SECTION D: Pain Associated with Medical Illness

INTRODUCTION

Understanding of fibromyalgia syndrome (FMS) has evolved over the past 20 years. Once thought to be related to muscular pain and inflammation, it is now more widely understood to be a largely noninflammatory, soft-tissue pain condition, best separated from the entity of myofascial pain, with which it has traditionally been grouped. FMS also has strong associations with other diseases that are deemed central sensitivity syndromes, suggesting that central sensitization plays an important role in the chronic nature of fibromyalgia.¹ Because of the complexity of the disorder, a multimodal approach has the most success in effectively treating the physical, psychological, and emotional aspects of FMS.

CLINICAL FEATURES

DIAGNOSIS

The hallmarks of FMS are widespread pain, fatigue, sleep disturbances, and cognitive changes, as well as psychological distress. Patients often complain of pain “all over my body.” They often report chronic insomnia, either having trouble falling asleep or waking up frequently in the night, leaving them exhausted and stiff in the daytime. They also complain about difficulty with cognition and concentration; the phenomenon of “fibro fog” is frequently mentioned in patient forums and websites. Additionally, patients experience depression; in one study, as many as 40% of patients with FMS were diagnosed with depression at the same time as their FMS was diagnosed.² Many features of FMS overlap with other diseases, and, indeed, FMS is often seen in conjunction with other diseases that lack structural pathology, including irritable bowel syndrome (IBS), interstitial cystitis, temporomandibular disorder, tension headache and migraine, chronic fatigue syndrome, posttraumatic stress disorder, and vulvodynia. These disease states all share a common feature of central sensitization and have been named central sensitivity syndromes to denote this.¹ Any patient with this broad spectrum of symptoms should be evaluated for FMS.

The diagnosis of FMS is criteria-based rather than a diagnosis of exclusion.² The American College of Rheumatology (ACR) developed criteria for FMS research that have been used clinically to diagnose FMS since their publication in 1990.³ The diagnosis depends on the presence of generalized pain in three or more sites, as well as the physical examination finding of tenderness in at least 11 of 18 defined anatomic locations (Table 59-1 and Fig. 59-1). Patients with FMS have pain with 4 kg of digital pressure; this can be estimated by pressing the examining thumb against the spot in question with enough pressure to blanch the thumbnail about halfway down the nail bed.²

Since publication of the ACR criteria, many clinicians have used them but bemoaned the lack of attention given to the other clinically important features of FMS such as fatigue and depression. Multiple other surveys, scales, and questionnaires have been developed to try to follow objectively these very subjective complaints. None has proved universally satisfactory, but consensus in research circles shows relevant aspects of FMS to be pain, fatigue, problems with sleep, diminished global as well as physical functioning, depression, anxiety, and cognitive dysfunction.⁴ These domains demonstrate areas that clinicians must investigate and follow in patients with FMS in order to better diagnose the disorder and to assess the results of treatment.

Although FMS is not a diagnosis of exclusion, other causes of reported symptoms should be investigated before concluding that a patient has FMS. FMS occurs frequently as a secondary diagnosis with a host of other rheumatologic diseases such as systemic lupus, rheumatoid arthritis, and Sjögren's syndrome. Conditions such as hypothyroidism, Lyme disease, tuberculosis, and HIV can cause similar findings as well. Conversely, after a patient is diagnosed with FMS, these other disease states can still occur and should not be overlooked.

There is no gold standard of testing for FMS. Rather, the clinician must rely largely on patient history for the diagnosis; there is a relatively minor role for the physical examination. Patients may report hyperalgesia (increased experience of pain to a normally painful stimulus) or allodynia (experience of pain with a nonpainful stimulus). Many clinicians still use the tender point examination, but the importance of this finding in the treatment of FMS is dwindling.

PATHOPHYSIOLOGY

New understanding of central sensitization (discussed elsewhere in this book) has led to useful information in understanding the etiology of FMS. Although the “causes” of FMS have not been discovered, it has proven useful clinically, and with regard to treatment, to view the disorder as one of altered sensory processing. Patients with FMS not only have increased pain with pressure applied to various body parts but also have lower pain thresholds for cold, heat, and electrical stimuli, as well as lower noxious thresholds to auditory stimuli.⁴ These findings imply that individuals with FMS experience a biologic amplification of sensory stimuli, which has been likened to an altered “volume control” with respect to their pain and sensory processing. Functional MRI (fMRI) studies of patients with fibromyalgia seem to support this concept. Patients with FMS consistently show increased activity in the so-called “pain matrix” of the primary and secondary somatosensory cortex, the insula, and the anterior cingulate cortex; these areas light up in healthy control participants undergoing painful stimuli, but they light up more often in people with FMS at baseline and light up more actively in people with FMS undergoing pressure stimuli.⁴

There is also a role for peripheral input or nociception. FMS is a soft-tissue pain disease, and many patients report deep aching pain, as well as increased pain with applied pressure. In attempts to locate structural pathology, multiple muscle biopsy studies of patients with FMS have been done, but none has borne out inherent differences when blinded and matched for inactive normal control participants.¹ Therapeutically, however, trigger point injections into tender muscle spots have had some success in ameliorating FMS pain despite a lack of randomized controlled trials (RCTs).⁵ Studies involving lidocaine and saline injection into muscles did show an interesting effect on decreasing heat hyperalgesia at a remote site in patients with FMS, indicating that perhaps there is a role for peripheral input.⁶ In some reports, there is a temporal relationship between physical trauma, especially of the trunk, and the development of FMS,⁴ implying that potentially some triggering incident provokes the altered processing, a concept widely accepted as the way in which central sensitization occurs.⁷ Other stressors such as infections (e.g., hepatitis C, Lyme disease, Epstein-Barr virus), emotional stress, and concomitant diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus) all predispose patients to develop FMS as well.

The role of neurotransmitters and cytokines is less clear, but there are abnormalities in patients with FMS. Cerebrospinal fluid analysis shows higher than normal levels of pronociceptive substances such as substance P,⁸ glutamate, and nerve growth factor⁹ and low levels of antinociceptive substances such as serotonin, norepinephrine, and dopamine metabolites.¹⁰ The overall effect of these imbalances supports the concept of altered processing of sensory information augmenting pain. Interestingly, the endogenous opioid system in patients with FMS seems increased rather than reduced; some authors suggest that this may explain why opioids often fail to help with the pain of FMS.⁴ Many of these findings have pointed in the direction of explaining responses to certain medications and suggest targets for future treatment.

EPIDEMIOLOGY AND PREVALENCE

The symptoms of FMS have a wide overlap with other disease states, making prevalence studies of FMS difficult. However, past studies and present evidence show that women are more likely to be affected than men, with U.S. prevalence rates of 3.4% for women and 0.5% for men and an overall population prevalence of 2%.¹¹ Patients between 20 and 60 years of age are most likely to have FMS. However, prevalence rates in women are highest between 70 and 79 years of age, with a rate of 7.4%; a smaller peak of 1% occurs in men in their 80s. A 2008 estimate suggested that about 5 million people in the United States are affected by fibromyalgia.¹² These trends are borne out in other surveys, including a 2011 European study that yielded a 2.9% to 4.7% prevalence across Italy, Spain, Portugal, France, and Germany.¹³

A longitudinal Norwegian study showed a 60% to 70% higher risk of FMS in overweight and obese women with body mass indexes of 25 or greater. The risk was greater in overweight women who were also inactive or exercised less than 1 hour per week.¹⁴ Exercise does not exert a wholly protective effect, however, as seen in a 2010 report showing a prevalence of FMS of 2% in competitive athletes.¹⁵

An interesting review of the health care quality of life impact of FMS showed the impact of FMS on productivity in workers; separated into mild, moderate, and severe symptoms; these individuals with FMS missed an average of 5, 13, and 39 days of work each year, respectively. Caregivers of patients with FMS provided an average of 47, 296, and 460 hours per year of unpaid help with activities of daily living to the mild, moderate, and severe groups of patients, respectively.¹⁶ All of these statistics illustrate the widespread financial, emotional, and physical effects of FMS on patients and their families and communities.

TREATMENT

Recent years have seen Food and Drug Administration (FDA) approval of three medications to treat FMS. Pregabalin, an α₂ ligand and antiepileptic agent, was approved in 2007, followed by duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), in 2008, and milnacipran, also an SNRI, in 2009. Although these have shown great promise, the treatment of FMS must take into account the chronic nature of the disease, including the physiologic and psychological stresses that contribute to its development and perpetuate the disease process. Given the spectrum of symptoms experienced by patients with FMS, there is clearly a role for a strong multidisciplinary approach to successful treatment. A team involving pain medicine physicians, rheumatologists, clinical psychologists, physiatrists, physical therapists, and social workers would be ideal to formulate and carry out a viable and ongoing course of treatment for patients with FMS. Treatment options include pharmacologic management, cognitive-behavioral therapy, exercise, trigger point injections, electrical stimulation, heat application, and massage.

It is important to recall that the mechanism of FMS is altered sensory processing, often triggered or worsened by peripheral input; any other source of pain or discomfort such as degenerative disc disease, cervical or lumbar radiculopathy, dysmenorrhea, temporomandibular disorder, or IBS should also be treated with disease-specific interventions to reduce the impact on FMS symptoms.

Similarly, each of the facets of FMS experienced by a patient should be addressed in developing a treatment strategy. If fatigue is a major symptom presenting in a patient, treatment for that problem must be incorporated into the overall FMS management. Depression often plays a large role in ongoing FMS and must also be assessed and treated if present.

In addition, patient education is extremely important in the treatment of FMS. It is not a disease with a quick fix; successful treatment typically requires major changes in patient lifestyle, exercise, and diet. Clinicians must play a role in helping patients take a crucial active role in their own treatment.

PHARMACOLOGIC MANAGEMENT

ANTIDEPRESSANTS

Alterations in the descending pain inhibitory pathways mediated by serotonin and norepinephrine are thought to play a significant role in the pain of FMS and other central pain states.¹⁷ Antidepressants are widely used in pain medicine, and FMS is no different. Before the creation of SNRIs, tricyclic antidepressants (TCAs) were used to help with neuropathic pain, sleep, and depression. The most used and studied agents have been amitriptyline and cyclobenzaprine. Cyclobenzaprine is a centrally acting muscle relaxant with a chemical structure similar to amitriptyline.⁴ A recent study indicated that a low dose of cyclobenzaprine in the evening could decrease fatigue, muscle pain, tenderness, depression, and anxiety, probably through its effects on sleep patterns.¹⁸ The beneficial effects of the TCAs are thought to be attributable to their serotonin and norepinephrine reuptake inhibition; however, the lack of specificity of the medications contributes to the side effects many patients complain about, namely dry mouth and sedation. The sedative side effect may be helpful if the medication is given at bedtime to help with sleep, but daytime use of these drugs is problematic. Starting with low doses of amitriptyline (10 mg) and cyclobenzaprine (5 mg) is advisable to improve patient tolerance and adherence.

Selective serotonin reuptake inhibitors (SSRIs) such as Prozac and Paxil do not seem to be effective for treatment of FMS pain. Duloxetine and milnacipran, both SNRIs, have undergone multicenter, large-scale RCTs demonstrating efficacy in controlling FMS symptoms. Duloxetine has slightly more serotonin reuptake inhibitor selection than norepinephrine; it has been shown to improve pain as well as other global functioning measures in FMS, decrease stiffness, and reduce the number of trigger points.^4,17 Typical dosages are 60 mg one or two times per day. Milnacipran offers slightly more norepinephrine reuptake inhibition activity than serotonin and shows promise in improving fatigue, physical function, and discomfort.⁴ Usual effective dosages for milnacipran are 25 to 50 mg twice daily. Side effects of both medications are mild and include nausea, diarrhea, constipation, dry mouth, and anorexia. These usually resolve with continued use.

α₂-δ LIGANDS

The anticonvulsants are thought to raise the threshold for depolarization of pain fibers, much the same way they act centrally to control seizures. The voltage-gated calcium channels mediate some of this activity. Pregabalin, one of three FDA-approved medications for FMS, is a ligand for the α₂-δ subunit of these calcium channels. It has analgesic, anxiolytic, and anticonvulsant properties and reduces the release of pronociceptive neurochemicals such as glutamate and substance P.¹⁹ Studies show improvement in pain, fatigue, and sleep disturbance, as well as improved global measures.²⁰ Usual effective dosages are 300 to 600 mg/day in two to three divided doses. Side effects such as somnolence and dizziness usually resolve after steady use; many clinicians start at low doses and gradually titrate up to improve tolerance and adherence. Occasionally, weight gain, peripheral edema, or blurry vision occurs but may improve with lower dosing.

Gabapentin is a structurally similar α₂-δ ligand that has shown efficacy in FMS and other neuropathic pain states. It is not FDA approved, but it can be used similarly to pregabalin in treating the symptoms of FMS.

ANALGESICS

Nonsteroidal anti-inflammatory drugs have not shown to be particularly effective in treating the pain of FMS. The role of opioids in treating FMS is controversial and lacks scientific evidence. The general consensus among most clinicians is that these medications are not particularly helpful in treating FMS and have major side effects and problems that outweigh any benefit.

Tramadol is a unique medication with weak µ-receptor activity as well as serotonin and norepinephrine reuptake inhibition. It has shown some benefit in treating pain in FMS, also when combined with acetaminophen.²¹ Dosages are typically in the range of 50 to 100 mg three to four times daily. Because of its SNRI activity, there is a risk of serotonin syndrome when combined with TCAs, SSRIs, or SNRIs, so education of the patient is important to assess for early signs of problems.

OTHER MEDICATIONS

One medication that has been used in FMS but has not succeeded in acquiring FDA approval for FMS is sodium oxybate. It is a γ-aminobutyric acid (GABA) metabolite, approved for use in narcolepsy and excessive daytime sleepiness. A small RCT with placebo control in patients with FMS showed increased sleep time, improved quality of sleep, less awakening, and less daytime sleepiness, as well as decreased pain perception and decreased tender points.¹⁹ Dosing requires two divided doses (usually 3–6 g/day) at night, about 2 hours apart; it is well tolerated, with nausea and dizziness usually abating after time.

Pramipexole, a dopamine receptor agonist approved for use in restless leg syndrome, shows some efficacy in FMS. Improvements in pain, fatigue, and global functioning were seen in a small RCT and warrant further investigation.²² Tizanidine, an α₂ receptor agonist that acts centrally, is a muscle relaxant that may improve similar measures such as pain, sleep, and quality of life.⁴

Some clinicians use benzodiazepines such as clonazepam or alprazolam to help with induction of sleep and to help with anxiety in patients with FMS. Caution is advised when these medications are combined with other sedative medications.

Topical medications have not been widely studied in FMS but may yield some benefit for symptom relief. Over-the-counter menthol preparations may provide some abatement of pain. Compound pharmacies can blend custom-ordered creams, including local anesthetics; muscle relaxants; and neuropathic medications such as ketamine, gabapentin, and amitriptyline. Patients may tolerate these with few side effects; however, their use is limited to the most painful areas because these compounds cannot be spread all over the body at once.

NONPHARMACOLOGIC TREATMENT

The importance of exercise in treatment of FMS has been shown in a large number of studies. The most consistent and widely studied type of exercise is aerobic activity, both land and water based. This type of exercise seems to help with many aspects of FMS symptoms, including pain, fatigue, and depression. Strength exercise also shows benefit, as does a mix of the two. In addition, other types of physical activity, such as Tai Chi, yoga, and Pilates, have shown benefit in reducing FMS symptoms.¹⁵ There is no strong evidence to suggest that one type of activity is better than another, so patient preference should guide any therapeutic program of activity. Typically, patients with FMS should start with low-intensity, low-resistance activity and gradually increase as tolerated so that they do not cause increased pain. Input from a physiatrist or physical therapist can be invaluable in constructing a well-tolerated and beneficial program.

The mechanism for the benefit of exercise in FMS is not completely understood but may relate to the decreased sympathetic output to muscles during exercise, as well as increased blood flow to muscles and heat generation. Additionally, the beneficial effect of exercise on symptoms of depression and stress may improve those FMS domains.²³

Cognitive-behavioral therapy approaches, including biofeedback, relaxation, and behavior modification, have shown benefit in FMS treatment. Psychotherapy, either individual or group based, also may be useful in helping patients cope and manage their psychological problems.⁴

The role of trigger point injections and Botox in FMS has dwindled in importance, but these modalities may still be helpful in treating specific problems such as painful trigger points in muscle and migraines.

Transcutaneous electrical nerve stimulation (TENS) devices have also been used successfully to help with FMS pain and stiffness; the benefit is temporary, but the side effects are negligible.²⁴ Heat application, whether through a hot bath or shower, electric heating pads, or microwavable heat packs, can also help temporarily with muscle pain, stiffness, and headache. Massage can also offer relaxation of stiff muscles, but often lighter massage is necessary in those with FMS.¹⁹

SUMMARY

Fibromyalgia syndrome is a complex disease encompassing symptoms of widespread pain, fatigue, and depression. Often, patients have sought opinions from multiple providers before being diagnosed with FMS, and many are disheartened and skeptical that improvement is possible. Education and awareness are vital to convince patients with FMS that they must commit to changing many of their attitudes toward exercise, sleep, and diet, as well as their attitudes toward their pain and functional limitations. With the advent of newer understandings of the nature of FMS along with newer medications, clinicians now have opportunities to instill patients with optimism that their symptoms can improve. A multidisciplinary and multimodal approach is typically the most effective in treating individuals with FMS.

REFERENCES

INTRODUCTION AND EPIDEMIOLOGY

INTRODUCTION

Muscles, representing approximately 50% of the body by weight, have long been recognized by clinicians as a source of common pain problems. Various terms have been applied to muscles and soft tissue pain, generally reflecting the prevailing concepts of muscle pain mechanisms or clinical observations of painful muscles. The changing concepts about the nature of muscle pain make it difficult to collect data on the incidence and impact of muscle-related pain. A brief review of the history of these concepts is presented.

DESCRIPTIVE TERMS

The terms muscular rheumatism¹ and nonarticular rheumatism² were used to suggest that pain and stiffness in the region of a joint were caused by soft tissue rather than articular dysfunction. Inflammation as the cause of muscle pain led to the terms fibrositis and myofibrositis,³ which were abandoned with the awareness that inflammation could generally not be demonstrated in painful muscles.

The palpable changes in the muscles, revealing increased resilience, ropiness, and nodularity, led to the terms Myogelosen (muscle gelling),⁴ Muskelhärten (hardened muscle),⁵ and Muskelschwiele (muscle callus). The term myofascial pain, suggesting pain originating in muscle and connective tissue, first used by Reynolds in 1952, is now confusingly used interchangeably with myofascial pain syndrome, suggested by Travell and Simons,⁶ referring to muscle pain originating in myofascial trigger points (TrPs).

PAIN DISTRIBUTION AND PUTATIVE ETIOLOGY AFFECT NOMENCLATURE

Littlejohn⁷ suggests that the term regionalized musculoskeletal disorders be used for muscle pain when the causes appear to be inflammation, sprain, strain, or degeneration of muscles and tendons. When no obvious etiology is present to account for muscle pain, tenderness, stiffness, and often associated nonanatomic dysesthesias and autonomic disturbances, four overlapping and confusing diagnoses are often used: (1) regional pain syndrome, (2) complex regional pain syndrome, and when muscle pain is widespread, (3) chronic widespread pain (CWP), or (4) fibromyalgia syndrome (FMS). Central nervous system (CNS) dysregulation is generally thought to underlie these diagnoses rather than peripheral muscle pain generators.

MUSCLE PAIN AND NEUROPLASTICITY

When muscle nociceptors (discussed later in the chapter) are sensitized, they stimulate and may sensitize dorsal horn neurons, which may result in opening previously ineffective synaptic pathways, leading to stimulation of neurons at adjacent and distant spinal levels. This mechanism may produce referred muscle pain. Sensitized CNS neurons and primary dysfunction in descending inhibitory pathways may lower the threshold for nociceptive stimulation and result in enhanced muscle pain. Pain from other tissue (nerve, joint, viscera) may refer to muscle and may result in the production of independently self-sustaining muscle pain and a confounded clinical presentation.

MUSCLE PAIN AS A CAUSE OF OR COEXISTING WITH OTHER SUSPECTED PAIN DIAGNOSES

Although diagnoses such as nonspecific low back, neck, and shoulder pain are often thought to be the result of sprains and strains of muscles and other soft tissue,^8,9 they would not show up in an epidemiologic survey as muscle-related pain. (The following discussion alludes to muscle pain as a representative for soft tissue pain, understanding that fascia, ligaments, and tendons are also sources of soft tissue pain.)

A large study showed that 70% or more of patients with acute low back pain (LBP) in an ambulatory setting were diagnosed as having nonspecific LBP, defined as sprains and strains of soft tissue,⁸ so it is remarkable that muscles are not considered in the etiology of LBP in guidelines from important national and international organizations.¹⁰ Pain presentations in a region of the body may be incorrectly labeled based on a body part (e.g., epicondylitis) and ignore the surrounding musculature,¹¹ which may be important in the total pain presentation.¹²

Tension-type headaches (TTHs) may be related to muscle-generated pain.¹³ Ten percent of pain complaints in patients with cancer are unrelated to the cancer or treatment and are generally thought to be caused by soft tissue.¹⁴ Therefore, statistics on the incidence and prevalence of muscle pain in the general population are confounded and we believe underestimate the clinical and economic importance of muscles in common pain syndromes.

EPIDEMIOLOGY

Fifty percent of adolescents reported previous lifetime incidence as well as prospectively for 1 to 5 years of LBP, CWP, FMS, shoulder pain, or musculoskeletal pain.¹⁵ Associated significant reductions in health-related quality-of-life scores were noted when pain occurred at least once a week at more than one site.¹⁶ A 2009 European study reported a 1-month period prevalence of LBP of nearly 40% in adolescents.¹⁷

Twenty-seven percent of adults reported LBP in the preceding 3 months, and 14% reported neck pain in the 2008 National Health Interview Survey Report.¹⁸ A 2009 study showed a rising prevalence of chronic LBP across all age groups during a 14-year period.¹⁹ In the United Kingdom, the lifetime prevalence of chronic LBP in the general population is estimated to be 6.3% to 11.1%.²⁰

The 12-month prevalence of neck pain was 30% to 50% in 2008 in The Bone and Joint Decade 2000–2010 Task Force on Neck Pain and Its Associated Disorders.²¹ The 1-month period prevalence of shoulder pain is between 20% and 33%.²²

U.S. and U.K. data for CWP show a 10% to 11% point prevalence, with women affected 1.5 times more often than men.^23–25 Point prevalence for FMS is 0.5% to 4% from the same data, with women affected 10 times more often than men. Data also show that patients with FMS frequently have a history of work-related neck and shoulder pain, whiplash, LBP, and muscle tension,^26,27 suggesting that many of these patients’ diffuse pain problems may have begun in clinically or subclinically damaged muscles.

DIAGNOSIS

HISTORY

Muscles may be the cause of pains mistakenly attributed to other tissue and may contribute to the overall pain presentation in patients who have pain from other sources (e.g., HNP, rotator cuff tear, arthritis). Therefore, unless a muscle assessment is a standard part of the physical examination of the patient in pain, it may not be considered in the pain diagnoses. For example, a detailed work and social history may reveal factors that could produce overt or subclinical muscle injury.

Work-related factors may include recent changes in the physical demands in the work setting, prolonged positioning, repetitive movements, and consistently physically or psychologically demanding labor. Sports-related activity may include changes in activity, type, intensity, frequency, and equipment. Examples are playing tennis for longer than usual, incorporating a new serve, and using a new racket. Upper body activities associated with the initiation or perpetuation of neck and shoulder pain include use of the computer keyboard with an elbow angle of less than 90 degrees, a nonergonomic monitor position, regular use of a phone without using a headset or speaker, and reading or watching television in bed.

SIGNS AND SYMPTOMS

Muscle pain may occur in a discrete area or in multiple regions as an activity-related aching discomfort but at times also at rest. Patients typically complain of a dull, aching sensation that is made worse with more aggressive activity of the painful region and prolonged positioning. If pain occurs with prolonged positioning, movement tends to initially reduce the pain (e.g., standing in one spot causing LBP, which is then diminished with walking). The painful muscle generally has diminished ability for maximal effort (pain inhibition) related to suppressed activity in the painful agonist with associated problems in coordination and diminished flexibility related to increased activity in the antagonist.²⁸

Because nerves traveling through or adjacent to contracted muscles may become compressed, the presentation may suggest a neuropathic problem. Piriformis syndrome is only one such example.²⁹

BASIC NEUROANATOMY AND NEUROPHYSIOLOGY OF MUSCLE PAIN

NEUROANATOMY OF MUSCLE NOCICEPTORS AND THEIR AFFERENT FIBERS

Small-diameter high-threshold afferent fibers have to be excited in order to elicit muscle pain. Histologically, they consist of thin myelinated (group III) and nonmyelinated (group IV)³⁰ fibers. The conduction velocity of these fibers is low: group IV fibers conduct at 0.5 to 2.5 m/s in a cat and group III fibers at 2.5 to 30 m/s. Group III fibers correspond to cutaneous Aδ- and group IV to C fibers. Not all of these small-caliber fibers are nociceptive; they also include thermoreceptive and mechanoreceptive fibers with a low threshold in the innocuous range.^31,32

The typical structure mediating muscle pain is the free nerve ending.³³ The term indicates that in a light microscope, no corpuscular receptive structure can be recognized (Fig. 60-1). Free nerve endings, having a high mechanical threshold in the noxious range or responding to pain-producing chemicals, are called nociceptors or nociceptive endings. They are not excited by light deformation of the muscle or physiological movements. The expression “pain receptor” should be avoided because a nociceptor does not measure pain but the intensity of a painful stimulus. Pain is the sequela of a strong excitation of nociceptors and originates in the cortex.

Whereas group III afferents terminate not only in free nerve endings but also in paciniform corpuscles, group IV fibers supply exclusively free nerve endings. The predominant location of free nerve endings is the adventitia of arterioles and venules. The muscle fibers proper are not supplied by free nerve endings.³⁵

The density of free nerve endings in the peritendineum (the connective tissue around a tendon) of the rat calcaneal tendon was several times higher than that in the gastrocnemius-soleus (GS) muscle.³⁵ The dense innervation of the peritendineum may explain the high prevalence of tenderness or pain in the tissue around tendons and their insertion sites.

NEUROPEPTIDE CONTENT OF NOCICEPTIVE FREE NERVE ENDINGS

There is evidence from studies on dorsal root ganglion (DRG) cells that substance P (SP) and, to a lesser extent, calcitonin gene-related peptide (CGRP) are characteristic of nociceptive units.³⁶ Other neuropeptides, such as somatostatin (SOM), vasoactive intestinal polypeptide (VIP), and nerve growth factor (NGF), are also present in unmyelinated fibers in muscle³⁵ but are not as closely related to a nociceptive function as SP and CGRP. A strong argument supporting a nociceptive function of SP is that noxious stimulation in the body periphery is followed by a release of SP in the dorsal horn of the spinal cord where nociceptive endings terminate. Both SP and CGRP are presumably released together when the afferent fiber is active because they coexist in nociceptive units.

Generally, the neuropeptide content of nerve fibers from muscle is similar to that of cutaneous nerves.^37,38 However, compared with skin nerves, muscle nerves appear to contain less SP. In rats in which a chronic myositis had been induced, the innervation density of the muscle with free nerve endings containing SP and NGF was significantly increased.³⁵

In the CNS, neuropeptides function as neuromodulators, substances that enhance or attenuate the action of neurotransmitters. Glutamate is the main neurotransmitter of nociceptive afferents in the spinal cord, and the neuropeptides enhance the central nervous effects of glutamate released by peripheral noxious stimuli.³⁹

PHYSIOLOGICAL PROPERTIES OF MUSCLE NOCICEPTORS

Whenever a nociceptor is excited, it releases the neuropeptides stored in its ending into the interstitial tissue. Many of these agents, particularly CGRP and SP, cause vasodilatation and an increase in vascular permeability of the blood vessels around the active ending. The result is a shift of blood plasma from the intravascular to the interstitial space. Here, bradykinin (BKN) is cleaved from plasma proteins, serotonin (5-HT) is released from platelets, and prostaglandin E₂ (PGE₂) is released from endothelial and other tissue cells. All of these substances sensitize nociceptors. Thus, the main tissue alteration induced by a noxious mechanical stimulus is a localized region of vasodilatation, edema, and sensitized nociceptors. These effects can also be evoked by the compression of a peripheral nerve or dorsal root, which triggers action potentials at the compression site. Action potentials traveling to the CNS cause neuropathic pain; those traveling to the body periphery lead to the release of sensitizing substances from the nociceptive ending. The result is a neurogenic inflammation (see Fig. 60-1) which may enhance the pain of patients with neuropathy.

SUBSTANCES EXCITING MUSCLE NOCICEPTORS

The membrane of a nociceptor is equipped with receptor molecules to which sensitizing or stimulating agents bind (Fig. 60-2) or that are sensitive to thermal or mechanical stimuli. The following substances are effective stimulants for muscle receptors, most of which are released together in damaged muscle.^40,41

CAPSAICIN

Capsaicin, the active ingredient of chili peppers, is the specific stimulant for the transient receptor potential receptor subtype 1 (TRPV1), formerly called VR1.⁴² The TRPV1 receptor is one of the most important molecules for the induction of pain; its endogenous ligands are H⁺ ions. The receptor is also sensitive to heat. Acidity of the tissue increases this sensitivity. For instance, in tissue with an acidic pH, as occurs after strenuous exercise, the normal body temperature is sufficient for activating the receptor and causing pain.⁴³ With fever, stimulation of TRPV1 may explain the often accompanying total-body ache. In humans, muscle nociceptors were found that could be activated by injections of capsaicin,⁴⁴ indicating the presence of the TRPV1 receptor.

MECHANICAL STIMULI

TRPV4 is a mechanoreceptor that is sensitive to both weak and strong (noxious) intensities of local pressure.⁴⁵ It may be the receptor for pain evoked by mechanical stimuli.

PROTONS (H⁺)

Protons are a particularly important stimulus for muscle pain because almost all pathologic changes in muscle (e.g., exhausting exercise, ischemia, inflammation) are accompanied by a drop in tissue pH. In these conditions, the pH of the muscle tissue can drop to 5 to 6. Protons bind to acid-sensing ion channels (ASICs), with ASIC3 being particularly important for muscle pain,⁴⁶ reacting to small pH changes (e.g., pH 7.4–7.1).⁴⁷ Muscle nociceptors respond to pathophysiologic decreases in pH, with the magnitude of response depending on the degree of acidity (Fig. 60-3). Repeated intramuscular (IM) injections of acidic solutions have been reported to induce a long-lasting hyperalgesia.⁴⁸

ADENOSINE TRIPHOSPHATE

Adenosine triphosphate (ATP) binds to the purinergic P2X3 receptor.⁴⁹ ATP is present in every tissue cell and is released during trauma and other pathologic cell changes. Therefore, ATP has been considered a general signal substance for pain.⁵⁰ ATP is particularly important for muscle pain because it is present in muscle cells in high concentrations.⁵¹ The ATP concentration released from a damaged muscle is sufficient to excite muscle nociceptors (see Fig. 60-3). When injected into human muscle, ATP causes pain.⁵²

NERVE GROWTH FACTOR

The receptor molecule for NGF is the tyrosine kinase A (TrkA) receptor.⁵³ NGF has a sensitizing action on peripheral nociceptors and neurons in the CNS. It has a close relationship to muscle: it is synthesized in muscle, and its synthesis is increased during pathophysiologic changes of the muscle (e.g., inflammation).⁵⁴ NGF appears to be the only substance that excites nociceptors exclusively without influencing non-nociceptive free nerve endings.³² However, the excitatory action of NGF is restricted to a special subset of nociceptors that have a strong sensitizing effect on spinal neurons (see later discussion).

BRADYKININ

Bradykinin is cleaved from plasma proteins when blood plasma moves from blood vessels into the interstitium. In intact tissue, BKN excites nerve endings by binding to the receptor molecule B2; however, in inflamed tissues, the receptor B1 is the predominant one.⁵⁵ Many of the pain-producing substances, including BKN, excite not only nociceptors but also low-threshold mechanosensitive free nerve endings. Therefore, BKN is not a specific excitant of nociceptors.

SEROTONIN

Serotonin (5-hydroxytryptamine, 5-HT) is released from blood platelets during blood clotting. The action of serotonin on nociceptors in the body periphery is predominantly mediated by the 5-HT₃ receptor. The serotonin concentrations usually released are likely to sensitize nociceptors rather than exciting them.

PROSTAGLANDIN E₂

Prostaglandins are released in a pathologically altered muscle by the action of cyclooxygenases. PGE₂ binds to the prostanoid receptor (EP2) in the membrane of the nociceptive ending. Similar to serotonin, PGE₂ may sensitize nociceptors without exciting them.⁵⁶

GLUTAMATE

Evidence indicates that receptor molecules for glutamate (e.g., N-methyl-D-aspartate [NMDA] receptors) exist on nociceptive endings in masticatory muscles.⁵⁷ In female rats, the responses of group III/IV muscle receptors to glutamate were greater than in male rats.⁵⁸ Thus, gender differences are present even at the level of the nociceptor. The NMDA receptor has been reported to be a mediator of inflammatory pain.⁵⁹ Hypertonic NaCl may excite free nerve endings indirectly through glutamate released by Na⁺.⁶⁰

SUBSTANCES EXCITING MUSCLE NOCICEPTORS INDEPENDENT OF MEMBRANE RECEPTORS

Hypertonic Saline

Hypertonic NaCl solutions (4.5%–6.0%) are often used to elicit pain from muscles in humans⁶¹ (for a review, see Graven-Nielsen⁶²). Injections of the hypertonic solution elicit a medium level of pain in healthy control participants. The mechanism of the pain produced by hypertonic saline is still obscure. Two members of the TRP receptor family appear to be sensitive to osmotic stimuli, named TRPV4⁴⁵ and TRPA1.⁶³

The different behavior of the various functional types of free nerve endings (nociceptors, mechanoreceptors, thermoreceptors) is probably due to the expression of special combinations of receptor molecules in their cell membrane.⁶⁴

Potassium Ions (K⁺)

K⁺ ions can excite nociceptors directly by depolarizing the membrane potential to threshold. This stimulus was used in many studies in the beginning of experimental pain research⁶⁵ but is no longer common. Nevertheless, K⁺ can be the cause of muscle pain when muscle cells are damaged and the intracellular K⁺ ions are set free.

CLINICAL PHENOMENA ASSOCIATED WITH MUSCLE-GENERATED PAIN

Tenderness

Pressure to muscles causing discomfort is the most obvious manifestation of common muscle pain. Such tenderness is found in acute muscle pain, for example, after blunt trauma or aggressive physical work or exercise. If additional provocations do not occur, the tenderness disappears.

Peripheral Sensitization

The reason for the tenderness is sensitization of the peripheral nociceptor by sensitizing inflammatory substances (the peripheral sensitization is, in most cases, combined with central sensitization; discussed later in the chapter). Many substances that are released from damaged muscle (e.g., BKN, PGE₂, NGF, tumor necrosis factor-α [TNF-α]) increase the mechanical sensitivity of nociceptors.^65,66 In intact tissue, a nociceptor has a high mechanical threshold, but when it is sensitized, it lowers its threshold into the innocuous range and is excited by everyday stimuli, such as weak muscle deformation. This transition from high- to low-threshold mechanosensitivity can be seen when an intact muscle is experimentally inflamed (Fig. 60-4). Some of the sensitizing effects are due to intermediate substances (e.g., TNF-α induces sensitization through the release of PGE₂).⁶⁷ Another example is the increased excitatory action of BKN after exposure to PGE₂ and serotonin.⁵⁶ A combination of BKN and 5-HT injected into the temporalis muscle in humans elicited stronger pain than that caused by each stimulant alone.⁶⁸

Central Sensitization

In the long run, every input from muscle nociceptors to the spinal cord probably sensitizes central nociceptive neurons. The central sensitization is associated with one or several of the following.

Appearance of New Receptive Fields

A receptive field (RF) of a central neuron is the body region from which the neuron can be excited or inhibited. In animal experiments, new RFs of a neuron can be induced by injecting a pain-producing agent into a muscle. For instance, a neuron that initially had a single high-threshold mechanosensitive RF in one muscle of the hindlimb acquired additional RFs in other muscles and tissues of that hindlimb.⁶⁹

The appearance of new RFs is probably caused by the opening of formerly ineffective synapses on the neuron.⁷⁰ Probably, the newly induced RFs originally had ineffective synaptic connections with the neuron, but after painful stimulation of the muscle sensitized the neuron, these connections became effective.

This unmasking of synaptic connections represents pain-induced changes in the wiring of the dorsal horn. When an entire limb muscle is damaged, many spinal neurons acquire new RFs. The result is that the input from a given muscle excites more neurons in the spinal cord. Thus, the spinal target area in which input from the damaged muscle excites dorsal horn neurons expands. Such an effect can be induced by an experimental muscle inflammation in the rat (Fig. 60-5).⁷¹ In these myositis animals, responses were obtained from neurons in the segment L3, where neurons do not normally respond to input from the inflamed GS muscle. The unmasking of ineffective synapses is partly due to neuromodulatory substances in the CNS (e.g., neuropeptides such as SP and CGRP or neurotrophins such as brain-derived neurotrophic factor).^72,73 When the central sensitization has become chronic, it is independent of further input from the damaged muscle.⁴⁸

The expansion of the spinal input area from a given muscle is the basis for the referral of muscle pain. When, for instance, rat neurons in the segment L6 are pathologically excited by input from the GS muscle (the normal target area of that muscle is L4 and L5), they send the signal “tissue-damaging stimulus in the pelvis” to higher centers because the neurons in L6 normally process input from the pelvis. Thus in humans, after opening of the formerly ineffective synaptic connections from the GS (triceps surae) muscle to the L5 and S1 segments, a patient may feel referred pain in the pelvis when the GS muscle is pathologically altered.

Central Sensitization by Subthreshold Potentials in Dorsal Horn Neurons

Many studies on central sensitization used high-frequency electrical stimulation (e.g., 100 Hz) to elicit the sensitization. However, one of the authors Mense has found that high-frequencies are not required for sensitization because in Mense's laboratory, in chronic pathophysiological muscle lesions, the afferent input does not reach mean frequencies exceeding 1 Hz. Recent data showed that even subthreshold synaptic potentials in dorsal horn neurons are sufficient to cause central sensitization. The subthreshold potentials were evoked by injection of NGF into the GS muscle. In single-fiber recordings, NGF was found to excite a large proportion of rat nociceptors,³² but the animals did not show any immediate pain reactions. One day after IM injection of NGF, the rats exhibited a marked mechanical allodynia and hyperalgesia. Intracellular recordings from dorsal horn neurons in rats showed that NGF elicited mainly subthreshold synaptic potentials in dorsal horn neurons.⁷⁴ The NGF-induced central sensitization involved the activation of NMDA receptors because administration of ketamine (an NMDA antagonist) prevented the NGF-induced allodynia and hyperalgesia. Svensson and colleagues⁷⁵ likewise observed the combination of lack of immediate pain followed by allodynia when they injected NGF into the masseter muscle in humans.

Glial Cells and Central Sensitization

Approximately 90% of all cells in the CNS are glial cells, but only recently have they been systematically studied in pain mechanisms.⁷⁶ Glial cells can be activated by nociceptive input from muscle and, when activated, release substances that sensitize dorsal horn neurons.^73,77 Among the various types of glial cells, microglia appear to be a key factor in the pain-related behavior of rats in which a chronic muscle inflammation has been induced. When the microglial activation was prevented by intrathecal (IT) administration of minocycline, the myositis-induced allodynia (Fig. 60-6) and reduction of locomotor activity were largely normalized.⁷⁸

In the clinical setting, it is difficult to distinguish between peripheral and central sensitization. The above animal data suggest that both forms of sensitization usually occur together. Therefore, when a patient presents with chronic muscle tenderness, often peripheral and central sensitization have already occurred.

Conditioned Pain Modulation

In contrast to CS, conditioned pain modulation (CPM; formerly known as diffuse noxious inhibitory control) is the phenomenon of one pain suppressing another pain. A painful stimulus can cause an increase in the threshold of spinal cord neurons outside the RF of the primary stimulus, which can result in decreased pain perception to a second potentially painful stimulus.⁷⁹ CPM is mediated through a spinal-medullary spinal pathway but appears to be under cortical control.⁸⁰ Conceptually, a painful stimulus could be emotionally assessed for its potential harm and then be selectively inhibited. It has been demonstrated that CPM can be impaired in the presence of chronic pain,⁸¹ such as osteoarthritis of the hip, and can be restored to normal after a hip replacement. An impaired CPM response has also been found in fibromyalgia,⁸² chronic TTH,⁸³ and irritable bowel syndrome⁸⁴ but not in chronic LBP.⁸⁵

Suboptimal CPM was found to be associated with an increased chance of developing chronic postthoracotomy pain.⁸⁶ Therefore, in the future, measurement of CPM could be found to be a useful factor in predicting persistent postprocedure pain.

Clinical Applications

Persistent tenderness occurs in muscles whose neurochemical and contractile apparatus is altered. Two common reasons for chronic muscle tenderness are TrPs and FMS (see later discussion). TrPs are tender nodules in the muscle and its attachments with altered neurochemistry that facilitates sensitization of muscle nociceptors. Sensitized nociceptors in the periphery stimulate nociceptive neurons in the dorsal horn and may cause central sensitization. Fibromyalgia, in contrast, is thought to be caused by an altered processing of nociceptive information in the CNS. One possible mechanism is a dysfunction in central pain-modulating pathways, resulting in lowered pain threshold to noxious stimuli with the associated phenomenon of tender points (TPs) in 11 of 18 areas. However, recent studies have shown the importance of peripheral pain generators in the genesis of FMS symptoms.⁸⁷

Digital palpation is generally used to determine tenderness, but its use presents two major problems. First, varying amounts of pressure by the examiner diminish the reliability of the examination and contribute to poor interrater reliability. Use of pressure-recording devices may improve the accuracy of the amount of applied pressure necessary to elicit discomfort in the patient.^88–90 Structured training programs to teach palpation skills may increase interrater reliability in the identification of TPs and TrPs, but the results are inconsistent.⁹¹ Second, palpation to elicit a subjective experience of pain is often performed on a sedentary muscle, but most functional muscle pain is experienced with activity rather than rest. Therefore, an examination of a resting muscle is likely to be less accurate in determining the muscle that is the source of the pain, frequently identifying a referred muscle pain, compared with an examination that is more consistent with a patient's experience, namely, muscle movement^92,93 causing pain (movement or muscle allodynia).

Pain During Contractions

Sensitized muscle nociceptors are excited at a lower than normal threshold, producing pain with everyday movement (muscle or mechanical allodynia), which is the usual clinical presentation of patients with painful muscles (vs. rest pain). Electrical stimulation has been reported to be more accurate than palpation in determining if a specific muscle is a source of regional pain.⁹² Multiple mechanisms in the muscle and surrounding tissue contribute to the experience of pain. The entire muscle may be involved in pain production, not just TrPs, which are found in the muscle attachments as well as the muscle proper⁹⁴ (see later for a discussion of TrPs). Electrical stimulation of a muscle to induce contraction is thought to cause pain by two mechanisms. First is traction on the sensitized nociceptors in the entheses. As pointed out earlier, the peritendineum has been found to have a particularly dense innervation with free nerve endings, including nociceptive ones. A persistent pull at the entheses by a shortened or overloaded muscle or one harboring a TrP probably releases sensitizing substances (a mechanical tissue lesion is generally assumed to be associated with a sterile inflammation caused by sensitizing substances⁷³). Second is deformation of the nociceptors in the muscle TrPs. Nociceptors in a TrP are likely to be sensitized because in the TrP, the concentration of sensitizing substances is high.⁹⁵ Because of their low mechanical threshold, sensitized nociceptors respond to light deformation of the muscle. The evaluation assumes that if pain is produced by minimal physical contraction of the muscle along its entirety from origin to insertion and not in adjacent suspected muscles, it is the putative source of pain and a target of treatment.⁹⁴ In addition, if pain is produced initially but is gone with continued stimulation, it is assumed that the muscle in question is stiff or tense and would respond, as it just did to conservative measures, such as neuromuscular stimulation, to eliminate the cause of pain.

Restricted Range of Motion

Muscles that are painful during normal activities typically have diminished flexibility. Muscle flexibility is measured as a function of joint movement. Restrictions in motion can be the result of articular pathology (capsule, bone, ligaments, cartilage), nerve, or muscle–tendon dysfunction. In the absence of articular and nerve dysfunction as causes of pain, active range of motion assessment may reveal the possible source to be tension or stiffness in the related muscles. Other causes are painful alteration of the entheses by persistent muscle pull at the insertion zone or central inhibition of the α-motoneurons supplying the muscles (see discussion later in the chapter).

Simple tests that can be incorporated into the physical examination are, for the lower body, straight leg raising for hamstrings, finger to floor touch with knees locked for the low back and hamstrings, and assessment of the symmetry of the position of the right versus the left knee when one leg is crossed over the other to gauge the stiffness of the hip rotator muscles. For the upper body, tests include forward flexion and abduction of the extended arm and functional internal and external rotation of the shoulder by measuring asymmetry in touching the upper back from above and below (see Fig. 60-10). Findings of stiffness suggest muscle–tendon dysfunction; possible sources of current pain; and in some cases, predictors of pain in the course of physically demanding activity. For example, deficits in functional (scapular–humeral or scapular–thoracic) internal rotation in a patient with shoulder pain suggest that the examiner may find tenderness in the infraspinatus, teres major, or rhomboid muscles; increasing hamstring flexibility in army recruits appears to decrease the incidence of overuse lower extremity injuries;⁹⁶ and increased tightness in the hamstrings or quadriceps in elite athletes was associated with an increase in lower extremity muscle injuries.⁹⁷

Weakness

Muscle weakness must be differentiated from neurogenic weakness associated with nerve compression or dysfunction. Painful muscles are frequently found to be weakened on muscle strength testing. It is assumed that the inability to perform a maximal contraction protects the “injured” muscle from further harm. Psychological distress also contributes to weakness.⁹⁸ The main mechanism underlying the weakness probably is the central inhibition of the α-motoneurons supplying the painful muscles. Because of impaired muscle coordination, weakness may result in damaged joints and thus form a source of additional pain. As early as 1984, Stokes and Young put forward a “vicious cycle” hypothesis of arthrogenous weakness describing reflex inhibition of muscles by joint input.⁹⁹ Elimination of the pain in the joint restores normal strength. Weakness over time may also be a function of endurance,¹⁰⁰ and rest in this case will restore strength.

Diminished muscle strength is typically assumed in clinical discussions of common pain syndromes such as LBP (i.e., core weakness), leading to the conclusion that core strengthening exercises would be helpful.¹⁰¹ However, the construct validity and treatment protocols for core strengthening programs have been questioned.¹⁰² Various nonspecific exercises have been associated with long-term improvement in patients with nonspecific low back pain (NSLBP).^103,104 The absence of subgroupings of patients¹⁰⁵ based on psychosocial variables and specific assessments for level of conditioning (strength and flexibility) may contribute to the failure to find any one exercise protocol superior to another. The muscle fasciae may also be a possible source of nociceptive stimuli resulting in NSLBP.¹⁰⁶

The clinician will generally not have equipment to measure the strength of postural muscles. Norman J. Marcus uses the KW test, which is a simple means to test for minimal muscle strength and flexibility of key postural trunk muscles.¹⁰⁷ In a large uncontrolled study, elimination of the deficiencies was correlated with improvement in LBP.¹⁰⁸ This is in contrast to a February 2011 Cochrane review showing no relationship between a positive clinical outcome and the putative target of the exercise for chronic NSLBP.¹⁰⁹

Spasm and Cramp

Involuntary long-lasting contraction of striated muscle accompanied by increased electromyography (EMG) activity is defined as spasm, which may or may not be associated with pain. Cramps are brief, self-limiting, and generally painful contractions of a muscle or muscle group, also accompanied by increased EMG activity.

Muscle spasm is often misunderstood because of (1) prior incorrect explanations of its pathophysiology and (2) other conditions that present clinical similarities to spasm. The classical understanding of the pain–spasm–pain cycle has been disproved. Although spasm, present for a long enough time, may result in muscle ischemia and pain, the pain does not in turn produce muscle contraction. On the contrary, painful muscles typically show diminished or absent EMG activity, but an antagonistic muscle typically shows increased EMG activity.³⁴ This phenomenon is thought to limit movement in an injured region to prevent further damage and facilitate healing.

The pain–spasm–pain concept states that the input from muscle nociceptors excites the homonymous α-motoneurons, causing a tonic (ischemic) contraction of the painful muscle. The ischemic contraction is painful and activates muscle nociceptors, which in turn excite the α-motorneurons.¹¹⁰ However, in clinical experiments on myofascial LBP, the low back muscle activity was reduced in the phase associated with normally high EMG activity.¹¹¹ This finding speaks in favor of an inhibition, rather than activation, of homonymous α-motoneurons. γ-Motoneuron activity was likewise not facilitated during nociceptive input from muscle.¹¹² Thus, the pain–spasm–pain hypothesis is not supported by recent experimental findings and has to be considered a misconception.

To date, the pain-adaptation model of Lund and colleagues¹¹³ has largely replaced the pain–spasm–pain vicious cycle. The model predicts decreased muscle activity in agonistic contraction phases and increased muscle activity in antagonistic phases of a painful muscle (i.e., contraction to inhibit motion). Collectively, the recent data show that a muscle spasm is not caused by a painful lesion in that muscle but by a lesion somewhere else. The true source of pain may be located in another muscle, a joint that is moved by the muscle, an inflamed nerve, or an internal organ, helping explain the frequent failure to obtain long-term benefit from injections into a muscle with painful spasm. The rigid abdomen that accompanies an inflamed appendix is an example of a spasm caused by a painful internal organ. The examiner has to find the original source of pain; otherwise, the treatment will not be successful.

Physical examination may detect a hardened, stiffened muscle. This may be the result of inappropriate muscle contraction (tension) or neurogenic involuntary muscle contraction (spasm), both associated with increased EMG activity. Tension may respond to a variety of biobehavioral approaches.^114–116 Hardened muscles may also be the result of increases in muscle tone or decreases in elasticity (from stiffness, contractures, or myofascial TrPs) that occur without accompanying increases in EMG activity, presenting a diagnostic and subsequently a treatment challenge. The absence of an animal model to study the various conditions associated with increases in muscle hardness and a testable pathophysiological mechanism further challenges our understanding and interferes in the development of effective treatment. A recent study suggests that an animal model may be possible for FMS.¹¹⁷

Because multiple overlapping mechanisms can contribute to spasm-like regional pain, it is understandable that a wide variety of pharmacologic interventions are thought to be possibly effective with as yet no demonstrated superiority between classes of medication^118,119 and no clear evidence of effectiveness for injection and denervation procedures for back pain thought to be related to painful muscles.¹²⁰

Cramps

Although cramps generally occur after age 60 years, they have also been observed in young exercisers.¹²¹ In elderly adults, they most often occur at night and involve the lower extremities. Movement of the painful part generally quickly diminishes and then eliminates the cramp. Cramps may be the result of a variety of neurologic diseases, including amyotrophic lateral sclerosis.¹²² The majority are from unknown causes but are thought to involve the spinal α-motoneuron, which appears to have a lowered electrical stimulation threshold frequency to produce cramping.¹²³ Two other possible mechanisms for the cramp pain are (1) not the whole muscle but only parts of it contract at the transition zone between cramping and inactive muscle parts (sheering forces may excite nociceptors), and (2) motor and nociceptive fibers are entrapped in the contracting muscle. The compressed motor fibers maintain the cramp, and the nociceptive fibers elicit pain.

Quinine has been the drug of choice for nonspecific cramping, but the U.S. Food and Drug Administration banned its use for anything but the treatment of malaria because of concerns about serious albeit nonfatal side effects. Comparisons of quinine with other possible treatments still favor quinine.¹²⁴ Nonpharmacologic treatments have not been found to be effective,¹²⁵ and a recent Cochrane review¹²⁶ opines that quinine is still the treatment of choice despite the chance of side effects.

Pain Affects Muscle Function and Patterns of Coordination

Painful muscles and joints affect our ability to perform tasks. Maximal effort, ability to sustain the effort, and coordinated movement are all detrimentally affected by pain. As a corollary, some physical activities can produce muscle pain.

Altered patterns of muscle activity may precede or follow the appearance of regional muscle pain (see later discussion). Patients have a decrease of the maximal voluntary contraction of a painful muscle and a variety of changes in the static (contraction without movement), resting, and dynamic activity level of regionally painful muscles compared with normal control participants. Exploring the mechanisms of these alterations may facilitate effective treatment.

Muscle activity may produce movement through a shortening muscle contraction (concentric contraction, e.g., quadriceps contraction going up stairs) or by a lengthening contraction (eccentric contraction, e.g., quadriceps contraction going down stairs). It is actually more demanding of our muscles to go down than upstairs. Prolonged eccentric contractions are often followed by delayed-onset muscle soreness (DOMS) with the pain peaking 1 or 2 days after the exercise.

When a painful muscle is activated, decreased activity in the agonist phase and increased activity in the antagonist phase occur.¹¹³ Such changes reduce the ability of the muscle to produce maximum contractions. It also leads to recruitment of adjacent muscles to substitute for the reduced capacity of the muscle proper to the task. The changes in muscle activation may be adaptive to promote healing by minimizing the work of the painful muscle but may also lead to additional and ongoing pain by using muscles that are inappropriate for a task and creating suboptimal conditions for joint movement and stability.¹²⁷

CHANGED PATTERN OF LOCOMOTION

IMPACT OF MUSCLE PAIN ON LOCOMOTION

The physiologic basis of the influence of muscle pain on locomotion is related to the synaptic connections between (nociceptive) group III and IV muscle afferents and the α-motoneurons in the ventral horn.^128,129 Normally, the activity in the many thousands of synapses on the surface of a single α-motoneuron is predominantly inhibitory, and as such, the motor unit supplied by the neuron is silent (i.e., a normal resting muscle has no EMG activity).

ELECTROMYOGRAPHIC ACTIVITY OF A RESTING PAINFUL MUSCLE

In patients with myofascial pain, both increased and unchanged resting EMG activities have been found. In fibromyalgia, Elert et al.¹³⁰ observed an increase in the resting EMG activity. The same finding was reported in temporomandibular pain,¹³¹ neck pain,¹³² and LBP.^133,134 DOMS can occur with EMG activity at rest¹³⁵ or without any EMG activity.^136,137

Thus, the overall evidence for increased resting EMG activity in humans during muscle pain is weak. Rather, there is an inhibition of α-motoneurons, which is partly attributable to a facilitated homonymous recurrent inhibition during experimental muscle pain.¹³⁸

However, in animal experiments on masticatory muscles, there was an increase in EMG activity during painful stimulation.¹³⁹ In these studies, the jaw-opening muscles showed the strongest activity. These findings cannot be transferred to limb muscles because the central wiring of the masticatory muscles differs from that of muscles supplied by spinal nerves. In the masticatory muscles, opening of the jaw is a protective pain reflex as is the reduced activity in painful limbs.

INFLUENCE OF MUSCLE PAIN ON STATIC CONTRACTIONS

During acute experimental muscle pain, the MVC is significantly lower than in control conditions.^140–142 Likewise, in localized clinical pain conditions such as lateral epicondylalgia, reduced MVC is also found in the sore arm.¹⁴³ In fibromyalgia, the reduction in strength is assumed to be caused by impaired central activation of motor units. In these patients, when the ulnar nerve is supramaximally stimulated, there is no reduced MVC of the adductor pollicis muscle.¹⁴⁴ In addition to reduced MVC, patients with muscle pain exhibit a decreased endurance during submaximal contractions.^145,146

It is worth noting that during static contractions, muscle pain decreases not only the activity of the painful muscle but also that of synergistic muscles.^147,148 Because of the inhibition of the painful muscle, the required force can be achieved only by a changed muscle recruitment pattern and eventual overload of otherwise nonpainful muscles. Spinal motoneurons as well as motor cortex motoneurons may be inhibited by nociceptive input from muscle.¹⁴⁹

MUSCLE PAIN AND DYNAMIC MUSCLE ACTIVITY

Experimental and clinical low back muscle pain influence muscle activity during gait. Such an influence was found in recordings of the activity of low back muscles on a treadmill. Muscle activity was increased in phases during which there is normally no EMG activity, and there was no or decreased activity in movement phases when pain-free subjects exhibited strong EMG activity.¹⁵⁰ Moreover, when pain is induced in the low back muscles, the feedforward response of the abdominal muscles is reduced. This effect may impair spinal stability.¹⁵¹

Muscle pain can also have a strong impact on joints, particularly in the legs. Gait analyses during experimental pain in the vastus medialis muscle showed that the pain resulted in impaired knee joint control and joint instability during walking.¹⁵² The impaired joint control may render the knee joint prone to injury and may perpetuate the chronicity of musculoskeletal pain.

FEAR THAT MOVEMENT WILL BE HARMFUL

Kinesiophobia, defined by Kori et al. as “an excessive, irrational, and debilitating fear of physical movement and activity resulting from a feeling of vulnerability to painful injury or re-injury,”¹⁵³ is a major impediment to recovery in patients with persistent pain.^154–156 Patients equate “hurt” with “harm” and avoid fear-producing activities.¹⁵⁷ This affects a patient's capacity to resume social activities after an injury¹⁵⁸ as well as the ability to maximally rehabilitate after surgeries.¹⁵⁹ It has been shown that in patients with negative beliefs about movement and exercise, even the thought of a specific movement can produce pain and swelling.¹⁶⁰

POSTURE

Posture, defined as the position or bearing of the body, whether characteristic or assumed for a special purpose when deviating from a theoretically healthy stance, has been thought to be a result of and a contributing factor to muscle pain.^161–163 Experimentally induced pain in the muscles surrounding the knee alters postural stability and may be associated with an increased likelihood of falling.¹⁶⁴ Awkward postures are a factor in work-related back, neck, and temporomandibular joint pain.^165,166 Postural changes, such as those observed in patients with an “antalgic” gait, are minimized with programs encouraging movement and use of the painful part.^158,167,168 Based on assuming a relationship between posture and pain, it is surprising that a systematic review of adults and a longitudinal study of children and adolescents did not find any association between posture and the occurrence of LBP,^169,170 and reviews of workplace interventions to diminish neck pain found no evidence of effectiveness on neck pain or sickness absence.¹⁷¹ Postural dysfunction appears to be related to multiple factors. Inactivity in adolescents was found to be associated with poor posture and the report of LBP.¹⁷² LBP inhibits anticipatory muscle contractions mediated through the anterior cortex.^173,174 Psychosocial factors may be associated with the production of muscle tension patterns resulting in postural changes and pain.^83,175–178 Because no standard of care exists for the physical and psychological examination to describe the patient in pain, identify painful muscles, or provide an accepted exercise routine, it is not surprising that no clear evidence has yet emerged supporting the widespread use of specific interventions to promote healthy postures.

OCCUPATIONAL MUSCLE PAIN (CHRONIC WORK-RELATED MYALGIA, REPETITIVE STRAIN INJURY)

Work-related myalgias (WRMs) contribute to loss in productive work time. In a 2002 U.S. study of more than 20,000 workers, 13% experienced pain-related reduced productivity at an estimated value of $61 billion,¹⁷⁹ representing the largest category of work-related illness in the United States, the Nordic countries, and Japan and accounting for the largest number of work absences and disabilities in the United States, Canada, Finland, Sweden, and England.^180,181

Physical factors include (1) high-intensity contractions to address jobs requiring high degrees of muscle strength; (2) continuous demands for output with minimal ability to rest, relax, and stretch fatigued muscles; (3) awkward posturing resulting in sustained muscle contraction; and (4) tasks requiring fine motor skills that rely on the coactivation of muscles to stabilize the extremity.¹⁸² Psychological factors are related to both the cognitive demands of the job and the emotional experience working in a particular job setting, both contributing to psychosocial tension and stress and resulting in myalgia-related physiologic effects.

OVERLOAD RELATED TO JOB DEMANDS

STRENUOUS WORK

Overload, subjecting muscle fibers to forces beyond their capacity, can produce pain and damage. This typically occurs in physically demanding jobs in industries such as manufacturing, mining, and agriculture. The muscles of a worker with the strength to manage most job demands may become strained in the event of the need to lift a heavier than usual object or with an awkward movement. A worker is best protected by being able to lift as much as 100% more than is typically demanded by the job task. But muscle strength alone is not sufficient to protect against pain and injuries. In relationship to back pain, the concept that strengthening (core strengthening) certain weakened deep paraspinal muscles could diminish or eliminate back pain has been challenged.^102,183 Repetitive demands on strong muscles without sufficient recovery time can produce muscle fatigue, dysfunction, and pain.

MONOTONOUS WORK AT A LOW WORKLOAD

Workers who perform seemingly nonstrenuous activity may develop muscle pain. Jobs that require repetitious muscle movement in a small range may be associated with a higher incidence of muscle pain and spasm. Hägg¹⁸⁴ observed that all muscle fibers do not contract at the same time. Some fibers may be recruited, and others in the same muscle are quiescent. At a low workload, muscle contraction typically involves recruitment of the type Ia muscle fibers first,¹⁸⁵ and these fibers are also the last to be derecruited, thus overworking the Ia fibers and possibly producing fatigue, dysfunction, and pain. At the suggestion of a colleague Mats Bjurvald, Hägg named his theory the Cinderella hypothesis.

NONSPECIFIC LOW BACK PAIN

Nonspecific low back pain is the most costly chronic pain condition facing our health care system.¹⁸⁶ Despite advances in our understanding of pain mechanisms and various treatments, we remain challenged by patients with persistent back pain. The pain generator remains controversial, frequently chosen on the basis of clinician's specialty and mode of practice.^187,188 Because muscle and other soft tissue is presumed to frequently account for NSLBP, it is surprising that the evaluation and treatment of muscular causes of LBP are not addressed in the American or European guidelines.^189,190

Of the wide variety of treatments commonly used, the most promising seem to be cognitive-behavioral interventions encouraging activity and exercise. Almost all other interventions have not demonstrated clear effectiveness when analyzed in rigorous, systematic reviews.^{172,189–209} Of all the putative pain generators that might respond to exercise—remaining active, massage, and relaxation approaches—logic suggests that muscle is a major target of these interventions and thus a source of pain. However, translating the concept of muscle-related NSLBP to successful treatment interventions has been a challenge. Attempts to incorporate proper ergonomic principles to proactively address musculoskeletal disorders in the workplace have not been effective.²¹⁰ Even the consensus that remaining active and at work is beneficial for patients with NSLBP has not dissuaded most physicians from advising patients not to work.²¹¹

Exercise, defined as a “series of movements to promote good physical health,” allows almost any activity to be defined as an exercise protocol. Indeed, a systematic review has concluded that various nonspecific exercises have produced long-term results in patients with NSLBP.²¹² However, idiosyncratic provision of exercise protocols without patient subclassification may confound outcome data and eliminate the possibility of meta-analyses. Systematic reviews of the effects of published exercise interventions^213,214 revealed that although most were statistically significant, many were not clinically meaningful.⁹ A much needed head-to-head study is currently under way to compare the effects of two different exercise protocols.²¹⁵

A suggested reason for the inability to show effectiveness in many exercise programs is the general absence of subgroups of patients²¹⁶ based on psychosocial variables and specific assessments for level of conditioning (strength and flexibility). Conversely, another hypothesis is that the effects of exercise are more related to central phenomena, such as improvement in coordination and reductions in kinesiophobia, than to any specific exercise effect.²¹⁷

Nonspecific LBP is assumed to originate in the soft tissues of the low back such as muscles, ligaments, and fascia.²¹⁸ Back muscles are relatively well established as a source of NSLBP, for instance, when they harbor myofascial TrPs²¹⁹ (see discussion later in the chapter). In contrast, the fascia have attracted much less interest.

THE THORACOLUMBAR FASCIA AS A POSSIBLE CAUSE OF NONSPECIFIC LOW BACK PAIN

The thoracolumbar fascia (TLF) is the largest fascia of the low back and wraps the genuine back muscles with a posterior and anterior lamina. It thus forms a sheath around the muscles which reduces friction during movements. Its role in the biomechanics of the lumbar spine is well established. The TLF transfers loads among the arm, spine, pelvis, and lower limbs. Actually, it links the legs and arms crosswise; that is, it is part of a biomechanical chain between the fascia latae of the leg and the fascia of the contralateral latissimus dorsi muscle that attaches to the upper arm. Moreover, it is the insertion site for the broad abdominal muscles and thus further stabilizes the trunk. The TLF contains myofibroblasts and therefore has contractile properties.²²⁰ It is a plastic structure and adjusts to altered tensions and forces that occur during long-lasting changes in posture and movement patterns.

FASCIA INNERVATION AND NEURONAL DATA PROCESSING OF INPUT FROM THE FASCIA

Little information is available about a possible sensory role of the TLF, particularly in NSLBP. If it really performs such a function, the TLF should have a dense innervation with sensory fibers, including nociceptors. However, the results of existing studies are inconsistent and partly contradictory. The group of Bednar and colleagues²²¹ did not find any sensory end organs in the TLF of patients with LBP and stated that in these patients, the fascia was “deficiently innervated.” In contrast, another group²²² demonstrated that the TLF is innervated. A recent study on the innervation of the fascia in rats and humans presented evidence for a possible contribution of the TLF to NSLBP.²²³ The main histologic findings were that (1) the fascia is densely innervated (Fig. 60-7); (2) it exhibits SP-containing free nerve endings, which are assumed to be nociceptors; and (3) it has an abundant innervation with efferent sympathetic nerve endings, accounting for more than 30% of all nerve fibers of the fascia. The purpose of this dense innervation with sympathetic fibers is obscure. Because the thickest layer of the fascia is not supplied by blood vessels, these fibers are probably not vasoconstrictors. Possibly, the sympathetic fibers modulate pain sensations from the fascia²²⁴ and may explain why some patients with NSLBP report that their pain is worse when they are under psychological stress.

Sensory endings in fascia have been found in the iliolumbar ligament²²⁵ and the fascia of the arm²²⁶ in addition to the TLF.

In another study of the group of Siegfried Mense,¹⁰⁶ the electrical activity of spinal neurons processing input from sensory endings in the TLF was recorded. Most neurons had no exclusive input from the fascia but showed a marked input convergence from the multifidus muscle and the skin (Fig. 60-8). The input from most tissues was dominated by nociceptors; that is, the neurons were excited by painful stimulation of their RFs (pinching, squeezing, injections of hypertonic saline). The neurons behaved like typical wide-dynamic range (WDR) neurons, one of the nociceptive spinal cell types. The input convergence from many tissues and receptor types of the low back may explain why the subjective nature of NSLBP is usually described as diffuse. An interesting finding was that an experimental inflammation of the multifidus muscle increased not only the proportion of neurons responding to stimulation of the inflamed muscle but also the proportion of those neurons that responded to input from the fascia.¹⁰⁶ This finding suggests that the fascia becomes more sensitive even if the original pain source is located in the low back muscles.

Recent human data underpin a nociceptive role of fascia tissue. For instance, DOMS in the lower leg appears to be partly attributable to nociceptors in the fascia of the anterior tibial muscle.²²⁷ In that study, the authors made systematic injections of a painful dose of hypertonic saline into the anterior tibial muscle and the overlying tissues after induction of DOMS in that muscle. When the hypertonic solution was injected directly underneath the fascia, it caused more pain than after injection into the muscle itself. These results show that the fascia of the human anterior tibial muscle is supplied with nociceptors and that these nociceptors are probably involved in DOMS.

PAIN CAUSED BY MYOFASCIAL TRIGGER POINTS

Trigger points are considered by many clinicians to be synonymous with myofascial pain syndrome and to account for most muscle pain, but others believe them to be nonsignificant epiphenomena.^228–231 TrPs are defined as palpable tender nodules in muscles that refer pain or discomfort to adjacent or distant muscles. Treatments are varied but usually involve needle placement (dry needling), the injection of one of a number of substances into the TrP, or both.

HISTORICAL PERSPECTIVE

Kellgren was the first to demonstrate muscle pain referral with his experiments with hypertonic saline,^232–234 but Travell and Simons described the typical patterns of referred pain from specific muscles.²³⁵ Shah²³⁶ has found biochemical alterations in the TrP that support the assumption that TrPs are a source of pain.

CURRENT HYPOTHESES OF TRIGGER POINT MORPHOLOGY AND FORMATION

Generally, the palpable myofascial TrP is assumed to consist of several contraction knots surrounded by normal muscle fibers.²³⁷ A contraction knot is a localized (segmental) contraction of only part of an individual muscle fiber. Actually, it is a contracture in the physiological sense (i.e., a contraction of a muscle fiber without electrical activation of the endplate). Therefore, a TrP is silent in the surface EMG. One of the few good histologic figures of a contraction knot was published long ago.²³⁸ The knot was found in the gracile muscle of a dog; it was located in a palpable TrP. The typical histologic feature of the contraction knot was a close packing of the A bands within the contracted region so that no individual A bands can be recognized. In the region of the contraction knot, the affected muscle fibers are swollen and therefore probably compress the accompanying capillaries.

It is unknown if a human TrP exhibits the same features, but evidence points in that direction. One of the few systematic studies on the morphology of human TrPs was performed by Reitinger and colleagues.²³⁹ The biopsy specimen were obtained from fresh cadavers that still exhibited palpable TrPs. Cross-sections showed large muscle fibers, which may have represented contraction knots. In electron microscopic sections, the I-band configuration was missing, which likewise indicates a contraction. The findings indicate that the cross-sectioned large muscle fibers were contracted and therefore had a greater diameter.

To date, there are no data on the TrP histology from living patients. Knowledge about the time course of TrP formation and morphologic differences between latent and active TrPs is completely missing. Large-scale open biopsies of TrPs would allow us to observe their evolution and help refine the understanding of the pathophysiological process. Therefore, the following considerations on the formation of a TrP, which are based on the minimally available scientific data, are largely hypothetical.

From clinical inspection, it appears that the first stage of TrP formation is the taut band, which often exhibits a latent TrP that exists without spontaneous pain but causes local, and sometimes referred, pain when mechanically stimulated. The next stage is the active TrP, which is spontaneously painful. Thus, there may be a sequence from the latent to the active TrP; that is, first there is a muscle lesion that does not cause pain, and then the active TrP develops.²⁴⁰

The integrated hypothesis of TrP formation was put forward by Simons²⁴¹ and later modified by Gerwin and colleagues.²⁴² The steps of this hypothesis are still not proven, but to date, there are no better hypotheses (Fig. 60-9). The formation of a TrP starts with trauma to the muscle, such as overuse, which mainly damages the endplate region of the neuromuscular junction. The damaged endplate releases excess amounts of acetylcholine (ACh), which release Ca⁺⁺ from the sarcoplasmic reticulum and cause contraction knots in some of the muscle fibers underneath the endplate. The key factor of TrP formation and maintenance appears to be localized ischemia of the muscle, probably caused by capillary compression by the contraction knots. Ischemia is known to release BKN and other inflammatory agents and sensitize muscle nociceptors (see earlier discussion). This explains the pain and tenderness of the TrP. Using a microdialysis needle, Shah²³⁸ has measured the concentration of inflammatory substances and H⁺ ions in active and latent TrP and found significantly higher concentrations for most of these agents in active TrPs. The ischemia in the TrP is also important for maintaining the contracture because ischemia results in diminished production of ATP, which is necessary for the relaxation of the myosin and actin filaments.

There are also ways of releasing Ca⁺⁺ from the intracellular sarcoplasmic reticulum independent of the neuromuscular junction: (1) dysfunctional ryanodine receptor calcium channels that control the release of Ca⁺⁺ from the sarcoplasmic reticulum into the sarcoplasm^243,244 or (2) damage to the muscle cell, which produces small leaks in the membrane. Rhabdomyolysis after strenuous exercise has been described in the literature,²⁴⁵ and it is conceivable that overuse of a muscle or part of a muscle damages its cell. Small leaks in the cell membrane would allow Ca⁺⁺ ions to enter the cell and cause sliding of the actin and myosin filaments underneath the leaky membrane. The basis of these considerations is that in the interstitial fluid around the muscle cell, the Ca⁺⁺ concentration is approximately 2 mM, but 0.01 mM is sufficient (see Fig. 60-9) for filament sliding to occur. It has to be emphasized that these hypothetical mechanisms have not yet been tested.

Even in healthy normal control participants, the region of the endplate has been found to be particularly sensitive to painful stimuli.²⁴⁶ This finding suggests a high density of nociceptors in that region and may explain—besides the location of the contraction knots underneath the endplate—why in many muscles, TrP pain is worst in the endplate region.

Even with an enhanced understanding of TrP pathophysiology, clinicians’ ability to identify TrPs is inconsistent.^247–252 Although the interrater reliability increases significantly with experienced versus novice clinicians, the experts’ intrarater reliability curiously diminishes with repeated assessments.²⁵³ Multiple criteria have been proposed to identify TrPs with palpation, such as finding a taut band, local tenderness, patient pain recognition, pain referral, a local twitch response, and a jump sign. In addition to not being applied uniformly across studies, the interrater identification of the criteria has proved to be generally unreliable.²⁵⁴ Further confounding the accurate identification of muscles harboring TrPs, Simons noted that TrPs also exist at the muscle attachment sites,²⁵⁵ but the usual examination for TrPs is solely in the muscle tissue, resulting in overlooking sources of pain and targets for treatment.⁹⁴

Various treatment protocols have been suggested to treat TrPs, including manual techniques, physical therapy modalities, and injections.²³⁷ Trigger point injections (TPIs) are done with a variety of injectates or with none (dry needling). Use of local anesthetics versus dry needling is reasonable because it results in diminished postinjection pain.²⁵⁶ Although all local anesthetics have been shown to be myotoxic (most profoundly with bupivacaine and chloroprocaine), they do not affect satellite cells. Damaged cells rarely produce clinically significant effects and generally regenerate in 4 to 6 weeks.^257,258 The cell damage from the injectate (and needling) may actually enhance the treatment effect through the elimination of dysfunctional fibers and by allowing the regeneration of normal fibrils. Although some studies suggest that there may be sustained benefit in the treatment of LBP with use of botulinum toxin or corticosteroids, systematic reviews^201,208 cannot support or reject their use. In a Cochrane review of neck pain,²⁵⁹ botulinum toxin was found to be no better than saline. Considering the cost and potential risks, the routine use of botulinum toxin or corticosteroids for TrPs does not appear to be justified.

It is not surprising that with lack of agreement on criteria for diagnosis, poor interrater reliability to find TrPs, varied treatments, and the absence of any consistent postinjection protocol,²⁶⁰ the outcomes for the treatment of TrPs do not rise to the level of evidence in the treatment of NSLBP (with or without sciatica).²⁶¹ To validate current approaches to assess and treat TrPs, head-to-head studies of competing methods to evaluate and treat muscle pain must be done to establish the most effective standard of care for identification of tender areas of muscles, injection techniques, injectates and their dosages, and postinjection protocols.

Two technologies to image muscles thought to harbor taut bands and TrPs have been suggested as possible means to more objectively identify the presence of pain-generating structures. Magnetic resonance elastography (MRE) allows visualization and identification of tissues with varied elasticity and has been shown to be capable of identifying taut bands that have diminished elasticity compared with normal muscle tissue. MRE appears to offer greater reliability than palpation in identifying taut bands.²⁶² Visualization of TrPs is more elusive, but recent studies have demonstrated the use of ultrasound in identifying TrPs.^263,264 Both of these techniques may help objectify the identification of taut bands and TrPs but have not yet been clinically tested to determine if they will improve the effectiveness of treatment for muscle pain.

Muscle pain is complicated. It is found as a sole source of common pain presentations and occurs as a result of painful phenomena in other tissue. More attention to the presence of muscle pain will facilitate refinement of our understanding of the initiation and perpetuation of common pain syndromes. It should therefore be included in our routine pain assessments and treatments. Absent a consensus opinion for addressing functional muscle pain, the below plan that incorporates many of the variables necessary to manage muscle pain is suggested by Norman J. Marcus.

Any patients with persistent pain should undergo a thorough examination of all muscles that could possibly contribute to the pain complaint.

1. Distinguish injectable muscle pain from pain related to tension, deficiency (weakness, stiffness, or both), and spasm. The KW test for strength and flexibility of key postural muscles for LBP and lower extremity pain identifies patients who are deconditioned (decreased strength and flexibility of postural muscles). Standard tests of upper body strength, along with assessment of forward elevation, abduction of the arm, and functional internal and external rotation of the shoulder (scapulohumeral and scapulothoracic motion) may find asymmetries of motion in the shoulder girdles, suggesting which muscle(s) may be involved (Fig. 60-10).

2. Attempt to identify primary versus referred muscle pain. (Identification through muscle stimulation appears to be more accurate than palpation.²⁶⁵)

3. Use a standardized exercise program to correct muscle deficiencies. Norman J. Marcus provides the Kraus exercises: 8 for the upper body and 21 for the lower body.²⁶⁶

4. Suggest conditioning exercises (i.e., all patients, if possible, gradually increase their daily walking up to 2 to 3 miles each day).

5. Marcus identifies a specific muscle as a pain source rather than a TrP, and calls the identified muscle “Muscle Pain Amenable to Injection (MPAI)” and the muscle injection is called “Muscle-Tendon Injection (MTI)” rather than a TPI. When injecting a specific muscle, pay particular attention to the entheses of the identified muscle rather than just TrPs and taut bands. Consider injecting only one muscle during a given injection session (Fig. 60-11).

6. If you use an injection procedure (MTI) that targets the entire muscle, 3 days of a postinjection physical therapy protocol will minimize postinjection soreness and stiffness.²⁶⁷

7. If more than one MPAI is identified and multiple treatments are planned, reassess the patient for continued presence of MPAI before injecting the next planned muscle. It is possible that changes may have taken place as a result of successful injections. These changes may be related to diminished central sensitization, resulting in the next muscle no longer being painful to manual or electrical stimulation or conversely the ability to discern a new muscle as painful after the previous, most severely painful muscle was successfully treated.

REFERENCES

INTRODUCTION

By late middle age 5% of men and women will have developed peripheral arterial disease and within 5 years 25% of these will develop pain at rest, ulceration, and gangrene (critical limb ischemia).¹ Physicians who practice in the specialty of pain medicine need to be familiar with the causes and treatment of pain due to peripheral vascular disease because it has a high prevalence. Appropriate therapy and management can significantly improve the quality of life for patients. Pain medicine physicians, by encouraging secondary or tertiary preventive therapy, have the opportunity to improve the life expectancy of their patients with symptomatic peripheral vascular disease of whom more than 50% have disease of the coronary and/or carotid arteries. This chapter will outline the disease conditions and treatments for pain associated with peripheral vascular disease.²

The ischemic pain of peripheral vascular disease can be approximated by sustained tourniquet inflation on an extremity. In experimental studies, as time passes, tissue oxygenation levels fall, metabolic byproducts accumulate, reactive cellular agents are released, nociceptive signals entering the central nervous system (CNS) increase, and patients report increasing intensity of pain. The affective descriptors for this pain differ and are more difficult to tolerate than pain produced by other experimental modalities. Patients with peripheral vascular disease experience this type of pain without the ability to restore blood flow by releasing the tourniquet. Effective management of this pain can restore quality of life for these patients.

PAIN OF ARTERIAL ORIGIN

Arterial insufficiency is most commonly the result of occlusive diseases with atheroma formation (arteriosclerosis obliterans), but less commonly occurs in thromboangiitis obliterans (Buerger disease), Raynaud syndrome, diabetic arteritis, and arteritis associated with collagen disease. Other diseases with vascular-related causes such as migraine and cluster headache are discussed elsewhere (see Chapter 3).

ATHEROMA AND ITS CONSEQUENCES: ARTERIOSCLEROSIS

The role of lipids was suggested with the early appearance of fatty streaks in young soldiers during emergency surgery and at autopsy in the 1970s. The role of lipids distinguishes arteriosclerosis from other arterial disease. Primary and secondary prevention strategies are available to reduce the incidence and/or aggressively treat the known risk factors of hypercholesterolemia, hypertension, cigarette smoking, and poor control of diabetes. As the disease progresses, plaque formation tends to occur at bifurcations in large and medium-sized arteries where turbulence, alteration of laminar flow, and shear stress may provoke an endothelial and/or vascular smooth muscle response. Arteriosclerosis is a dynamic process that involves vascular and inflammatory tissue responses with decreased release of nitric oxide (NO) and other protective secretions, increased release of cytokines by inflammatory cells responding to exposed matrix, and release of growth factors from the endothelium, as well as platelet activation. Arteries may respond initially to this process with an increase in size, but arterial remodeling may not be sustained in the face of ongoing plaque accumulation. Although a full discussion of arteriosclerosis is beyond the scope of this chapter, understanding of the causes at the gene and cellular level will suggest effective treatment options.

PROGRESSION OF ATHEROMATOUS PLAQUES

Although arteriosclerosis is most prominent at bifurcations, the straight femoropopliteal segment is involved in 60% of lower limb disease; the upper limbs are less often involved. Initially, as vessel diameter decreases, flow can be maintained if velocity increases. Vessel size also may increase, specifically at the arteriolar level, forming a collateral supply. As vessel diameter continues to decrease beyond 70%, the patient may develop symptoms, especially if the process is affecting collateral vessels as well. Initial symptoms usually occur during exercise when the circulation is stressed. Even in patients with severe claudication, blood flow may be near normal at rest. With progression, critical limb ischemia develops with an incidence of 0.5 to 1 per 1000.³

MECHANISM OF PAIN FROM ARTERIAL DISEASE

Oxygen is the most flow-limited nutrient for muscle and skin. Striated muscle is capable of working anaerobically, with delayed repayment of the oxygen debt. Lactate and pyruvate levels rise as oxygen debt continues. It is assumed that the accumulation of these products of metabolism trigger firing of C-fiber nociceptors, thus triggering the pain cascade.

As oxygen tissue levels fall, hypoxia triggers altered Ca²⁺ signaling in vascular smooth muscle,⁴ gene transcription for expression of inflammatory cytokines such as tumor necrosis factor,⁵ Interleukin-1 and 10 (IL-1, IL-10),⁶ and cytokine factors promoting vessel growth,^7,8 particularly growth of small vessels less than 200 microns in diameter.⁹ Endothelial dysfunction is associated with altered release of a mediator such as NO, eicosanoid, endothelium-derived hyperpolarizing factor, endothelin, and angiotensin II.¹⁰ Inflammatory cytokines also affect the coagulation system; for example, hypoxia-triggered release of IL-1 can decrease tissue plasminogen activator and stimulate release of plasminogen activator inhibitor-1.¹¹ Decreased release of NO leads to increased endothelial adhesiveness to circulating white blood cells.¹² Inflammatory mediators may both directly and indirectly trigger C-fiber nociceptor barrage into the CNS.

CLINICAL PICTURE OF OCCLUSIVE ARTERIAL DISEASE

The patient may have complaint of claudication and/or rest pain. Claudication is defined as pain in a muscle group (commonly the calf, less often the thigh, instep or buttock) that occurs while walking and forces the patient to stop. Pain is rapidly relieved by rest after which walking can be resumed. Walking distance typically decreases as the disease progresses. The diagnosis can often be made with a careful history. Another disease such as arthritis may produce infirmity so the patient is unable to tolerate exercise. In these patients the diagnosis may be made by examination. In patients with severe coronary disease, the angina linked to very low-effort walking may occur before claudication, masking this presentation of the disease. Often the reverse is true, and the presence of claudication may limit the patient's exercise tolerance so that even significant coronary disease may remain quiescent. Because 50% of patients with symptomatic peripheral vascular disease have coronary artery disease, patients with claudication have a 50% 10-year survival rate with most deaths due to myocardial infarction.¹³ Patients with claudication should receive preventive treatment to reduce the risk of myocardial infarction.

The differential diagnosis of claudication includes venous and neurogenic claudication. The latter is often associated with stenosis of the central spinal canal. In spinal stenosis during walking or standing, the cauda equina can become constricted within the narrowed canal, with decreased perfusion causing progressively intense lower extremity. In this case, pain may be worse with trunk extension and better with flexion. Watch for this clinical pearl when the patient reports that walking downhill (extending the spine) is more painful than walking uphill, especially in the setting where peripheral pulses are strong on examination. Lack of spina canal stenosis on computed tomography (CT) or magnetic resonance imaging (MRI) makes this diagnosis less likely. If the history is adequate, the site of claudication may also indicate the level of occlusion (Table 61-1). Intermittent claudication is more common in men than in women in whom it is rare before menopause.

Pedal ischemia rest pain occurs in the toes or forefoot with or without ulceration or gangrene. The history of ischemic pain is invariably that of pain occurring at night (after a variable recumbent period), which causes the patient to arise and is relieved by limb dependency. The patient may indicate that sleep is better in a chair. As the condition progresses, pain becomes continuous and the toes deteriorate. Ulceration or gangrene may occur. Spontaneous tissue necrosis may occur in the most peripheral distribution and is likely to affect the toes. It may also occur following trauma, overzealous chiropody, or orthopedic procedures including bunionectomy and treatment for ingrown toenails. Usually preceded by claudication, pedal ischemia may appear in patients who have little or no claudication pain.

OTHER RELEVANT HISTORY

Arteriosclerosis is a systemic disease and the history may be positive for myocardial ischemia (infarcts or angina), stroke, hypertension, arrhythmias, and transient ischemic attacks (in the form of focal neurologic deficits resolving within 24 h). A careful medication history may reveal the extent to which secondary prevention efforts have been successful. The extent of aspirin use and monitoring of cholesterol concentration in a follow-up of patients in the British regional heart study showed that most patients with intermittent claudication without history of myocardial infarction (MI), angina, cerebrovascular accident (CVA), were not receiving appropriate secondary prevention.¹⁴ Behavioral interventions may be helpful if a history of tobacco use is elicited and psychosocial stressors are present.¹⁵ An excellent review of the effect of smoking and cessation on mortality, morbidity, and quality of life was published in 2010.¹⁶ In an 11-hospital study, 711 consecutive Dutch patients with surgical treatment of peripheral arterial disease were followed prospectively for 5 years. Interestingly, there was a negative result for the primary aim among 5-year survivors.

PHYSICAL EXAMINATION

The general examination includes blood pressure measurement, cardiac auscultation, and funduscopy. Local examination will reveal ischemic tissue loss and poor capillary circulation. Low input arterial pressure can be enhanced by elevating the legs above the heart for 2 minutes while the patient repeatedly dorsoplantar flexes the ankles; this will produce elevation pallor.

All accessible pulses should be palpated and large vessels (e.g., femoral) should be auscultated for presence of a bruit as indication of proximal stenosis. The data should be charted, as shown in Table 61-2.

INVESTIGATIONS

The general assessment of the patient is aided by chest radiography, cardiography, complete blood count (CBC), and blood chemistries that include a lipid profile. Echocardiography¹⁷ testing of coagulation activity includes prothrombin time (PT), partial prothrombin time (PTT), and international normalized ratio (INR) for patients on coumarin. Testing fibrinogen and plasminogen activator inhibitor-1 levels has been suggested.¹⁸ Noninvasive localization of disease by technology such as combined echo-Doppler (duplex) is preferred both for diagnosis and choosing between surgery and percutaneous transluminal angioplasty (PTA).¹⁹ Magnetic resonance technologies are capable of providing high quality noninvasive studies with sensitivity and specificity comparing favorably to digital subtraction angiography.²⁰ The standard test remains the ankle-to-arm ratio (ankle-brachial-index [ABI]). Systolic pressure at the ankle is compared with systemic arterial pressure measured in the arm. This measure is far more sensitive than pulse oximetry.²¹ Observed values are related to clinical state (Table 61-3). When distal vessels are calcified and poorly compressible, the ABI may prove unhelpful and values greater than 1.50 may be obtained. Angiography is generally performed prior to reconstructive surgery.

MANAGEMENT OF MAJOR ARTERIAL OCCLUSION

Management of a patient with an ischemic lower limb is summarized in the flow chart

TREATMENT OF CLAUDICATION

Conservative treatment includes observation and treatment of associated conditions such as diabetes, anemia, or polycythemia. Efforts to assist patients with smoking cessation and to engage in regular exercise have been shown to improve outcome and quality of life.²² Over 3 months of supervised treadmill exercise (at claudication threshold for 30 to 40 minutes three times each week), marked improvement was demonstrated with increased time to claudication, increased peak walking and improved endothelial function.²³ Thought to mediate these positive changes, NO concentration increases with exercise but for patients with claudication, a reduction in NO stores may limit this effect. Might it be possible to boost the benefit of exercise in these patients by increasing NO stores, for example by increasing the concentration of its immediate precursor, plasma nitrite $(NO2−)$? This may be the case when increased oral consumption of dietary nitrates $(NO3−)$, converted by a salivary enzyme to $(NO2−)$, results in increased time to claudication and exhaustion, 32 and 65 seconds, respectively (Fig. 61-1).²⁴

The severity of claudication, response (or lack of response) to medical management, impact on lifestyle, and quality of life must be weighed against the risks before proceeding with a surgical treatment or percutaneous transluminal angioplasty (PTA.) The PTA procedure has high success rates for large vessels with short lesions such as the common iliac, and may be performed as a same-day procedure. Stenting may improve success rates when lesions are more complex or repeat therapy is required. In smaller vessels, PTA is less effective so that, for example, prominent pedal ischemia mandates consideration of vascular surgery if it is technically feasible. Arterial reconstruction may utilize endarterectomy, in situ or reverse venous or synthetic grafting material. The many variations and details are beyond the scope of this chapter; however, the efficacy of bypass surgery for treatment of lower limb ischemia is supported by evidence-based medicine review.²⁵

PAIN RELIEF MEASURES

SYMPATHECTOMY

Interruption of the lumbar sympathetic chain has a time-honored place in the treatment of peripheral ischemia. Before the advent of arterial reconstruction, it was the only surgical measure that produced pain relief. The indications for sympathectomy have diminished considerably over the last 50 years. Currently this treatment has a limited role.^26,27 Reports of the procedure performed successfully by laparoscopy and with chemical sympathectomy continue to appear in the literature.^28,29 Sympathectomy may improve blood flow to the foot and may improve rest pain, heal ulceration, and prevent skin necrosis.

If the affected foot is warmer than the unaffected foot, this suggests that autosympathectomy has occurred (especially in diabetic patients) and that the procedure will not be beneficial. However, there are patients who do not respond despite favorable characteristics. If the popliteal inflow index (Doppler inflow pressure in a popliteal artery vs. arm pressure) is 0.7 or greater, a good response can be predicted. It is unlikely that a favorable response will be obtained if the ankle to arm ratio is less than 0.35.³⁰

Lumbar sympathectomy can be achieved by injection or surgery. The technique of lumbar sympathetic block is well described in the references.³¹ An accurate block of the sympathetic chain at L3 may be adequate and it may not be necessary to use multiple needles; however, the use of radiographic control will make the procedure easier and safer. If repeated blocks with dilute local anesthetic solution produce appreciable circulatory improvement, a neurolytic block with 5 mL aqueous phenol 5% solution can be considered as an alternative to surgical sympathectomy.³²

Operative sympathectomy may be completed by a relatively atraumatic extraperitoneal approach under general anesthesia in which lumbar ganglia 2, 3, and 4 are excised together with the chain connecting them. Post sympathectomy neuralgia, an aching pain in the femoral nerve distribution, is a complication that may resolve in 6 to 8 weeks. This is also a complication of chemical sympathectomy if the agent spreads through the prevertebral fascia to the level of the L-1 nerve root or through the psoas fascia to reach its major peripheral nerve.

OTHER METHODS OF IMPROVING THE PERIPHERAL CIRCULATION

Intravenous Regional Sympathetic Block

An effective alternative means of producing sympathetic block in a limb is to administer intravenous agents affecting postganglionic neurons to produce noradrenergic block using an intravenous regional anesthesia (IVRA) technique. Before its manufacture was discontinued, guanethidine was used IV with some success in complex regional pain syndrome (CRPS) and peripheral vascular disease (PVD).^33,34 By acting on postganglionic neurons, guanethidine first releases norepinephrine and then causes noradrenergic block by preventing the reuptake of norepinephrine by the neurons. Other drugs such as clonidine,³⁵ phentolamine,³⁶ bretylium,³⁷ ketorolac, and corticosteroid, reported effective in management of pain due to CRPS and administered by IVRA technique, may find application in management of pain due to PVA. In the IVRA technique, a tourniquet is placed around the proximal part of the limb and inflated. The limb may be elevated for several minutes to enhance venous drainage prior to inflation of the tourniquet. The drug diluted in 50 mL of normal saline may be injected into an indwelling intravenous catheter in the affected leg or arm after tourniquet inflation. Lidocaine can be added to help the patient tolerate the tourniquet. The tourniquet is kept inflated for 15 minutes. The technique may be valuable for patients who are receiving anticoagulant therapy in whom paravertebral lumbar sympathetic block could cause significant hemorrhage. The technique can also be used for patients in whom the effects of operative lumbar sympathectomy are receding.

SPINAL CORD STIMULATION

Initial reports of the value of large fiber nerve stimulation suggested that patients with pain from peripheral arteriosclerotic disease who had not responded to arterial bypass surgery and/or sympathectomy might respond to stimulation of posterior spinal roots using implanted electrodes. Plethysmographic blood flow and skin temperature were also noted to increase. More recently it has been suggested that the primary effect may be occurring within the lamina of the dorsal horn of the spinal cord. Pain transmission in this layer is controlled by wide dynamic range neurons. Substance P was one of the first neuropeptides identified as modulating pain transmission, and may be particularly affected by descending traffic modulating pain transmission. It is likely there are multiple mechanisms involved. The stimulating electrodes may be introduced into the epidural space under direct surgical visualization or by means of a 15-gauge Tuohy needle with the electrodes placed between T 9 and T11.³⁸ This area of the spinal cord corresponds to lumbar segmental level output. Spinal cord stimulation at this level is associated with increased skin temperature, blood flow, decreased edema, and prolonged pain relief. The stimulating electrodes may be adjusted until stimulation of large fiber afferents produces a tingling paresthesia that overlies the painful region.³⁹ According to Augustinsson and coworkers, the vasodilating effects of spinal cord stimulation could be explained by (1) segmental inhibition of vasoconstrictor fibers, (2) antidromic activation of posterior root fibers, and (3) activation of ascending pathways to supraspinal autonomic centers. Interestingly, stimulation over lumbar spines or peripheral nerves was ineffective in these patients.^40,41 The long-term efficacy of spinal cord stimulation for pain from peripheral arteriosclerotic disease is reported to be excellent at 70% to 90% when compared to results of 50% to 70% for neuropathic pain.^42,43

DRUG THERAPY

The search for a noninvasive treatment of peripheral ischemia has highlighted many drugs that, after a brief popularity, have vanished from our treatment armamentarium. The following discussion of drug therapy approaches include vasodilators, antithrombotic measures, fibrinolysis, phosphodiesterase inhibitors, antiplatelet drugs, metabolic agents, arachidonic acid derivatives, and gene therapy.²⁴

VASODILATORS

Because the regulation of blood flow in the normal foot is affected by decreasing or increasing sympathetic tone, α-adrenergic blocking agents have been used, including thymoxamine, phentolamine, phenoxybenzamine, and clonidine. Other drugs have a local effect on vascular smooth muscle, which include papaverine and derivatives of nicotinic acid. Priscoline is an α-receptor blocker that has a direct effect.

Systemic use of vasodilators may reduce blood flow in the worst affected limb by shunting blood to healthier areas (the vasodilator paradox).⁴⁴ A local effect may be obtained by direct intra-arterial injection or by retrograde intravenous infusion (Bier technique). Ketanserin, a serotonin-2 receptor antagonist, and nifedipine, a calcium channel blocker, may play a role in therapy;⁴⁵ however, lowered systemic blood pressure and perfusion pressure to the ischemic tissue, and the maximal dilation of local vessels in the ischemic region suggest vasodilator treatment might not be effective.

ANTITHROMBOTIC MEASURES

Anticoagulant treatment has not been shown to be effective in peripheral vascular disease as thrombosis, when it occurs, is the final episode in the generation of the ischemic limb.

FIBRINOLYSIS

Fibrinogen is the substrate for thrombin that converts it to fibrin. Dissolution of fibrin can be achieved using streptokinase, urokinase, and tissue plasminogen activator. Although it would not affect the atheroma, and restenosis may follow cessation of therapy, it may delay progression and be a useful therapy in acute occlusion. Its use should be followed by arteriography to assess the need for reconstruction.

PHOSPHODIESTERASE INHIBITORS

Two drugs approved by the FDA for use in intermittent claudication are cilostazol and pentoxifylline. Both drugs exhibit phosphodiesterase inhibition that can increase the concentration of cyclic AMP leading to inhibition of platelet aggregation, thromboxane release, and increase in prostacyclin release. Unlike milrinone, which has similar effects on vessels and platelets, cilostazol does not display significant inotropic effect.⁴⁶ Pentoxifylline also affects blood rheology and specifically increases flexibility of red blood cells.

ANTIPLATELET DRUGS

Drugs such as aspirin, dipyridamole, ticlopidine, and prostacyclin inhibit release of thromboxane A and prevent platelet aggregation. Because the latter occurs in turbulent flow proximal or distal to atheromatous stenosis or occlusion, such treatment is of secondary importance in peripheral arterial disease. However, in conjunction with lipid-lowering drugs, antiplatelet drug therapy is the mainstay of secondary prevention to prevent myocardial infarction (MI) and stroke in patients with peripheral artery disease, even those who do not have signs or symptoms of coronary or carotid disease. Among drugs available in generic formulation, aspirin in low dose between 81 and 325 mg per day is efficacious and economical.

METABOLIC AGENTS

Naftidrofuryl was marketed first as a vasodilator, but it is purported to influence muscle metabolism beneficially through the Krebs cycle. Although a meta-analysis of seven randomized controlled trials involving 229 patients showed reduction in pain and analgesic consumption, the results were not statistically significant and in 1995 the drug was withdrawn in the United States for treatment of peripheral arterial disease.⁴⁷ Levocarnitine and propionyl levocarnitine are two drugs that may provide benefit by lessening the acylcarnitine metabolite build-up resulting from an impaired mitochondrial electron transport in ischemic muscle; however, propionyl levocarnitine is not FDA approved.⁴⁸

ARACHIDONIC ACID DERIVATIVES

The term prostaglandin was first used by Von Euler⁴⁹ who discovered some of the pharmacologic effects of semen. Endoperoxides derived from cell membrane arachidonic acid are converted to thromboxane A₂ in platelets (vasoconstrictor and platelet aggregator) or to prostacyclin in blood vessel endothelium (vasodilator and inhibitor of platelet aggregation). The balance between these two classes of compounds maintains intravascular hemostasis.

The earliest report of the use of prostacyclin in ischemic feet used prostaglandin E₁ by intra-arterial infusion; the same team later administered the drug by the intravenous route. In both instances, they reported dramatic relief of rest pain in small groups of patients and healing of some ulcers.^50,51 Prostaglandin I₂ (PGI₂₎, also a platelet inhibitor and vasodilator, can be administered daily as an intravenous infusion (Iloprost), or given orally (Beraprost) with encouraging results.⁵²

GENE THERAPY

Gene therapy may be helpful in restoring blood flow to ischemic extremities. A Boston group reported results in a small phase I study. Human DNA coded to make vascular endothelial growth factor (VEGF) was introduced into Escherichia coli plasmid which was grown in culture, purified, and administered by intramuscular injection into ischemic muscles of patients with critical limb ischemia. Ischemia is defined as rest pain with nonhealing ischemic ulcers in human volunteers identified as poor candidates for revascularization surgery. VEGF, secreted by endothelial cells, is the same protein as vascular permeability factor. It has binding sites limited to endothelial cells and therefore is site specific. Injection of plasmid VEGF DNA manufactured by E. coli produced significant transient edema in the limbs where it was injected. ELISA measured VEGF concentration also increased transiently and was associated in time with increased small blood vessel formation that persisted after VEGF levels returned to baseline, increased ankle-brachial index, healing of ulcers, increased exercise tolerance and resolution of rest pain. The authors cautiously interpreted their data as supportive for the strategy of IM gene therapy for therapeutic angiogenesis in patients with critical limb ischemia.⁵³

PAIN DUE TO PERIPHERAL ARTERIAL DISEASE

RAYNAUD PHENOMENON

Raynaud phenomenon differs from other peripheral arteriopathies because it affects mainly the hands. It was described first by Maurice Raynaud⁵⁴ in 1862. Allen and Brown⁵⁵ advanced our understanding by separating affected patients into those with and without a known underlying cause.

Raynaud disease (also known as primary Raynaud phenomenon) includes the classic clinical picture of pallor in the distal two-thirds of the fingers (a result of arterial shutdown), cyanosis (from partial relaxation of arterial spasm and deoxygenation of blood), and rubor (reactive hyperemia); all occur in response to cold or emotion. As the condition progresses, the pain becomes more severe and continuous. The condition is more common in women than in men; usually it becomes apparent by the age of 40 years. It occurs much less often in the lower limbs. Raynaud disease describes patients in whom no underlying condition can be found.

Raynaud syndrome (also known as secondary Raynaud phenomenon) comprises those patients with Raynaud phenomenon secondary to underlying pathologic disorders (Table 61-4). Interestingly, 10% of patients with primary pulmonary hypertension may exhibit symptoms.⁵⁶

Raynaud syndrome is particularly important because the associated condition may be treatable. However, the prognosis is worse, and patients may develop pathologic changes of ulceration, subungual infection, and pulp loss after digital arterial occlusion (Fig. 61-2). Porter and Rivers⁵⁷ reported 383 patients observed in a 10-year period. Of these, 162 had no associated disease and 137 had proven or suspected connective tissue disorder (57 of the latter had systemic sclerosis).

RAYNAUD MANAGEMENT

General Measures

Simple avoidance of cold, either of the body or of the hands, may be all that is required in mild cases. A change of occupation may be necessary if vibrating tools are used. Cessation of smoking has been advocated.

Sympathectomy

Because nervous control of digital blood flow occurs simply as a result of increasing or decreasing sympathetic tone, pharmacologic or surgical sympathectomy has been used extensively. Drugs such as methyldopa, thymoxamine, reserpine, debrisoquine, and phentolamine have been administered orally and intra-arterially. Most of the studies are anecdotal, uncontrolled, or rely on subjective assessment. If no effect can be proved when a drug is given intra-arterially, it is unlikely that it will work systemically. The pain of Raynaud phenomenon has been controlled by IVRA sympathetic block with guanethidine (no longer manufactured). Agents used in IVRA to treat other pain syndromes may find application in Raynaud treatment as guanethidine alternatives are investigated (see section “Intravenous Regional Sympathetic Blocks”).

Surgical sympathectomy can be done using an open procedure, but temporary and permanent Horner syndrome may occur. Transaxillary endoscopic coagulation to destroy thoracic ganglia 2 to 5 is another approach.⁵⁸ A thoracoscopic approach that is minimally invasive has also been described.^59,60 The immediate effect usually is good, although recurrence is common within 6 to 24 months and this treatment may be less effective than others.⁶¹ Digital sympathectomy using microvascular techniques has also been reported.⁶²

Sympathetic Blockade

Where the condition is not severe and particularly if it is seasonal, a stellate ganglion block can be effective. A paratracheal approach at the C6 level reduces the risk of pneumothorax and intravertebral artery injection. The accuracy may be increased by the use of radiographic control and a radiopaque dye that can identify the occurrence of dural cuff injection. A sympathetic block with local anesthetic does not tend to produce a sustained response.

Other Treatments

Although Ketanserin was initially⁶³ considered to be a helpful therapy, recent reviews suggest no significant clinical effect.⁶⁴ Temperature biofeedback was recently shown to be inferior treatment in comparison with calcium antagonist.⁶⁵ Nifedipine or other calcium channel blockers are highly effective for patients who do not experience adverse effects. Interestingly, the dihydropyridine calcium channels are closely associated with the endothelin-1 receptor, suggesting endothelin-1, found in higher concentration in Raynaud patient serum, may be a neuron-independent vasoconstrictor.⁶⁶ Prostacyclin infusion and administration of a stable oral preparation may be effective and were described above. As noted above, spinal cord stimulation could be of value.

BUERGER DISEASE

Thromboangiitis obliterans was the name Leo Buerger⁶⁷ gave to a specific arterial disease which he believed was confined largely to Eastern Europeans. This disease subsequently was shown to be prevalent in Sri Lanka, Korea, and Japan where it was the most common form of arterial pathology. By the 1970s it was reported that 75% of 1641 cases of femoropopliteal occlusion were caused by this condition.⁶⁸ A gradual decrease in the incidence has been reported.⁶⁹

Clinical Picture

More than 90% of Buerger disease sufferers are men younger than 40 years of age who are smokers. They have instep claudication or painful ischemic changes in the feet. Less than 50% of patients have manifestations in their upper limbs, usually thrombophlebitis or minor ischemic changes. Upper extremity circulation may be assessed with an Allen test. The patient makes a fist while occluding radial and ulnar arteries at the wrist. The hand is relaxed and ulnar arterial pressure is released. Failure of the hand to regain color constitutes a positive test. The test is repeated for patency of radial artery. In these patients, foot pulses and later popliteal pulses are absent.

Buerger disease is an inflammatory process; the affected artery is surrounded by fibrosis whereas the normal structure of the vessel wall may be preserved, in contrast to the typical disruption of internal elastic lamina and media in arteriosclerosis and other systemic vasculitides.⁷⁰ The pathology is specific with thrombosis in crural arteries and veins. Giant cells are a histologic feature, even in early cases.

Management

Universally, it is accepted that for smokers, treatment must begin with smoking cessation. If patients stop smoking, this alone may be sufficient to provide relief.

Local treatment is directed toward debridement and draining infections. Prostaglandin in the form of iloprost may provide benefit particularly during the period when patients first discontinue smoking.⁷¹ Sympathectomy and spinal cord stimulators are used in management of difficult cases. As with arteriosclerosis, gene therapy may offer promise.⁷²

VENOUS DISEASE

Venous disease may occur as acute (deep venous thrombosis [DVT]; thrombophlebitis) or chronic (DVT with recanalization or gravitational disease). Deep venous thrombosis occurs when normal venous flow is disturbed according to the Virchow triad: (1) diminished flow velocity after illness, operation, childbirth; (2) alteration in the characteristics of the contained blood producing increased viscosity, such as polycythemia, abnormal plasma protein fractions, leukemia, or thrombocythemia; and (3) local intimal damage. In most patients, more than one factor is responsible. The disease apparently arises spontaneously in healthy people; however, a search for underlying condition (such as malignancy or collagen-vascular disease) should be undertaken. Often without initial symptomatology, the disease may present with death due to pulmonary embolism. The focus should be on prevention rather than treatment, particularly for patients at increased risk due to immobility, including patients admitted to the hospital for surgery. For further information about venous thromboembolism, see the excellent discussion by Geerts et al.⁷³

ACUTE VENOUS DISEASE

The clinical diagnosis of DVT is made by the triad of local tenderness, swelling, and color change. Clinical diagnosis alone does not detect the more subtle changes and may overdiagnose the condition. In the presence of atheroma, false-positive and false-negative results comprise 50% of tests.

When edema is present, it implies that the deep veins are occluded; embolization is less likely, but local sequelae are more likely. The clinical picture is either the white leg (milk leg), which is pale and shows infragenicular pitting edema, or the blue leg, which involves the entire leg as far proximally as the root of the limb. The former is a result of femoropopliteal obstruction; the latter indicates iliac-caval obstruction. The blue leg causes much discomfort, and if tissue pressure continues to rise, peripheral gangrene may supervene.

Acute thrombophlebitis is easily recognizable because there is visible swelling and tenderness along the course of a superficial vein. Apart from the underlying conditions already mentioned, the condition may be the harbinger of carcinoma of the pancreas or lung.

CHRONIC VENOUS DISEASE

Occlusion of the major veins is followed by recanalization with valve destruction. This allows transmission of the full force of the column of blood from the right atrium to the heel (+ 80 to 90 torr). The patient may have complaint of a resting pain in the calf, which, when associated with walking, is known as venous claudication.

Gravitational changes are more serious because of their reputation for intractability. These changes include pigmentation, distended intracutaneous veins (in the inframalleolar position, so-called venous flare), edema, liposclerosis, and ulceration (Fig. 61-2). The pain of a venous ulcer may be excruciating; it usually is worse at night and is unrelated to ulcer size. Investigation of venous disease is directed toward the following:

1. Proving the diagnosis. Isotope studies may be helpful in diagnosis of acute DVT. Duplex ultrasonography and impedance plethysmography are useful in establishing the diagnosis. The “gold standard” investigation is venography, which should be universally available. Testing for the D-dimer fibrin degradation product combined with clinical criteria has a high sensitivity and low false-negative results.^74,75

2. Demonstrating an underlying cause. A complete blood count (CBC), erythrocyte sedimentation rate (ESR), chest x-ray (CXR), liver diagnostic tests, urinalysis, renal function tests, serum proteins, and immunoglobin level tests and tests for lupus erythematosus, rheumatoid, and other collagenoses may be required.

Management of Venous Disease

Acute Deep Venous Thrombosis

The classical mainstay of treatment used to be a 5000 unit bolus of heparin followed by a continuous intravenous infusion in a dose of 40,000 units in 24 hours. This treatment was designed to prevent the spread of the thrombus and embolization until the clot became adherent and stabilized. In the absence of bleeding complications, therapy was maintained for 5 days, the last 3 of which overlap with the commencement of oral anticoagulation therapy with coumarin which was maintained for 3 months. Vitamin K antagonist treatment to maintain an INR of 2.5 is the most frequent secondary treatment for patients with venous thromboembolism. In four studies with 1500 patients, a meta-analysis revealed reduction for risk of recurrent events as long as treatment was maintained. As the risk of recurrent event may decrease over time, this benefit may eventually become outweighed by the risk of hemorrhagic complication that does not decrease over time.⁷⁶

The availability of a low-cost outpatient management option has resulted in shortened hospital stays with many cases in the United States being treated with subcutaneous injections of low molecular weight heparin. A meta-analysis of 4754 patients in 14 randomized prospective controlled studies showed low molecular weight heparin was as effective as unfractionated intravenous heparin in preventing recurrent DVT. The risk of hemorrhage was lower during treatment and mortality at follow-up was also lower for the outpatient treatment protocol.⁷⁷

ACUTE THROMBOPHLEBITIS

This usually is a self-limited condition that can be treated by local warm compresses and an anti-inflammatory drug (such as ibuprofen.) If the process involves the saphenous vein in the thigh, it may be necessary to ligate it at the groin to prevent the thrombosis from spreading into the femoral vein.

Chronic Venous Insufficiency

The venous hypertension that follows extensive valvular obstruction after DVT includes various stigmata in the gaiter area of the leg, the most disabling of which is ulceration. There are a number of causes of leg ulceration, and it is important to exclude concomitant arterial disease, diabetes, and rheumatoid disease because these will render standard treatment ineffective. The linchpin of venous ulcer treatment is effective graded dynamic elastic compression to oppose the harmful effects of venous hypertension. Topical therapies include antibiotics, corticosteroids, and enzymes. However, they are all largely ineffective. They also may be expensive and can produce sensitization reactions that may be worse than the original condition.

Pain control with analgesic drugs during the healing phase is important; a decreasing need for analgesia is a good indication of progress toward healing.

SUMMARY

Interestingly, services for patients with pain due to peripheral vascular disease are delivered by a multitude of specialists including vascular surgeons, radiologists, anesthesiologists, rheumatologists, cardiologists, internists, dermatologists, primary care physicians, and podiatrists. The explosion of basic science and clinical research promises improved understanding and additional management options for these severely disabling diseases. Meanwhile, the author encourages the reader, irrespective of specialty, to take every opportunity to encourage smoking cessation, regular daily exercise, and other preventive measures that produce so much benefit to so many.

REFERENCES

INTRODUCTION

Ischemic pain affects millions of people worldwide. It is a detriment to quality of life and carries with it significant morbidity and mortality. Ischemic pain occurs when there is obstruction of the circulation to an area of the body. The myocardium, lower extremities, and mesentery can be affected primarily from the development of atherosclerosis obliterans. Pain management centers are becoming more involved in the care of patients with ischemic diseases because the centers can offer interventional procedures applicable to these diseases. This chapter provides a review of the pathophysiology of ischemic disease, existing and emerging therapies available and their efficacy, and the role of the pain specialist in the management of patients with peripheral, coronary, and mesenteric ischemic disease.

PERIPHERAL ARTERY DISEASE

CHARACTERISTICS

Limb ischemia can be caused by atherosclerosis obliterans as well as atheroembolic or thromboembolic disease, vasculitis, trauma, and other disease processes. Limb ischemia affects macrovascular and microvascular circulation. Peripheral artery disease (PAD) is a marker for cardiovascular disease (CVD) and affects 8 million Americans.

Ischemic pain in PAD is insidious and gradual in onset. The pain is described as an aching and cramping sensation that is worse at night and improves when the legs are in a dependent position, which improves blood flow. Most patients have atherosclerotic changes for 5 to 10 years before they have symptoms. Intermittent claudication is the earliest sign of vascular insufficiency, which is characterized by cramping, tightness, and heaviness that increase with exercise. The pain is relieved with rest and the claudication distance remains fairly constant until further progression of the disease. The differential diagnosis for intermittent claudication is listed in Table 62-1.