Muscle Pain and Cramps

Nociceptor Terminal Stimulation and Sensitization

Stimuli of afferent axons can be mechanical or chemical (for review see ). Mechanosensory transduction is mediated by mechanosensitive ion channels such as piezo2, transient receptor potential cation channel, subfamily A, member 1 (TRPA1), transient receptor potential cation channel, subfamily V, member 4 (TRPV4), or members of the degenerin/epithelial sodium channel (DEG/ENaC) family.

Endogenous chemical stimuli of muscle nociceptors include protons (H ⁺ ) and adenosine triphosphate (ATP), which are increased in muscle with damage. In humans, injection of acidic buffered solution into muscle elicits pain, which activate the acid-sensing ion channels (ASICs), a subfamily of the DEG/ENaC superfamily. ASICs are expressed on sensory axons innervating skeletal and/or cardiac muscles. One member, ASIC3, may initiate the anginal pain associated with myocardial ischemia. The heat and capsaicin receptor TRPV1 can also be activated under strong acidic conditions.

The second important chemical cause of muscle pain is ATP. ATP is present in increased levels in muscle interstitium during ischemic muscle contraction. Injection of ATP also elicits pain. Many peripheral nociceptors express purinergic receptors, which include two subfamilies: the P2Y receptors (G-protein-coupled receptors) and P2X receptors (ATP-gated ion channels formed from a trimer of P2X receptors). In muscle, the release of ATP primarily activates the receptor complexes composed of a combination of P2X ₂ and/or P2X ₃ receptors. Pharmacological inhibition or genetic deletion of P2X ₂ or P2X ₃ receptor antagonists can reverse mouse models of hyperalgesia induced mechanically or by inflammation.

Other chemical substances (bradykinin, serotonin, prostaglandin E2 [PGE2] and nerve growth factor [NGF]) that most likely do not activate pain afferents at physiological levels can induce pain at supraphysiological levels, or can sensitize peripheral nociceptive afferents. Sensitization of nociceptive axon terminals is reduction of the threshold for their stimulation into the innocuous range. Sensitization of nociceptor terminals can have two effects on axons: (1) an increase in the frequency of action potentials in normally active nociceptors or (2) induction of new action potentials in a population of normally silent small axons.

Bradykinin, serotonin, and prostaglandins are normally sequestered in normal tissue and increase in damaged tissue. Bradykinin is the protease product of the plasma protein kallidin. In damaged tissue, kallidin is exposed to and cleaved by tissue kallikreins forming bradykinin. Serotonin is normally stored in platelets and is released when the platelets are in damaged tissue. Bradykinin and serotonin are only mildly painful when injected into human muscle. Bradykinin produces more pain after the injection of PGE2 or serotonin.

PGE2 is present in delayed-onset muscle soreness (DOMS). PGE2 is released from endothelial and other tissue cells. The depression of muscle nociceptor activity by aspirin may reflect inhibition of the effects of PGE2.

Endogenous substances proposed to play roles in activating or sensitizing peripheral nociceptive afferents include neurotransmitters (serotonin, histamine, glutamate, nitric oxide, adrenaline), neuropeptides (substance P [SP], tachykinins, bradykinin, NGF, calcitonin gene-related peptide [CGRP], endothelin 1), proteases (that activate proteinase-activated receptor 2 [PAR2]), and inflammatory mediators (prostaglandins, cytokines). In humans, intramuscular injection of glutamate, capsaicin, levoascorbic acid, hypertonic saline (sodium chloride 5%–6%), and potassium chloride causes pain. Glutamate is an important neurotransmitter in the CNS pain pathway, and, peripherally, is probably more important in sensitizing muscle afferents. Increased levels of glutamate in muscle correlate temporally with the appearance of pain after exercise or experimental injections of hypertonic saline. There are no specific membrane receptors for hypertonic saline (sodium chloride 5%–6%) and potassium chloride; they activate muscle nociceptors through changing membrane equilibrium potential.

Lactate, an anaerobic metabolite, probably does not play a primary role in directly stimulating muscle pain. Patients with myophosphorylase deficiency do not produce lactate under ischemia yet experience pain. Lactate may potentiate the effects of H ⁺ ions on ASIC3 channels in activating pain-related axons.

Many receptors that respond to chemical stimuli are also activated by changes in temperature: TRPA1, TRPM3, and TRPM8 receptors are activated by cold temperatures; TRPV1 and TRPV3 by warm temperatures. Gain-of-function TRPA1 mutations are associated with familial episodic pain syndromes ( ).

No matter what the stimuli, the propagation of generated pain signal is dependent on sodium channels. Important sodium channels expressed in muscle nociceptive afferents include the sodium channels (Na _v ) 1.7, 1.8, and 1.9 ( SCN9A , SCN10A , and SCN11A , respectively). Na _v 1.7 and 1.9 act as threshold channels—causing an initial depolarization leading to additional sodium channels to open; Na _v 1.8 acts to sustain depolarization in the setting of sustained noxious stimuli. Mutations in genes for these channels may cause loss or increase of pain ( ).

Nociceptive Axons

Many of the afferent axons that transmit painful stimuli from muscle (nociceptors) have free nerve endings (see review by ). These free nerve endings do not have corpuscular receptive structures such as pacinian or paciniform corpuscles. They appear as a “string of beads,” thin stretches of axon (with diameters of 0.5–1.0 μm) with intervening varicosities. Most free nerve endings are ensheathed by a single layer of Schwann cells that leave bare some of the axon membranes, where only the basal membrane of the Schwann cell separates the axon membrane from the interstitial fluid. A single fiber has several branches that extend over a broad area. These terminal axons (nerve endings) end near the perimysium, adventitia of arterioles, venules, and lymphatic vessels, but do not contact muscle fibers ( Fig. 29.1 , A ). It is not clear whether nociceptive afferents can have both cutaneous and muscle branches. The varicosities in the free terminals contain granular or dense core vesicles containing glutamate and neuropeptides such as SP, vasoactive intestinal peptide (VIP), CGRP, and somatostatin. When the afferents are activated, neuropeptides are released into the interstitial tissue and may activate other nearby muscle nociceptors.

Action potentials arising in nociceptor terminals induce or potentiate pain by two mechanisms: centripetal conduction to central branches of afferent axons brings nociceptive signals directly to the CNS. Centrifugal conduction of action potentials along peripheral axon branches causes indirect effects by activating other unstimulated nerve terminals of the same nerve and causing release of glutamate and neuropeptides into the extracellular medium. These chemical substances can stimulate or sensitize terminals on other nociceptive axons. This is the basis for the axon reflex and the wheal and flare around a cutaneous lesion.

Group III (class Aδ cutaneous afferent) thinly myelinated and group IV (class C cutaneous afferent) unmyelinated afferent axons conduct the pain-inducing stimuli from muscle to the CNS. Group III nociceptive axons are thinly myelinated and conduct impulses at moderately slow velocities (3–13 m/sec). Group III fibers can end in free nerve terminals (possibly for mediating a more spontaneous pain) or other receptors such as paciniform corpuscles. Group IV fibers are unmyelinated, conduct impulses at very slow velocities (0.6–1.2 m/sec), end as free nerve endings, and are the main mediators of the diffuse, dull, or burning muscle pain.

Group II axons are large and myelinated, and conduct impulses at rapid velocities, mainly from muscle spindles. They normally mediate innocuous stimuli, and stimulation may reduce the perception of pain (by acting on the nociceptive afferents in the spinal cord). Inflammation or repetitive stimulation can sensitize group II afferents (phenotypic switch), which then mediate mechanical allodynia in some tissues.

The cell bodies of all afferents are located in the dorsal root ganglion; the central process enters the CNS through the dorsal root ( Fig. 29.2 ). Central terminals of nociceptive axons from muscle end in lamina I of the superficial dorsal horn and laminae IV–VI of the neck of the dorsal horn of the spinal cord. Cutaneous afferents end in the same areas, but in addition can also terminate in lamina II. Dorsal horn neurons have convergent inputs from afferents from both muscle and skin, and therefore activation of cutaneous afferents may be experienced as muscle pain.

The central terminals of the peripheral nociceptors express N-type (Ca _v 2.2) channels, which control calcium entry and release of synaptic transmitter spinal dorsal horn neurons. One of its auxiliary (and not pore-forming) subunits is the α2-delta (α2δ) subunit; one of its subunit family member, α2δ-1, is the target of gabapentinoids.

Glutamate is the main neurotransmitter of pain in the CNS and binds N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. With short-lasting or low-frequency discharges, glutamate is only able to activate AMPA receptors, causing short-lasting and ineffective depolarization of the dorsal horn neuron. Additional inhibitory signals are also present to suppress the conductance of the pain signal: (1) inhibitory signal from the group II myelinated peripheral afferent; and (2) the inhibitory descending pain tracts which contact the central process of the peripheral afferent using glycine and γ-aminobutyric acid (GABA) as inhibitory neurotransmitters. With long-lasting and high-frequency discharges, persistent glutamate signal activates NMDA receptors, which have been shown to be critically important in the development of chronic nociceptive hypersensitivity. In addition, SP, when released, activates tachykinin receptor NK1 receptors, which lead to increased NMDA receptor conductivity and de novo expression of NMDA receptors. Functional changes in AMPA/NMDA receptor activity are one mechanism resulting in central sensitization. Other mechanisms include metabolic changes in neurons and surrounding glia, and changes in synaptic structure.

Dorsal horn neurons convey pain signals primarily through the contralateral lateral spinothalamic tract, with minor projections through the spinoreticular and spinomesencephalic tracts. The spinothalamic tract terminates in the lateral thalamic nuclei and then relays to the primary and secondary somatosensory cortex, prefrontal cortex (for cognitive and affective pain), anterior cingulate cortex, and insular cortex.

The spinoreticular tract relays information to the medial nuclei of the thalamus, and mediates the autonomic component of pain sensations. The spinomesencephalic tract projects to the amygdala (which processes the emotional and memory aspect of pain).

Afferents conveying muscle pain have different midbrain and thalamic relays than do cutaneous afferents and activate different cortical areas. In addition, interneurons and descending CNS pathways modulate muscle afferents differently than cutaneous afferents. For example, descending antinociceptive pathways that originate in the mesencephalon with connections in the medulla and spinal cord are an important modulator of pain and may be stronger for muscle afferents. These pathways utilize α ₂ -adrenergic, cannabinoid, opioid, and serotonin (5-HT) receptors.

General Features of Muscle Pain

In the clinical setting, patients describe muscle discomfort using a variety of terms: pain, soreness, aching, fatigue, cramps, or spasms. Pain with muscle cramps has an acute onset and short duration. Cramp pain is associated with palpable muscle contraction, and stretching the muscle provides immediate relief. Pain originating from fascia and periosteum has relatively precise localization. Cutaneous pain differs from muscle pain by its distinct localization and sharp, pricking, stabbing, or burning nature. Pain with small-fiber neuropathies is often present outside length-dependent distributions and may be located in proximal as well as distal regions. In fibromyalgia syndromes, it is common for patients to complain that fatigue accompanies their muscle discomfort. Depression is more common in patients with chronic musculoskeletal pain than in a population without chronic pain.

Evaluation of Muscle Discomfort

The basis for the classification of disorders underlying muscle discomfort can be anatomical, temporal in relation to exercise, muscle pathology, and the presence or absence of active muscle contraction during the discomfort ( ). Evaluation of muscle discomfort typically begins with a history that includes the type, localization, inducing factors, and evolution of the pain; drug use; and mood disorders. The physical examination requires special attention to the localization of any tenderness or weakness. The pain may produce the appearance of weakness by preventing full effort. Typical of this type of “weakness” on examination is sudden reduction in the apparent level of effort, rather than smooth movement through the range of motion expected with true muscle weakness. The sensory examination is important because small-fiber neuropathies commonly cause discomfort with apparent localization in muscle. A general examination is needed to evaluate the possibility that pain may be arising from other tissues such as joints. Blood studies may include creatine kinase (CK), aldolase, complete blood cell count, sedimentation rate, potassium, magnesium, calcium, phosphate, lactate, thyroid functions, and evaluation for systemic immune disorders. CK values of African Americans are higher than those of other races (up to 3 times higher than Caucasian Americans) ( ). Evaluate urine myoglobin in patients with a high CK and severe myalgias, especially when they relate to exercise. Electromyography (EMG) may suggest myopathy or if normal may indicate that muscle pain is arising from anatomical loci other than muscle. Nerve conduction studies may detect an underlying neuropathy, but objective documentation of small-fiber neuropathies can require quantitative sensory testing or skin biopsy with staining of intraepidermal nerves. There is reduced innervation of blood vessels within muscle in patients with small-fiber neuropathy (see Fig. 29.1, B–E ) ( ).

Magnetic resonance imaging (MRI) could show increased muscle signal on short tau inversion recovery (STIR) sequences. Muscle ultrasound can be a useful and noninvasive method of localizing and defining types of muscle pathology. Muscle biopsy is most often useful in the presence of another abnormal test result such as a high serum CK, aldolase, lactate, or an abnormal EMG. However, important clues to treatable disorders such as fasciitis or systemic immune disorders (connective tissue pathology, perivascular inflammation, or granulomas) may be present in muscle in the absence of other positive testing. Examination of both muscle and connective tissue increases the yield of muscle biopsy in syndromes with muscle discomfort. There is increased diagnostic yield from muscle biopsies if in addition to routine morphological analysis and processing, histochemical analysis includes staining for acid phosphatase, alkaline phosphatase, esterase, mitochondrial enzymes, glycolytic enzymes, C _5b-9 complement, and major histocompatibility complex (MHC) class I. While disorders of glycogen and lipid metabolism often result in abnormal muscle histochemistry, deficiencies in some enzymes (e.g., phosphoglycerate kinase or carnitine palmitoyltransferase [CPT] II deficiencies) may not cause muscle pathology and diagnosis is best made by genetic testing. Ultrastructural examination of muscle rarely provides additional information in muscle pain syndromes.