standard against which to test the extent to which the

sensation which one individual describes as an aching pain is physiologically

the same as that which another individual means when describing aching pain.

The problems presented by the subjective quality of pain perception and the lack of

a precise descriptive terminology regarding it are more than semantic. The official

definition of pain by the International Association for the Study of Pain (IASP)

emphasizes this aspect:

Pain is an unpleasant sensory and emotional experience associated with actual or potentialtissue damage or described in terms of such damage

(Merskey and Bogduk 1994).

Cortical imaging studies show that individuals with pain due to the same

stimulus in the same part of the body may exhibit activations in different parts of

the brain or different degrees of activity in the same part. Pain is an individual

experience, particularly if it is chronic, and is influenced by past life experiences

and several other factors (e.g., genetic, emotion, attention, etc).

2 S. Mense and R.D. Gerwin

Chronic pain has a dimension of suffering not characteristic of acute pain.

Apparently, patients describing their chronic “pain” actually describe suffering

caused by the persistence of pain. Most practitioners do not have a comparable

experience, and therefore are likely to have difficulty understanding what the

patient is trying to communicate. Chronic pain activates brain areas that are distinct

from those activated by acute pain. This has been demonstrated by cortical imaging

studies (see May 2007 for review). Generally, acute pain mainly activates the

primary sensory cortex, whereas chronic pain elicits strong activation in the anterior

cingulate gyrus, and in other cortical areas that are associated with the affective–

motivational component of pain.

The subjective nature of pain makes it impossible to prove or disprove that the

patient is in pain. For these reasons, the examiner must accept the patients’ pain at

face value. Validation of the patient’s complaint of pain by the examiner is critical

in establishing a therapeutic relationship. If patient’s descriptions seem exagger-

ated, it may be due to the patient’s impression that the examiner is discounting what

is reported. It is also possible that peripheral and central sensitization (see Chaps. 3

and 4) results in pain complaints that may seem out of proportion to the cause of the

pain or to the physical findings.

1.2 Established Pain Terms (partly after Merskey

and Bogduk 1994; Loeser and Treede 2008)

1.2.1 General Terms

1.2.1.1 Nociception

Pain originates in the cortex; therefore, all the processing of neuronal information

about a noxious stimulus in the central nervous system (CNS) below the cortex is

called nociception. Nociception can be studied in an anesthetized individual, but

pain cannot (under anesthesia, there is nociception but no pain). Fibers conducting

the information about a noxious stimulus are called nociceptive fibers; when a

sufficiently high level of activity in these fibers reaches the cortex, pain may be

perceived.

1.2.1.2 Noxious Stimulus

An actual or potential tissue-damaging event.

1.2.1.3 Nociceptor

A sensory receptor that is capable of transducing and encoding noxious stimuli.

1 Introduction 3

1.2.1.4 Nociceptive Neuron

A central or peripheral neuron that is capable of encoding noxious stimuli. Noci-

ceptive central neurons are

1. Wide-dynamic range (WDR) neurons, which have a low threshold for activation

and reach maximum discharges during noxious stimulation, and

2. High-threshold (HT) or nociceptive specific (NS) neurons, which have a high

stimulation threshold in the noxious range. These neurons require noxious

stimuli for activation.

1.2.1.5 Pain Matrix

The term includes all structures of the brain that are activated – more or less

specifically – by painful stimuli. The matrix includes the insula, prefrontal cortex,

anterior cingulate cortex and amygdala (parts of the limbic system), and the thalamus.

1.2.1.6 Central Pain

Pain initiated or caused by a primary lesion or dysfunction in the CNS.

1.2.2 Increased Sensitivity

1.2.2.1 Allodynia

Pain due to a stimulus that does not normally evoke pain. Pain threshold is

decreased, and the stimulus and the response are of different sensory modalities

(categories). An example is pain evoked by gentle tactile stimulation.

1.2.2.2 Hyperalgesia

An increased pain response to a stimulus that is normally painful (stimulus and

response are of the same modality). Many cases of hyperalgesia have also features

of allodynia. The IASP (Loeser and Treede 2008) proposes to use hyperalgesia as

an “umbrella term” for all cases of increased pain sensitivity, because it is often

difficult to know if a stimulus is capable of activating nociceptors.

1.2.2.3 Hyperesthesia

Increased sensitivity to stimulation. The increased sensation is of the same category

as the applied stimulus.


1.2.2.4 Hyperpathia

A painful syndrome characterized by abnormally painful reaction to a stimulus,

especially a repetitive stimulus, as well as an increased threshold. There is an

increased threshold and increased response, and stimulus and response are of the

same category.

1.2.3 Decreased Sensitivity

1.2.3.1 Analgesia

Absence of pain in response to stimulation which would normally be painful.

1.2.3.2 Hypoalgesia

Diminished pain in response to a normally painful stimulus. There is an increased

threshold and decreased response, and stimulus and response are of the same

category.

1.3 Established, But Often Ill-Defined, Pain Terms

1.3.1 Contracture (in the Physiological Sense)

Sliding of the actin and myosin filaments of a muscle without preceding acti-

vation of the neuromuscular endplate. For instance, contractures can occur when

Ca++ is released from the sarcoplasmic reticulum (the intracellular calcium

store of the muscle cell) not by action potentials propagating along the mus-

cle fiber, but by chemical agents (e.g., high doses of caffeine; for details see

chaps. 2–4 in the companion volume by Mense and Gerwin 2010).

1.3.2 Muscle Spasm

Spasm can be defined as an involuntary, longer-lasting contraction of a muscle or a

muscle group. If the contraction is painful, it is often called cramp. Spasm and

cramp in the sense of this definition are associated with electromyograph (EMG)

activity. If chronic involuntary shortening of a muscle occurs without EMG

activity, the term contracture is more appropriate.

1 Introduction 5

1.3.3 Muscle Stiffness

The term is used to describe discomfort with movement of a joint. It is also used in

the engineering sense: with increased stiffness, greater force is required to produce

the same movement. In this sense, spastic muscles have increased stiffness.

1.3.4 Muscle Tone

The tone of a muscle is usually defined as its resting tension, clinically determined

as resistance to passive movement. Muscle tone has two main components: (1) the

viscoelastic component. It is independent of nerve activity and reflects the passive

physico-chemical properties of muscle tissue (tension of elastic fibers, osmotic

pressure of cells). (2) The contractile component. It is due to a low-frequency

activation of a small number of motor units. Its presence can be detected in the

EMG. Note that a completely relaxed muscle has only viscoelastic tone, i.e., it is

“silent” in the surface EMG. (In the needle EMG, however, there is low-level

activity in some motor units).

1.3.5 Projected Pain

Pain caused by a lesion of nerve fibers (compression or inflammation) along their

course in a peripheral nerve or dorsal root. At the site of the lesion, action potentials

are generated that reach central nervous neurons via the same afferent fibers that

normally signal the presence of a stimulus at the receptive ending. The central

neurons cannot recognize the origin of the action potentials, and interpret any

activity in a nerve fiber as coming from the receptive ending. Therefore, projected

pain is felt in the innervation territory of the damaged nerve fibers.

1.3.6 Referred Pain

Referred pain is not felt at the site of a tissue lesion but remote from it. The area of

referred pain is often discontinuous with the site of the lesion. Referred pain can

occur together with local pain (at the lesion site) or in isolation. Since pain

originating in a given muscle tends to exhibit a relatively constant pattern of

referral, it is often possible to identify the muscle from which the pain originates

if the pattern is known. If the pain is referred from one site to several remote

locations it is often described as “radiating.” Referred pain is usually – but not

always – segmental, occurring in myotomes innervated by the same nerve root or

neighboring nerve roots which innervated the original source of pain. Trigger points


in axial (trunk) muscles can thus refer pain through the body, so TrPs in dorsal

muscles can have a ventral body representation. Thus, referred pain is due to a

central nervous mechanism (see Chap. 5) and does not necessarily occur in the

same segment, whereas projected pain occurs exclusively in the innervation terri-

tory of a lesioned nerve or dorsal root.

1.3.7 Spread of Pain

The term used by patients for describing the expansion of a body region in which pain

is felt. In contrast to referred pain (see above) the expansion is often continuous with

the original site of pain. The mechanisms underlying spread of pain are probably

identical to those leading to referral of pain, and probably involve central sensitization.

1.4 General Aspects of Pain and Nociceptor Function

Centuries ago, pain was assumed to be an emotion like pleasure and fear. In the

nineteenth century, the hypothesis was put forward that pain is due to activation of a

set of specialized nerve endings, i.e., pain is a sensation like touch. Max von Frey

(1896) was the first to link pain to fine nerve terminals in the skin. Recently, the old

view has returned in a certain way: pain is often viewed “more like a motivational

drive than a sensation, resembling hunger, thirst or sexual drive” (Scholz andWoolf

2002). Pain is not a homogenous entity. Pain is classified by its underlying mecha-

nisms. Thus, there is nociceptive pain (due to excitation of nociceptors by external

stimuli), inflammatory pain (mediated by inflammatory mediators released by an

inflamed organ), and neuropathic pain (evoked by lesions of the central or peri-

pheral nervous system). Pain can arise from different organ systems. Thus, cutaneous,

visceral, and musculoskeletal (somatic) pain can be distinguished.

The term “nociceptor” is derived from the Latin word “noxius” for damaging or

harmful. It denotes a sensory ending that detects actual or potential tissue damage.

Usually, the stimulation threshold of a nociceptor is just below tissue-damaging

intensity. The nociceptive system is supposed not to signal tissue damage but to

have primarily a warning function: it is activated when stimuli approach tissue-

threatening intensity. However, not all pain is associated with potential tissue

damage. Distension of hollow viscera such as the bladder, and stretching of organ

capsules can give rise to nociceptive activity. Excitation of nociceptors may cause

pain in humans and pain-related behavior in animals. The information originating

in a nociceptor together with the neuronal structures carrying this information are

called nociceptive (“measuring harmful stimuli”); the stimulus exciting a nocicep-

tor is a “noxious” one.

A nociceptor can also be defined by its capability of distinguishing between an

innocuous and a noxious stimulus. This means that a nociceptor’s discharge

frequency increases with the intensity of a stimulus, not only until pain threshold

1 Introduction 7

is reached but also within the noxious range. (In contrast, the discharge of a

sensitive mechanoreceptor levels off when the stimulus reaches noxious intensi-

ties). The term “pain receptor” instead of nociceptor should be avoided, because

receptive endings are named after the stimulus they measure and not after the

sensation they can cause. Thus, pain is the result of an activation of nociceptors,

but nociceptors do not measure pain.

Excitation of nociceptors does not always evoke pain. Actually, the link between

nociceptor activation and induction of pain is relatively loose: there are situations in

which massive traumas do not cause pain (e.g., in soldiers in combat), and in other

situations there can be pain without activation of nociceptors (e.g., in patients with

phantom pain (Nikolajsen and Jensen 2006)). Moreover, there are pain-modulating

pathways in the CNS that enhance or reduce pain. Therefore, the occurrence of pain

depends on the balance between pain-promoting and pain-inhibiting influences, and

not only on the presence of a noxious stimulus or excitation of nociceptors.

Nociceptive free nerve endings are present in almost all tissues and organs of the

body. Exceptions are the brain, parenchyma of the lung, liver, and cartilage, where

nociceptors are missing. Conversely, pain is the predominant or only sensation that

can be elicited by stimulation of cornea, dura mater, and tooth pulp.

The great majority of nociceptors are connected to the CNS by unmyelinated

afferent fibers. (An afferent fiber, or “afferent” for short, conducts action potentials

from the periphery to the CNS). In morphological studies of the endings of

unmyelinated fibers, it may be difficult to distinguish postganglionic sympathetic

(efferent) fibers from unmyelinated afferent ones. The presence of neuropeptides is

an important criterion, since ¼ calcitonin gene-related peptide (CGRP), for exam-

ple, is absent from postganglionic sympathetic fibers (Ju et al. 1987), but is present

in and released from most unmyelinated nociceptive nerve endings.

Not all unmyelinated afferent fibers supply nociceptors. In cutaneous nerves,

there are thermoreceptors and low-threshold mechanoreceptors with unmyelinated

afferent fibers, and low-threshold mechanoreceptors with unmyelinated afferents

can also be found in skeletal muscle (Light and Perl 2003; Hoheisel et al. 2005).

The latter ones are assumed to mediate pressure and tension sensations from muscle

tissue (Graven-Nielsen et al. 2004). Another important function for these non-

nociceptive endings in muscle is to adjust circulation and respiration to the require-

ments of muscle work. In contrast to nociceptive fibers, these slowly-conducting

muscle afferents are activated by a physiological degree of exercise (moderate

contraction force and physiological stretch) and send their information to the

circulatory and respiratory centers in the medulla (McCloskey and Mitchell 1972).

1.5 Muscle Pain Versus Skin Pain

While painful sensations derived from the human skin are associated with brisk movements,with rise of pulse rate, and with a sense of invigoration, those derived from deeperstructures are often associated with quiescence, with slowing of the pulse, a fall of blood


pressure, sweating, and nausea. The last phenomenon, nausea, is responsible for thecommon designation “sickening,” which is applied to pain derived from the deeperstructures but never to cutaneous pain. This syndrome, or vasovagal response, to deeppain occurs frequently when joints are painfully stimulated; it has also been witnessed inpainful stimulation of muscle, deep fascia, and periosteum and in puncturing arteries. ......It never occurs, apparently, with cutaneous pain

Thomas Lewis 1942

1.5.1 Subjective Differences

1.5.1.1 First and Second Pain

Some of the subjective differences between muscle and skin pain are listed in

Table 1.1. First plus second pain occurs when a fast, short-lasting stimulus acts on a

cutaneous nerve or innervation territory of a skin nerve, for instance an electrical

stimulus or a sudden blow to a skin region. The first pain has as a sharp, pricking

character, whereas the second pain is felt much later, has a dull or aching character

and often includes after-sensations. The first pain in the skin is due to impulses in

the relatively fast-conducting thin myelinated fibers. In muscle, activity in these

fibers is apparently not felt, and therefore there is no first pain from muscle.

1.5.1.2 Pain Localization

In contrast to cutaneous pain, which is localized with great accuracy, muscle pain is

difficult to localize. However, in older studies on pain from other deep somatic

structures (subcutaneous tissues excluding viscera), e.g., fascia and periosteum, the

painful sensations are often described as originating in a single spot (Kellgren 1938;

Staff 1988).

From a teleological point of view, there is no need for a good localization of

muscle pain, because the typical body reaction to this type of pain is guarding or

immobilization of the painful muscle. In contrast, cutaneous pain typically exhibits

the good localization necessary for removing external noxious stimuli by well-

directed motor reflexes and voluntary body movements. Muscle pain is not avoided

or abolished by such reflexes or movements.

Table 1.1 Subjective differences between muscle and skin pain

Muscle pain Skin pain

No first and second pain upon electrical

stimulation

First and second pain upon electrical

stimulation

Ill localizable Well localizable

Tearing, cramping, pressing character Stinging, burning, cutting character

Strong tendency for pain referral No pain referral

Hard to tolerate, strong affective component Better tolerable, weak affective component

1 Introduction 9

One possible explanation why a painful stimulus to muscle is less easy to

localize than a stimulus to the skin is the lower innervation density of muscle tissue

(see also Chap. 2). However, direct quantitative comparisons between the innerva-

tion density of muscle and skin have not been published so far and are difficult to

make, because muscle tissue is three-dimensional and skin largely two-dimensional.

It is generally assumed that innervation density decreases in the order: skin, muscle,

and viscera. Nevertheless, the innervation density of muscle tissue is high enough to

ensure a multiplicity of sensory functions. In the rat gastrocnemius–soleus muscle

nerve, more than half of all fibers are afferent, i.e., they conduct impulses from

receptive nerve endings to the spinal cord (Baron et al. 1988). These data underline

the function of skeletal muscle as a sense organ.

Moreover, in addition to innervation density, many other factors determine the

capacity to localize a stimulus, e.g., the degree of convergence in the CNS.

Convergence means that many afferent fibers from different tissues contact one

central neuron. A high spatial resolution of a neuronal network requires a combi-

nation of a high innervation density of the peripheral tissue with little convergence

in the CNS.

1.5.1.3 Nature of Pain

Typically, muscle pain is described as aching and cramping, while cutaneous pain is

characterized by its sharp, pricking, and stabbing nature. For the differences in the

character of muscle and skin pain, no ready explanations are available, except the

speculation that both pains activate different areas in the cortex, which may lead to

different sensations (Svensson et al. 1997a).

1.5.1.4 Referral of Pain

Electrical stimulation of muscle nerve fascicles with a needle electrode has been

shown to elicit localized muscle pain at low intensities of stimulation; at high

intensities, the area of pain first expanded, and then pain referral to regions not

innervated by the stimulated nerve appeared (Torebjork et al. 1984). High-intensity

stimulation of a cutaneous nerve fascicle did not lead to pain referral (Marchettini

et al. 1990). The skin very rarely refers pain to other regions.

Visceral pain resembles muscle pain in that it is difficult to localize. The main

difference between these two types of pain is that visceral pain is mainly referred to

the skin, whereas muscle pain is referred generally to deep somatic structures.

Another difference is that tissue-threatening (noxious) stimulation of muscle and of

skin always elicits pain, if strong enough. However, noxious stimulation of viscera,

e.g., cutting or crushing – which are effective pain stimuli for muscle and skin –

do not produce pain, if the area of stimulation is small (Bielefeldt and Gebhart

2006). Both muscle and visceral pains are associated with autonomic symptoms


such as drop in blood pressure, sweating, and nausea. In cutaneous pain, these

reactions are missing.

The strong tendency of muscle pain to be referred may be due to the spinal

connectivity of nociceptive fibers from muscle, and their capacity to induce

changes in the excitability of neurons in the CNS. Nociceptive input from muscle

is known to be more effective in this regard than cutaneous input (Wall and Woolf

1984). This view is supported by the finding that temporal summation is more

pronounced with stimulation of periosteum and muscle than skin (Nie et al. 2005).

Temporal summation of pain means that the pain increases when painful stimuli of

constant intensity are repeated at short intervals (seconds).

1.5.1.5 Affective Pain Component

Muscle pain is typically harder to tolerate than cutaneous pain; the affective–

emotional (suffering) component of the pain sensation is stronger with muscle

pain (Svensson et al. 1997b). This difference may be due to the different supra-

spinal centers to which the nociceptive neurons project: the centers for muscle pain

appear to have stronger connections with the limbic system, which is responsible

for the affective–emotional component of pain.

1.5.2 Objective Differences

Most of the objective differences listed in Table 1.2 were discovered in animal

experiments.

1.5.2.1 Flexion Reflexes

When the skin of a limb is painfully stimulated, a flexion reflex is elicited. The

reflex consists of a contraction of flexor muscles of the limb, resulting in withdrawal

of the limb from the noxious stimulus (an example is the reflex removal of the

Table 1.2 Objective differences between muscle and skin pain

Muscle pain Skin pain

No flexion reflexes when muscle is stimulated Marked flexion reflexes when skin is stimulated

Weak synaptic contacts of unmyelinated

muscle afferents with dorsal horn neurons

Strong synaptic contacts of unmyelinated

cutaneous afferents with dorsal horn neurons

Supraspinal processing of muscle nociception

mainly in mesencephalon, strong projection

to anterior cingulate gyrus in cortex

Supraspinal processing of cutanous nociception

mainly in thalamus, weak projection to

anterior cingulate gyrus

Strong effect of descending antinociceptive

system on nociception from muscle

Weak effect of descending antinociceptive

system on nociception from skin

1 Introduction 11

hand from a flame). Teleologically, the lack of flexion reflexes elicited from

muscle makes sense, because a painful lesion in muscle is not influenced by flexing

the limb.

1.5.2.2 Differences in Synaptic Effectiveness and CNS Targets of

Afferent Fibers

In animal experiments, the weak synaptic contacts between unmyelinated muscle

afferents and dorsal horn neurons become obvious when the action potentials of dorsal

horn neurons are recorded. Approximately 10% of the dorsal horn neurons respond to

the stimulus when unmyelinated muscle afferents are stimulated electrically; the

proportion is greater than 30% to stimulation of a cutaneous nerve (sural n.) (Hoheisel

et al. 1997). One of the reasons for this difference is the tonic inhibition of nociceptive

fibers from muscle by activity in thick afferent fibers from the skin. When the thick

fibers are blocked pharmacologically, the unmyelinated fibers frommuscle havemuch

stronger synaptic effects (Lambertz et al. 2006). This means that generally the

excitatory action of nociceptive fibers from muscle in the spinal cord is small, but

their modulating effects on dorsal horn neurons are strong.

Dorsal horn cells driven by muscle nociceptors show marked convergence of

input from skin and other deep somatic tissues and probably also from viscera

(Grubb et al. 1993; Yu and Mense 1990), i.e., these neurons can be excited by

stimulation of all these tissues. This applies particularly to neurons having input

from soft tissues in the low back (Taguchi et al. 2008).

Dorsal horn cells processing information from cutaneous nociceptors show little

convergence, i.e., they cannot be driven by input from different types of tissue (e.g.,

skin, muscle, viscera). Many appear to receive input exclusively from nociceptors

in the skin. The highly convergent input from various tissues to neurons processing

information from muscle nociceptors may contribute to the diffuse nature of muscle

pain in comparison to cutaneous pain.

In the CNS, the information from muscle and cutaneous nociceptors is processed

differently. One example is that the nociceptive information carried in spinal

afferent fibers from deep tissues and the skin, respectively, terminates in different

regions of the spinal cord: noxious stimulation of skin excites neurons in all laminae

of the dorsal horn, whereas following muscle stimulation, no neurons in lamina II

(substantia gelatinosa) are activated (Ohtori et al. 2000). In the mesencephalon,

there are similar differences: Neurons responding to stimulation of muscle noci-

ceptors are located in the ventral periaqueductal gray matter (PAG), whereas cells

responding to cutaneous nociceptors are located in the lateral PAG (Keay and

Bandler 1993; Ohtori et al. 2000). Thalamic nuclei with strong spinal nociceptive

input from the skin are the ventral posterolateral (VPL) and medial intramedullary

nuclei, whereas for nociceptive input from muscle, the ventrolateral (VL) nucleus is

an important relay (Gholami et al. 2006).

In other brain areas, too, differences in the termination between nociceptive input

from muscle and skin were found. In the rat, a particularly strong input from muscle


nociceptors was found in the accumbens and amygdala nuclei as well as the para-

ventricular nucleus of the hypothalamus (Ohtori et al. 2000). In an fMRI study of the

cortex in humans, a stronger activation of the anterior cingulate gyrus was found

when a skeletal muscle was stimulated in comparison to stimulation of the overlying

skin. However, in this study the differences were not significant (Svensson et al.

1997a). The authors concluded that “the perceived differences between acute skin

and muscle pain are mediated by differences in the intensity and temporospatial

pattern of neuronal activity within similar sets of forebrain structures.”

1.6 Descending Pain-Modulating Influences

The PAG in the mesencephalon – one of the main supraspinal centers for the

processing of nociceptive impulses from muscle – is also the site of origin of

descending pain-modulating pathways (Fields 2004). There are not only pathways

that inhibit pain sensation (antinociceptive tracts) but also those that facilitate

(enhance) them (pronociceptive tracts). In electrophysiological experiments on

rats, a stronger action of the descending antinociceptive system on dorsal horn

neurons mediating nociception from muscle was found (Yu and Mense 1990). This

finding may relate to the observation that long-lasting physical exertion (e.g., in

sports competitions) which is known to activate the descending antinociceptive

tracts, reduces pain sensations from deep somatic tissues to an extent that lesions of

the musculoskeletal system go unnoticed.

1.7 Transition from Acute to Chronic Pain

One definition of chronic pain is that pain which persists past the normal time of

healing; in clinical practice, a period of 3–6 months is accepted as a dividing line

between acute and chronic pain (Merskey and Bogduk 1994). Muscle pain is well-

known for its tendency to become chronic.

In chronic pain patients, the pain has lost the function of a warning system; it has

become a disease of its own. The factors controlling the transition from acute to

chronic muscle pain are still under investigation. In Chap. 4, some of the mechan-

isms governing this transition are presented in more detail.

1.8 Interactions Between Psychosocial and Somatic Factors

There can be no doubt that psychosocial factors modulate pain perception. This is

particularly valid for chronic pain. Since it is likely that affective status has some

influence on pain perception, the remaining questions are by what mechanisms

and by what magnitude do psychosocial influences cause somatic dysfunctions.

1 Introduction 13

This problem may be linked to another question, namely why one patient with an

acute lesion recovers normally and another patient with the same lesion develops

chronic pain. The answer that in one patient the lesion resolved, relieving the pain,

whereas in the other the lesion did not resolve and the pain persisted, is much too

simple. There is general agreement that exactly the same lesions in two patients can

show quite different time courses, one resolving completely and the other leading

to chronic pain. Therefore, as well as somatic factors, other influences must

be involved. A possible explanation is that in different patients the descending

pain-inhibiting or -facilitating pathways have different degrees of activity. It is

conceivable that a low tonic discharge rate in neurons of the descending pain-

inhibiting pathway is associated with a propensity to develop chronic pain.

Another explanation is the influence of psychosocial factors. This does not mean

that in these cases the chronic pain is psychogenic; pain is aggravated and perpe-

tuated by psychosocial problems and dysfunctions. The neuroanatomic basis of

these influences is strong connections between the limbic system (e.g., the amyg-

dala which is involved in fear and stress reactions) and those mesencephalic nuclei

that mediate muscle pain. The psychosocial factors are often overlooked because

they are so varied, and it takes great experience to identify them. In some patients,

psychological stressors can be potent aggravating factors (for instance, in fibromy-

algia and chronic temporomandibular pain). For details, see Chaps. 4–7 in compa-

nion volume by Mense and Gerwin (2010).

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1 Introduction 15

Chapter 2

Functional Anatomy of Muscle: Muscle,

Nociceptors and Afferent Fibers

S. Mense

Contents

2.1 Structure and Basic Function of Skeletal Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

2.2 Morphology of Muscle Nociceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

2.2.1 Structure of Muscle Nociceptors in the Light and Electron Microscope . . . . . . . . . 25

2.2.2 Receptor Molecules in the Membrane of Nociceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

2.2.3 Neuropeptide Content of Nociceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

2.3 The Nociceptive Afferent Fiber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

2.4 Fiber Composition of a Muscle Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

2.5 Muscle Receptors Other Than Nociceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

2.6 Free Nerve Endings in Tendon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

2.7 Free Nerve Endings in Fascia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

2.8 Efferent Functions of Nociceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

2.8.1 Release of Neuropeptides from the Nociceptive Ending . . . . . . . . . . . . . . . . . . . . . . . . . 41

2.8.2 The Axon Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

2.8.3 Neurogenic Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Abstract Nociceptors are free nerve endings, but not all free nerve endings in

skeletal muscle are nociceptive. Nociceptive free nerve endings are connected

to the CNS by thin myelinated fibers or unmyelinated afferent fibers. In the light

microscope, free nerve endings look like a string of beads, i.e., they consist of axonal

expansions (varicosities) connected by thin axonal segments. The neuropeptide

substance P has been reported to be present predominantly in nociceptive afferent

fibers.

In the electron microscope, a prominent feature of nociceptive nerve endings

is that they are not free in the strict sense but ensheathed by Schwann cells.

S. Mense

Universitat Heidelberg, Mediz. Fakultat Mannheim CBTM, Neuroanatomie, Ludolf-Krehl-Str.

13-17, R. C614, 68167, Mannheim, Germany


S. Mense and R.D. Gerwin (eds.), Muscle Pain: Understanding the Mechanisms,DOI 10.1007/978-3-540-85021-2_2, # Springer-Verlag Berlin Heidelberg 2010

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