Pain Amplification Syndromes

Pediatric rheumatologists encounter children with acute and chronic pain for which an overt primary cause for the pain cannot be found. In these disorders the pain seems disproportional or amplified. In this chapter, the approach and evaluation of pain in children will be addressed, followed by a review of the presentation and treatment of children with amplified musculoskeletal pain syndromes.

Historical Review

Chronic musculoskeletal pain in children received scant attention until the latter half of the twentieth century. In 1951, Naish and Apley published their landmark study on pediatric limb pains due to nonarthritic causes, in which they considered emotional factors to play a causative role. Since then, it has been increasingly recognized that a significant number of children suffer from both chronic and amplified musculoskeletal pain. Reflex sympathetic dystrophy (complex regional pain syndrome [CRPS]) was first described in a child in 1971. This 12-year-old girl had resolution of all signs and symptoms of CRPS on the day she was to see the psychiatrist, an indicator of the psychological aspects of this condition. The first description of childhood fibromyalgia was published in 1985. CRPS and fibromyalgia are the subject of most studies, whereas other, less clearly classified amplified musculoskeletal pain conditions are less frequently reported.

Definition and Classification

In this chapter, the term amplified musculoskeletal pain is used because it is descriptive, does not presume an etiology, and differentiates children from adults with chronic pain. The word amplified refers to the idea that the body amplifies the pain and does not imply that the child is willfully exaggerating the symptoms.

Current terms used to describe these conditions are inadequate and confusing because many children have features that are shared among different subsets. Children are categorized depending on the presence of physical features (e.g., the presence of overt autonomic signs, number of painful points with a variety of systemic symptoms) or location (localized [one or two body regions] or diffuse [three or more body regions]). At times, the different terms used to describe these conditions can be helpful in defining a specific subset of children with amplified pain for studies; however, there is a great deal of similarity between the subsets of amplified pain regarding the presentation, evaluation, and treatment.

When evaluating any particular study of pain amplification, it is important to know which classification criteria were used ( Box 52-1 ). Discrete subsets exist in each of the groups. Specifically, criteria for diffuse idiopathic musculoskeletal pain include those with fibromyalgia, and localized idiopathic musculoskeletal pain includes those with CRPS. Children with intermittent amplified musculoskeletal pain in whom the criterion for duration is not satisfied are nevertheless included in some reports due to the severity of their pain and marked dysfunction that may reoccur over years. Because CRPS and fibromyalgia are very distinctive and each has its own literature, these terms are used in this chapter when discussing these specific subsets.

Box 52-1

Sets of Criteria for Different Subsets of Amplified Musculoskeletal Pain

Budapest Clinical Diagnostic Criteria for Complex Regional Pain

All of the Following Four Criteria Must Be Met:

  • 1.

    The patient has continuing pain, which is disproportionate to any inciting event.

  • 2.

    The patient has at least one sign in two or more of the categories below.

    • Sensory: hyperalgesia or allodynia

    • Vasomotor: asymmetric temperature or skin color

    • Sudomotor/edema: edema or asymmetric sweating

    • Motor/trophic: decreased range of motion, motor dysfunction, or trophic changes (hair, skin, nail)

  • 3.

    The patient reports at least one symptom in three or more of the categories below.

    • Sensory: reports hyperesthesia or allodynia

    • Vasomotor: reports asymmetric temperature or skin color

    • Motor/trophic: reports decreased range of motion, motor dysfunction, or trophic changes

  • 4.

    No other diagnosis can better explain the signs and symptoms.

1990 American College of Rheumatology Criteria for Fibromyalgia

Both Criteria Must Be Satisfied

  • 1.

    Widespread pain (bilateral, and above and below the waist and axial pain) present for at least 3 months

  • 2.

    Pain (not tenderness) upon digital palpation with 4 kg of pressure on 11 of the following 18 sites:

    • Occiput: at insertion of suboccipital muscle

    • Low cervical: at anterior aspect of the intertransverse spaces of C5-C7

    • Trapezius: at the midpoint of the upper border

    • Second rib: just lateral to the second costochondral junction at the upper rib border

    • Scapula: the medial border just above the spine of the scapula

    • Lateral epicondyle: 2 cm distal to the epicondyle

    • Gluteal: in the upper outer quadrant of the buttocks

    • Greater Trochanter: 1 cm posterior to the trochanteric prominence

    • Knees: at the medial fat pad 1 cm proximal to the joint mortise

2010 American College of Rheumatology Criteria for Fibromyalgia

All Three Conditions Must Be Satisfied:

  • 1.

    Absence of a disorder to explain the pain

  • 2.

    Symptoms present for 3 months

  • 3.

    At least one of the following

    • Widespread pain *

      * Widespread pain equals the number of areas of pain in the last week (scale: 0-19). Areas include: shoulder girdle, upper arm, lower arm, buttocks/trochanter, upper leg, lower leg, jaw, upper back, lower back ( 2 points if bilateral) and 1 point each for chest, abdomen, neck.

      index ≥7 and symptom severity score ≥5

    • Widespread pain * index 3-6 and symptom severity score ≥9

Yunus & Masi Criteria for Childhood Fibromyalgia

All Four Major and Three Minor or the First Three Major and Four Painful Sites and Five Minor Need to Satisfied


  • 1.

    Generalized musculoskeletal aching at three or more sites for three or more months

  • 2.

    Absence of underlying condition or cause

  • 3.

    Normal laboratory tests

  • 4.

    Five or more typical tender points (see sites under 1990 ACR criteria above)


  • 1.

    Chronic anxiety or tension

  • 2.


  • 3.

    Poor Sleep

  • 4.

    Chronic headaches

  • 5.

    Irritable bowel syndrome

  • 6.

    Subjective soft tissue swelling

  • 7.


  • 8.

    Pain modulation by physical activities

  • 9.

    Pain modulation by weather factors

  • 10.

    Pain modulation by anxiety or stress

Symptom severity score (0-12).

Fatigue, waking unrefreshed, cognitive symptoms scored 0 to 3 each.

(0 = no problem, 1 = mild or intermittent, 2 equals moderate or considerable, 3 = severe, continuous).

Plus considering a host of somatic symptoms rated as 0 = no symptoms, 1 = few symptoms, 2 = moderate number of symptoms, 3 = great deal of symptoms (somatic symptoms include muscle pain, irritable bowel syndrome, tiredness, thinking problems, muscle weakness, headache, abdominal pain, numbness and tingling, dizziness, insomnia, depression, constipation, upper abdominal pain, nausea, nervousness, chest pain, blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud phenomenon, hives, tenderness, vomiting, heartburn, oral ulcers, dysgeusia, seizures, xerophthalmia, shortness of breath, loss of appetite, rash, sensitivity, hearing difficulties, easy bruising, hair loss, urinary frequency, dysuria, bladder spasms).

There are two kinds of CRPS: type I and type II. Type II CRPS is similar to the older term causalgia and implies the presence of nerve damage. It is exceedingly rare in children and all subsequent discussion refers to CRPS Type I. Many children present with more than one form of amplified pain such as CRPS of a limb and localized pain to the back or abdomen or even total body pain. Some children meet the definition for both fibromyalgia and CRPS but actually there is only one underlying condition (e.g., amplified pain); however, both have overlapping clinical characteristics, demographics, and response to therapy.


Incidence and Prevalence

Population surveys of school children confirm that musculoskeletal pain is common; back pain occurs in as many as 20%, and limb pain has been reported in 16%. A systematic review noted the prevalence of chronic and recurrent musculoskeletal pain in up to 40% of children. Fibromyalgia, and widespread pain, has been reported to have a frequency in children and adolescents of 2% to 6%. The incidence of complex regional pain syndrome in adults is estimated to be 5 to 26 per 100,000. There are no data regarding the incidence of childhood CRPS or specific data regarding the other amplified musculoskeletal pain syndromes, but 5% to 8% of new patients presenting to North American pediatric rheumatology centers most likely have a form of amplified musculoskeletal pain. Many pediatric rheumatologists believe they are seeing increasing numbers of children with amplified musculoskeletal pain in the past two decades, although this may represent a recall bias.

Age at Onset

Amplified musculoskeletal pain has been described in patients as young as 2 years of age, but the majority of reports involve children in late childhood and adolescence. Older adolescents may be underrepresented in pediatric series, presumably because they are referred to adult specialists.

Sex Ratio

Girls are more commonly affected than boys in a ratio of approximately 4 : 1, and the difference increases with age. Because women seek medical advice more often than men, there may be a selection bias; however, given the disability involved, this is most likely not a major factor in children. In Finland, predictors of widespread pain in children were older age, being female, reporting more depressive symptoms, and having back pain.

Geographic and Racial Distribution

There have been no formal investigations regarding the relationship of amplified pain syndromes to ethnicity; however, a series from Philadelphia reported a disproportionate number of white patients (15 of 15). All reports are from developed countries and comparisons with developing nations are not possible.

Etiology and Pathogenesis

The cause, or causes, of amplified musculoskeletal pain syndromes are unknown. Childhood pain syndromes seem to differ from those occurring in adults. For example, compared to adults, children with CRPS more frequently have lower rather than upper extremity involvement, the technetium bone scintigraphy shows decreased rather than increased uptake, and in both complex regional pain syndrome and fibromyalgia, children have different outcomes. Children respond more readily to physical and occupational therapy. Nevertheless, in many children, as in adults, these syndromes seem to be causally related to injury, illness, or psychological distress, either singly or in combination.

Physical Trauma

Injury, including surgery, frequently precedes complex regional pain syndrome in adults, and minor injury is commonly reported in children. Rarely, overt trauma may be the inciting event. Minor trauma may play a role in localizing the site of amplified musculoskeletal pain. CRPS has been reported following vaccinations. An adult developed CRPS following a corticosteroid injection for tenosynovitis. Children who are hypermobile may be at increased risk of developing the fibromyalgia form of amplified musculoskeletal pain, perhaps due to chronic microtrauma; however, Mikkelsson et al. found no relationship between hypermobility and musculoskeletal pain in 1637 grade 3 and grade 5 Finnish children.

The role of ischemia in the production of pain in CRPS and fibromyalgia has been a recurring theme. Ischemic injury has been noted on biopsy, and decreased blood flow to the painful region has been demonstrated by contrast-enhanced ultrasound.


Amplified musculoskeletal pain has been observed in children with a variety of illnesses, including arthritis, cerebral palsy, muscular dystrophy, new-onset diabetes, systemic lupus erythematosus, and leukemia. These associations may or may not be coincidental. A series of eight children with mitochondrial disease had CRPS in the setting of multiple other, generally neurologic, symptoms. There are abnormalities in the mitochondria in the muscles of adults with end-stage CRPS who underwent amputation, but their significance is not clear because none had other symptoms to suggest mitochondrial dysfunction.

Sleep Disorders

Fibromyalgia was thought to be a manifestation of a sleep disorder, and many adults and children with fibromyalgia have abnormal polysomnography, specifically, increased α-δ sleep. However, children who resolved their fibromyalgia with an intense exercise program had normal sleep but no change in the abnormal amount of α-δ sleep. Likewise, sleep abnormalities are not always present, and treating the sleep disorder does not correlate with improvement in symptoms. Only three of 108 (3%) consecutive adult patients presenting to a disorder sleep clinic had fibromyalgia, which is similar to the normal population. Therefore, sleep does not seem to play a role in the etiology of amplified pain.

Psychological Factors

Psychological distress is a recurring theme in most reports of children with amplified musculoskeletal pain, although controlled studies are lacking. School is more stressful in children with amplified pain than in those with chronic arthritis. Missing school is a frequent problem and can be the nidus for school avoidance. Children with amplified pain may have inappropriate roles within the school (taking classes that are too advanced) or family (caretakers, peacemakers, or being overly busy). Clearly, there are children and families who are overtly psychologically dysfunctional or distressed, but whether this is the cause of, the effect of, or unrelated to the development of an amplified musculoskeletal pain syndrome is not known. Two Finnish population studies indicate that children who are depressed subsequently develop chronic pain or fibromyalgia. Geertzen et al. found 79% of patients with CRPS to have recent stressful life events compared to 21% of controls. Stress directly relates to the endocrine and immune system and may play a pivotal role in some of the mechanisms discussed below. However, it is important to note that not all families with a child with amplified pain are inappropriately distressed.

Gender Differences

The reason girls are more frequently affected is not clear. Contraceptive or hormonal replacement therapy is not associated with fibromyalgia, nor are there differences in estrogen, progesterone, luteal hormone, follicular-stimulating hormone, or testosterone during the menstrual cycle between women with fibromyalgia and controls. However, stress hormones may be at play in fibromyalgia because patients have lower baseline cortisol levels and lower expression of corticosteroid receptors. Women with fibromyalgia reporting childhood abuse have higher diurnal cortisol. Girls have lower pain thresholds as well as differences in coping and cultural expectations, especially in Western countries. Girls are also more frequently hypermobile but hypermobility may or may not be associated with amplified pain.

Neurologic Abnormalities

Amplified pain is related to increased sympathetic nervous system activity and α-adrenoceptor responsiveness. Deconditioning increases sympathetic tone, which leads to ischemia, which can be ameliorated by exercise. Ackerman and Ahmad studied the sympathetic activity with laser Doppler imaging in adults who had CRPS following carpal tunnel surgery who required repeat surgery. Of those with increased sympathetic activity, eight of 11 had recurrent CRPS, whereas only three of 23 with normal sympathetic activity had recurrent CRPS. It is postulated that this may be modulated at the level of the spinal cord.

Functional magnetic resonance imaging (fMRI) has shown abnormal activation in the basal ganglia and parietal lobe in children with CRPS and that these abnormalities persist when the children are symptom-free, possibly partially explaining the risk for recurrent CRPS. Adults with fibromyalgia showed enhanced brain activity as measured by magnetoencephalography when presented with a painful stimulus. Many patients complain of inability to concentrate and Maihofner et al. showed decreased tactile learning in adults with CRPS. LeBel suggests there are significant brain circuitry changes in the “CRPS brain.” This may be another factor in creating central sensitization in which neurons regulating the pain pathway are hyperexcitable. Quantitative sensory testing in children suggests central sensitization may play a significant role. Browning et al. surmise that neuroimaging may eventually help classify somatoform disorders such as the amplified pain syndromes.

There is recent evidence of small fiber dysfunction in fibromyalgia and CRPS manifested by decreased intraepidural nerve fiber density. Oaklander et al. has also reported this phenomenon in children with a host of somatic, neurologic, and immunologic abnormalities and in erythromelalgia. It is unknown if this is a primary process or an epiphenomenon.

Inflammation and Immune Response

There has been recent interest in the role of inflammation in the amplified pain syndromes. There is localized, but not systemic, cytokine imbalance with high levels of TNFα and IL-6 in experimentally obtained blister fluid from the involved limb compared to the uninvolved limb and in skin biopsies, but not serum, in adults with CRPS; however, the degree of TNFα and IL-6 did not correlate with clinical characteristics or the duration of CRPS. Autoantibodies directed against sympathetic and myenteric plexus neurons have been found in 13 of 30 (43%) adult patients with CRPS but none of 30 controls and in only one of 20 patients with noninflammatory neuropathy, such as in diabetes, and in one of 20 patients with peripheral nerve lesions. Involvement of the innate immune system is suggested by the presence of elevated L-selectin on monocytes and elevated spontaneous hydrogen peroxide production by neutrophils in adults with fibromyalgia.

Genetic Background

Amplified musculoskeletal pain syndromes have been described in siblings, parent–child pairs, spouses, and multiple family members. Buskila et al. noted fibromyalgia in 28% of 58 offspring of 20 mothers with fibromyalgia. Pellegrino and colleagues reported that 52% of 50 parents or siblings of 17 patients with primary fibromyalgia also had fibromyalgia, and a set of identical twins developed fibromyalgia within 6 months of each other. Others have noted that not only fibromyalgia but other chronic pain conditions are more common in family members of children with fibromyalgia. In the Netherlands, 31 families were identified with up to five family members with CPRS, but a clear mode of inheritance was not observed. No particular gene has been implicated, although one small study of CRPS suggested that women with HLA-DR2(15) may be more resistant to treatment. There is interest in the role of catechol- O -methyltransferase (COMT) because it controls the metabolism of catecholamines. COMT polymorphisms found in fibromyalgia may influence the degree of central sensitization, psychological distress, and outcome. If genetic factors are important in amplified pain conditions, it is probable that multiple genetic polymorphisms are involved that predispose the individual to develop amplified pain when inciting environmental and cultural factors are present.

Evaluation of Musculoskeletal Pain

Pain is the subjective expression of an unpleasant sensation or emotional experience associated with actual or perceived tissue damage. It is difficult, if not impossible, for an observer to know with any certainty to what extent another person is in pain. Although parents and children tend to make a similar assessment of the degree of pain, parents may over- or underestimate their child’s pain in relation to the child’s own self-report. An important premise in the evaluation and management of a child in pain is that the child’s report of pain and its severity must be accepted at face value. “Pain is what the patient says it is, and exists when he says it does.” Prolonged malingering in childhood is exceedingly rare. Effective management requires that the child knows that he or she is believed. Many interacting issues determine whether a child’s pain disturbs the child’s and the family’s functioning, and when, if ever, medical help is sought ( Fig. 52-1 ).


Factors influencing pain expression and seeking health care.

Many children with pain amplification have been seen by multiple healthcare providers, have undergone multiple investigations, and have failed multiple therapeutic trials before the correct diagnosis is made. Unfortunately, attempts to identify an increasingly rare and unlikely cause for the pain or escalating empiric treatment aimed at organic pain can result in perpetuating the amplified pain.

History and Physical Examination

It is imperative to obtain a complete history of pain-related symptoms ( Box 52-2 ), as well as a complete past history and review of systems, and to perform a directed physical examination to ascertain the child’s overall health status. This is especially important in children with amplified pain because it is the initial step in establishing a trusting relationship with the child and family, who often feel that their concerns have not been considered seriously. A few key observations to be made during the physical examination are listed in Box 52-3 .

Box 52-2

History of Musculoskeletal Pain

What Is the Character of the Pain?

  • Which body parts are painful?

  • How long has it been present?

  • Is the pain getting better, worse, or staying the same?

  • What makes the pain better?

  • What makes the pain worse?

  • Is there diurnal variation in the severity of the pain?

  • Is the pain present at night and if so, does it waken him or her?

  • Does the pain interfere with function, and if so, what specifically?

  • What descriptive terms are used to describe the pain?

  • Does the pain radiate, migrate, or spread?

  • Is the painful area tender to touch or to clothing?

  • Is the painful area either cool or warm to the touch?

  • Does the painful part look abnormal or swollen?

  • What is the child’s or parent’s assessment of the pain severity?

Are There Other Symptoms?

  • Fever?

  • Rash?

  • Change in gastrointestinal function?

  • Weight loss?

  • Upper or lower respiratory tract symptoms?

  • Muscle weakness?

  • Sleep disturbance?

  • Depression?

  • Anxiety?

Family and Social History

  • Ankylosing spondylitis, reactive arthritis, or inflammatory bowel disease?

  • Back pain, heel pain, or acute iritis?

  • Psoriasis?

  • Fibromyalgia, complex regional pain syndrome or other chronic pain condition?

  • Is there an identifiable stressor in the family, school, or peer group?

  • Are there significant or recent life changes?

  • Where is the child sleeping?

  • What activities does the child participate in and how busy are they during the week?

  • How does the child perform in school?

  • How do the parents describe the child’s personality?

  • If there was inciting injury, is there a lawsuit in place or contemplated?

Box 52-3

The Clinical Examination

Several Key Observations

  • Does the child look well or ill?

  • Is the child’s affect consistent with the reported level of pain?

  • Does the child exhibit la belle indifference ?

  • Is there any joint swelling?

  • Is there any muscle weakness or atrophy?

  • Is there any tenderness to palpation and if so, is it over joints, entheses, or muscles?

  • Is there any area of allodynia, and if so, is the area constant or does it vary over time?

  • Is there any color, temperature or perspiration change?

  • Does function vary when observed or when an activity is being focused on and when the child does do not realize he or she is being observed or is distracted?

  • Are there any inconsistencies on repeat examination?

  • If asked to perform an activity that has been reported as being unable to do can the child do it?

  • Is there any neurologic dysfunction?

  • Does the pain occur in an area defined by a dermatome or peripheral nerve distribution?

  • Are there abnormal child-parent interactions such as enmeshment, hostility, berating?

  • Is there evidence of concurrent conversion symptoms?

  • In children with back pain, are signs of nonorganic back pain present?

Amplified pain is a clinical diagnosis with the presence and absence of salient features ( Box 52-4 ). Although there are differences between localized and diffuse amplified musculoskeletal pain syndromes, the medical history and physical examination are surprisingly similar.

Box 52-4

Common Patterns Observed in Amplified Pain

  • Insufficient inciting event to cause such pain and disability (minor trauma or illness)

  • Increasing pain over time

  • Increasing dysfunction over time

  • Disproportionate pain

  • Disproportionate dysfunction

  • Lack of response to medicinal and physical treatments

  • Incongruent affect

  • La belle indifference

  • Typical personality (mature, perfectionistic, pleaser, driven)

  • Multiple life changes or psychological stressors present

  • Allodynia with a variable border

  • Able to do things that they previously were not able to do when asked

Even when reporting severe pain or other somatic symptoms, the child often has a markedly incongruent affect, smiling even when reporting severe pain (up to 10 out of 10), and display la belle indifference about the pain and dysfunction it causes. A few children, usually but not exclusively those with localized amplified musculoskeletal pain, demonstrate marked pain behaviors such as crying or screaming. Children with amplified musculoskeletal pain often seem mature for their age, are accomplished in school and extracurricular activities, and are described by their parents as perfectionistic, empathetic, and pleasers.

In all forms of amplified musculoskeletal pain, conversion symptoms are not uncommon. Numbness is frequently reported, but children can manifest paralysis, pseudoseizures, or conversion spells, shaking or rigidity, blindness, or a bizarre (histrionic) gait. Eating disorders may be present.

Additionally, patients may have symptoms of an altered autonomic system, including lightheadedness when standing, orthostatic tachycardia, functional abdominal pain, or headaches. They frequently complain of not being able to think clearly; however, most children maintain their usual grades in school.

Assessment of Pain and Its Effects in Children with Amplified Musculoskeletal Pain

There are two major independent variables to consider when assessing pain: the quality and quantity of the pain complaint itself, and the amount of dysfunction as a consequence of the pain. The report of pain is always valid because, by definition, pain is subjective. Therefore, the most useful measurement of pain is the self-report on a verbal or visual analog scale. The quality of pain can be assessed using various instruments, such as the McGill Pain Questionnaire or Pediatric Pain Questionnaire.

The amount of reported pain does not directly correlate with the degree of incapacity, which can vary from almost none to being bedridden. An important observation is that with treatment function usually returns before the pain diminishes. Functional measurements vary depending on the location of the pain and the presence of coexisting conditions, such as arthritis or, more commonly, conversion symptoms. Children with both amplified musculoskeletal pain and conversion paralysis can be extremely dysfunctional.

Children with amplified musculoskeletal pain appear to suffer more than children with other musculoskeletal conditions, which may indicate the degree of psychological distress present. In one comparison of the degree of well-being, children with CRPS ranked themselves as significantly more disabled as measured by a visual analog scale than did those with juvenile rheumatoid arthritis.

Psychological dysfunction is almost universally present by the time the diagnosis is made. The psychological toll on the child and family is often severe although these syndromes are not necessarily psychological in cause. The degree of psychosocial pathology is highly variable and may range from mild anxiety or poor coping to borderline personality disturbance, or may involve siblings and other family members. Not only are such symptoms frequent, but the author has observed an increase in self-cutting (Sherry D.D., unpublished observation).


In children with CRPS, minor trauma that might not be clearly recalled is common (“someone must have stepped on my foot”). The pain and consequent disability increase over time in spite of medication. A cast or splint may increase the pain or, at best, minimize the pain while it is worn. Immobilization is an important factor in perpetuating the pain, and once the cast is removed the limb should not be further immobilized. In adults with wrist fractures, the presence of pain of 5/10 or greater after one week in a cast was very predictive of the development CRPS. Autonomic signs (edema, cyanosis, coolness, increased perspiration) may be persistent or transient, or may not occur. In a study of 70 children with CRPS, all had pain; 86% had allodynia (pain caused by normally nonpainful stimuli), 77% edema, 77% coolness to the limb, 73% cyanosis, and only 31% had hyperhidrosis. Allodynia can be marked (“the breeze of someone walking by hurts”) and can lead to significant impairment. This phenomenon, too, can be transient. Any body part can be involved, and the child may have several areas of pain. The lower extremity is more commonly involved than the upper extremity, and peripheral body parts are more commonly involved than central areas. Occasionally, only one small area is involved, such as a finger, the nose, or a tooth. Localized pain is usually continuous.

Notable points on physical examination include the absence of findings suggesting an underlying disease, a normal neurologic examination, and frequently the presence of allodynia. Careful sensory testing, with special attention to dermatomal and peripheral nerve innervation, is required. Allodynia is present if pain is reported when lightly touching the skin or gently pinching a fold of skin. The border of the allodynia can vary dramatically and may occur in a glove-and-stocking distribution. Signs of autonomic dysfunction, especially coolness and cyanosis, may only be present after exercising the limb, or may become apparent if the limb is held in a dependent position for a few minutes. Many children have near total body allodynia but the face, genitalia, and breasts are frequently spared.

Diffuse Amplified Musculoskeletal Pain

In diffuse amplified musculoskeletal pain, the onset is usually more gradual and may be vague in location and character. Autonomic nervous system signs are absent, but affected children complain of poor sleep and depression more often than do those with localized pain. However, some children with diffuse amplified musculoskeletal pain initially have very localized pain, which may spread to involve the entire body. Children with diffuse amplified musculoskeletal pain frequently report a multiplicity of symptoms. The pain is often centrally located involving the back, chest, abdomen, and head, as well as the extremities.

Older criteria for fibromyalgia include counting painful points (although frequently called tender points, the patient needs to identify them as causing pain not just tenderness when 4 kg of pressure is applied) as outlined in Box 52-3 . Pressure should also be applied at control points such as the forehead, shin, and thumbnail to define the extent of the amplified pain. A number of children with diffuse amplified pain do not have the painful points of fibromyalgia, although they are otherwise indistinguishable.

Prolonged back pain in childhood may be due to a serious illness and should be carefully investigated. However, some children have nonorganic back pain, usually in conjunction with diffuse amplified musculoskeletal pain. Distinguishing signs include the axial loading test, distracted straight leg raising, passive rotation test, overreaction, and allodynia ( Table 52-1 ).

TABLE 52-1

Signs of Nonorganic Back Pain

Axial loading test A positive test occurs when back pain is reported while the examiner exerts downward pressure on the top of a standing patient’s head. Neck pain may be elicited and is not a positive test.
Distracted straight leg raising In a positive test, flexion of the hip causes back pain when the patient is supine but not when sitting.
Passive rotation test A positive test occurs when the patient reports back pain with passive rotation at the ankles and knees, keeping the pelvis, back, and shoulders in the same plane.
Overreaction Overreaction is defined as excessive wincing, muscle tremors, screaming, or collapsing with pain. “Excessive” is quite subjective and may vary based on age, mental status, cultural influences, or fear.
Allodynia Report of pain to light touch or a gentle pinch of the skin, usually with a border that varies on repeat testing.

Data from G. Waddell, J.A. McCulloch, E. Kummel, et al., Nonorganic physical signs in low-back pain, Spine 5 (1980) 117–125.

Laboratory Examination

After taking a history and performing an examination, the diagnosis of an amplified pain syndrome is often certain and no further investigations are required. It is unwise to make a diagnosis of a noninflammatory condition in a child with an abnormal blood count, or increased acute-phase reactants, unless the abnormalities can be clearly ascribed to an intercurrent illness. The most common “abnormal” test is a low-titer positive antinuclear antibody (1 : 40 to 1 : 160), which should be discounted if the clinical presentation is typical. There may be normal or slightly slowed nerve conduction velocity in patients with CRPS. Any laboratory testing should be done with caution because the more tests that are performed, the more likely is the occurrence of false positive results leading to unjustified doubt about the diagnosis, anxiety concerning more serious illnesses, and delay in initiating treatment.

Radiographic Examination

Imaging studies should be directed to rule in or out a specific diagnosis (e.g., plain radiographs or bone scintigraphy to exclude trauma or tumor and magnetic resonance imaging to exclude spinal cord lesions).

Radiographic findings are normal or demonstrate disuse osteoporosis depending on the duration and degree of disability; rarely children have the spotty osteoporosis that occurs in adults with CRPS. Technetium radionuclide bone scans are probably the most useful study if the diagnosis is in doubt. The most frequent abnormality is decreased radionuclide uptake in the affected limb. A normal study is evidence against an underlying bone disease such as osteomyelitis, osteoid osteoma, or a stress fracture, but abnormal scans are subject to differing interpretations, especially if the finding are subtle, because interobserver variation in reading mildly abnormal scans is common. Bone scintigraphy in adults with CRPS had a sensitivity of only 0.80 and a specificity of 0.73. Magnetic resonance images in children with localized amplified pain document regional bone marrow edema with T1-weighted images of low signal intensity and T2-weighted images with high signal intensity; it has been reported that MRI is more sensitive than scintigraphy; however, early in the disease course, there may be difficulty distinguishing between the edema of amplified musculoskeletal pain and the edema of trauma, including subtle fractures.


There is a dearth of information concerning the histopathology of connective or nerve tissues from children with amplified musculo­skeletal pain syndromes. Three children with CRPS had findings on biopsies of skin, muscle, and nerve consistent with ischemic injury. Endothelial swelling, basement membrane thickening and reduplication, and patchy fiber atrophy of muscle were observed. The author had one patient with CRPS with ischemic changes present in the synovium of her knee. Various abnormalities have been demonstrated in the muscles of adults with fibromyalgia although it is not clear that these are related to the etiology or are an effect of another process such as ischemia. Skin biopsies have shown decreased intra-epidural nerve fiber density interpreted as a small fiber neuropathy.

Differential Diagnoses

A number of other painful conditions should be considered in the evaluation of a child who may have an amplified musculoskeletal pain syndrome. Table 52-2 lists disorders that may be confused with amplified pain syndromes. In children with back pain, enthesitis-related arthritis is a consideration. The most common misdiagnoses for children who actually have an amplified pain syndrome are trauma, especially Salter-Harris I fractures, mechanical pain, or arthritis.

TABLE 52-2

Differential Diagnoses in Children Presenting with Marked Pain

Fabry disease Adolescents Episodic, excruciating, burning pain in the distal extremities; blue maculopapular, hyperkeratotic lesions clustered on the lower trunk and perineum; erythrocyte sedimentation rate is usually elevated
Neoplasia Any Episodic or migratory pain or arthritis, generalized malaise, anorexia, and bone pain
Spinal cord tumors Any Abnormal neurological examination, altered gait, or spinal curvature
Erythromelalgia Adolescents Pain with erythematous, warm, swollen hands or feet that is eased by cold to the point that patients refuse to remove ice or cold water from their affected limbs
Pernio (chilblains) Any Burning pain with associated red to purple, swollen papules on exposed fingers or toes after cold injury
Raynaud disease Adolescents Tricolor change (white, blue, red), associated with tingling; usually not very painful
Hypermobility Children Intermittent nocturnal pains that may occur after certain activities
Restless legs syndrome Adolescents Nocturnal discomfort in, and an inability to keep from moving, the legs; paresthesias, not pain per se, are common and rarely cause awakening
Myofascial pain Adolescents Sustained contraction of part of a muscle, especially those about the head, jaw, and upper back; pain well localized and reproduced when that part of the muscle is palpated
Chronic recurrent multifocal osteomyelitis Any Specific point tenderness
Chronic compartment syndrome Adolescents Severe muscle pain (usually calf) after exercising
Progressive diaphyseal dysplasia Adolescents Severe leg pain, fatigue, headaches, weight loss, weakness, and an abnormal, waddling gait; radiographs show cortical thickening and sclerosis of the diaphysis of the long bones
Peripheral mononeuropathy Adults Posttraumatic mononeuropathy
Transient migratory osteoporosis Adolescents Rapidly developing, painful osteoporosis
Vitamin D deficiency Adults Hyperesthetic pain in debilitated patients with multiple reasons to be deficient in vitamin D
Thyroid disease Any Widespread musculoskeletal pain with either hypothyroidism or hyperthyroidism with associated symptoms of thyroid dysfunction


The plethora of widely disparate treatments attests to the fact that there are no proven therapies demonstrated by well-controlled therapeutic trials in children with amplified musculoskeletal pain. Therefore, treatment is based largely on clinical experience and a very few larger patient series. Extrapolation of results from studies in adults to children is of limited value because children with CRPS or fibromyalgia significantly differ from adults with these disorders. Furthermore, a recent Cochrane review concluded that there was no high quality evidence for most therapies for adults with CRPS. When considering therapy for children with amplified pain syndromes, it is best to exercise great circumspection and consider the risks involved compared to more standard, conservative therapy.

Treatment has two goals: restoration of function and relief of pain. Although less than ideal, restoration to full function without total pain relief occasionally has to be accepted. Helping the child to develop skills to cope with the pain is often effective in relieving distress and dysfunction even if the pain persists.

Psychological Therapy and Support

Chronic pain significantly affects individual and family dynamics. All children and their families should have a psychological assessment to explore the individual and family psychodynamics and to address psychological issues that may exist. School issues, both social and academic, need to be explored. Therapy needs to address the family or marital dynamics. Cognitive-behavioral therapy (CBT) can help the child develop coping strategies to deal with pain and dysfunction.

Using progressive muscle relaxation and guided imagery, Walco and Ilowite treated five girls with fibromyalgia for four to nine sessions and four reported no pain an average of 10 months later. Gedalia et al. reported that only two of five children with fibromyalgia found CBT to be helpful. In a randomized controlled trial of CBT involving 114 children (half in an education group) Kashikar-Zuck et al. showed that both groups resolved depressive symptoms but there was no significant difference in sleep quality, physical activity, pain severity, or meaningful reduction in pain. Those treated with CBT, however, had a greater reduction in their Functional Disability Inventory (FDI) score, although final scores were in the moderately disabled range. fMRI data in adults suggests that CBT may alter pain pathways, however this was not shown by lower pain scores or pain sensitivity. It is the author’s experience that children benefit from CBT primarily as an adjunct to intense physical and occupational therapy and further psychotherapy and family therapy. More attention to family issues has been advocated (Sherry D.D., unpublished observation). Some children, especially those who have difficulty with verbal expression, may benefit from creative arts therapy such as music therapy or art therapy. A Cochrane review concluded that psychological treatments are effective for long-term pain control in children with headache and may improve pain control in children with musculoskeletal and recurrent abdominal pain, but there was little evidence available to estimate effects on disability or mood. Guite et al. found parental worry about their child’s physical health but not their emotional health fostered more functional disability and suggested education and support of the parents to reduce protective behaviors. Formal psychotherapy based on an initial psychological evaluation has been advocated by some. Children with fibromyalgia are less prone to depression than adults but have a higher incidence of anxiety that may interfere with function and may warrant psychiatric evaluation for medication.

Physical and Occupational Therapy

Physical and occupational therapy aimed at increasing function are recommended for all children ; however, patient response to various intensities of physiotherapy varies widely. Understanding that it is not physiologically damaging to use the affected limb enables some children to work through the pain, restore function, and resolve the pain without formal therapy. Others respond with home exercises or local physical therapy, whereas some others require a very intense program.

Bernstein et al. and others reported outstanding results in a large number of children with CRPS treated exclusively with physical and occupational therapy, without medication. In children who do not respond to limited treatment with physical and occupational therapy, a very rigorous program of 5 to 6 hours of daily therapy has been successful in children with CRPS and fibromyalgia. Using such a regimen, Sherry et al. reported a 92% success rate in 103 consecutive children with CRPS and over 5 years later, 88% were symptom free. Similar programs in Pittsburgh and Portland reported 32 children with CRPS in whom 89% became pain-free. Children with CRPS treated with physical and occupational therapy only had a relatively low relapse rate, and many were able to treat themselves if they relapsed, without needing subsequent formal treatment. Using a less rigorous therapy program together with pain medications Logan et al. reported significant improvement in Functional Disability Inventory (FDI) and decreased pain in 56 children with CRPS. A systematic review of adults with CRPS found strong evidence for the use of rehabilitation physical therapy interventions to reduce pain and improve function. However, there still remains a paucity of controlled trials of physical and occupational therapy in children with amplified musculoskeletal pain.

There are fewer reports of children with fibromyalgia being treated with intense physical and occupational therapy. A randomized con­trol pilot study of weekly aerobic training (n = 14) versus anaerobic (Qigong) training (n = 18) demonstrated a significant drop in pain rating in the aerobic training group compared to the anaerobic group. There were no exacerbations of fibromyalgia symptoms despite aerobic training. Nine children with fibromyalgia treated with 5 hours of physical and occupational therapy daily along with psychotherapy improved from severely debilitated (FDI 31) to normal (FDI 4), and their pain level dropped from 65 (with 100 being the highest) to 17.

Vierck and Thompson make a compelling argument that physical therapy in adults with fibromyalgia be first-line therapy based on its salubrious effects on muscle vasoconstriction, stress, depression, fatigue, concentration, and sleep. A meta-analysis by Kelley and Kelley confirms improved well-being in adults with fibromyalgia who exercise. A recent review of three evidence-based guidelines for management of fibromyalgia in adults emphasizes individualization of therapy, especially self-management strategies, including exercise and cognitive-behavioral techniques.

There are reports of the use of transcutaneous nerve stimulation (TENS) in small numbers of children with CRPS, but no controlled trials. In experimentally induced ischemic pain in normal volunteers, there was no difference between actual TENS and placebo.

There are no efficacy trials of acupuncture in children with amplified pain. Sham acupuncture was as effective and needle placement was not critical when treating 114 adults with fibromyalgia. Leo documented the successful use of electrical stimulation at several acupuncture sites together with physical therapy in a 10-year-old girl; However, the author has had several children report significantly increased pain after acupuncture (Sherry D.D., unpublished observation).

Medical Treatment

No drugs are approved for the treatment of amplified pain syndromes in children and most reports in pediatrics are single case studies or small series.

Tricyclic Antidepressants

Tricyclic antidepressants block the reuptake of serotonin and norepinephrine. Amitriptyline, and to a lesser extent, nortriptyline, have been used extensively in adults with fibromyalgia with mixed results. A recent systematic Cochrane review noted that there is no supportive unbiased evidence to substantiate its use. Initially, amitriptyline was proposed to restore normal sleep pattern because sleep studies in patients with fibromyalgia showed excessive α-δ sleep non–rapid eye movement (NREM). However, a placebo-controlled trial showed it had no effect on the NREM abnormalities. In an open label study of 175 adults with fibromyalgia, amitriptyline was equally effective as routine physical therapy over 6 months. Frequently, amitriptyline has been used in conjunction with other medications and procedures making it hard to discern its effect. It is important to note that a significant number of children will have electrocardiographic findings that contraindicate the use of amitriptyline. Side effects of amitriptyline include gastrointestinal upset, drowsiness, dizziness, weakness, insomnia, weight gain, and headaches as well as blurred vision, photosensitivity, and dry mouth. Young people taking tricyclic antidepressants need to be warned of the increased risk of suicide, especially initially, and monitored for this.

Other Antidepressants

Selective serotonin reuptake inhibitors, dual serotonin and noradrenalin reuptake inhibitors, and monoamine oxidase inhibitors have been tested in adults with fibromyalgia in randomized controlled trials. Uceyler et al. systematically reviewed these trials and found all the studies were limited by short durations (6-12 weeks) and that there was little evidence of superiority of one class of antidepressant over another. The mean improvement in pain was 26% and improvement in quality of life was 30%; generally these findings were independent of an effect on depression. They concluded that antidepressant medication can be recommended for the short term in adults, but there are no data regarding their long-term use. Side effects were common and may have interfered with the blinding and, in children and young adults, these medications are associated with increased risk of suicide.


The antiepileptics most commonly used for CRPS and fibromyalgia are gabapentin and pregabalin, although pregabalin is not presently approved for pediatric use. The mechanism of action is unknown, although pregabalin binds to calcium channels in the central nervous system and may act by reducing insular glutamatergic activity as evidenced by neuroimaging. A meta-analysis of both agents in fibromyalgia in adults concluded that pregabalin reduced pain by 30%, but that its use was limited by side effects, including dizziness, drowsiness, dry mouth, weight gain, and edema leading to one quarter of patients stopping therapy. Reports of gabapentin use in children are limited to a few case studies. A meta-analysis concluded that moderate to higher doses of pregabalin were effective in a minority of patients with fibromyalgia, and side effects were frequent. Roskell et al. systematically reviewed nine drugs (duloxetine, fluoxetine, gabapentin, milnacipran, pramipexole, pregabalin, amitriptyline, cyclobenzaprine, and tramadol plus acetaminophen) in adults with fibromyalgia and concluded that all were equally effective, but that milnacipran and pregabalin were more likely to be discontinued due to side effects. Topiramate, another anti-epileptic drug, was not shown to be effective in adult fibromyalgia.


Kubalek et al. reported the use of pamidronate in 29 adults with CRPS related to trauma, diabetes, drugs or cancer. The pain resolved in 86% in the short term. Resolution of pain in an 11-year-old patient treated with pamidronate and physical therapy has been reported. Neridronate was studied in a double blind placebo, controlled trial in 40 adults within 4 months of onset of CRPS and showed marked benefit at 40 days, but there was a surprisingly good initial response to placebo. A systematic review found strong evidence for the use of bisphosphonates used early in the disease course, but long-term studies are needed. There are concerns of serious side effects, including osteonecrosis of the jaw and optic neuritis.


Oral corticosteroids were reported by Ruggeri et al. to be without benefit in six children, although a small, randomized study in adults showed short term benefit in 13 adults with CRPS. A study of intrathecal methylprednisolone in CRPS was stopped early due to lack of effect. Many authors use corticosteroids in combination with other treatments, so it is difficult to discern any specific effect. Systemic and injected corticosteroids have too many side effects to recommend their use.


Cyclobenzaprine acts in the central nervous system to reduce tonic muscle activity probably due to actions on both the α and γ motor neurons. It is structurally related to the tricyclics. Eleven of 15 children (73%) with fibromyalgia judged cyclobenzaprine to be helpful but the durability of benefit was not reported. Another study reported that only three of 33 children with fibromyalgia indicated that they would recommend cyclobenzaprine to other individuals with similar pain. There has been an absence of reports studying the efficacy of cyclobenzaprine in children since the 1990s, and it is one among many poorly studied agents in adults.


Opioids should not be used in children with amplified pain. A recent Cochrane review concluded there is, at best, only equivocal evidence of the efficacy of opioids in adults with neuropathic pain. The author knows of two children who died following opioid use for the treatment of pain amplification, and several others who have required drug rehabilitation (Sherry D.D., personal observation).


Ketamine is an anesthetic agent that is an antagonist of the NMDA receptor, which may be activated and upregulated in the spinal cord in patients with chronic pain. However, it is associated with psychomimetic side effects; that is, it can produce hallucinations or paranoid delusions identical to psychotic symptoms. In a 12-week study of 60 patients with CRPS there was a significant decrease in pain at week 1 but by week 12 there was no difference between those receiving ketamine and those receiving placebo. Niesters et al. showed no difference between ketamine, morphine, and placebo in conditioned pain modulation using a cold water bath model in patients with neuropathic pain. Even when there is an initial response to ketamine, the duration of effect is brief (3-4 weeks). There is an increasing recognition of untoward effects, including hepatotoxicity and prolonged mania. Ketamine coma is not approved in the United States, is very controversial, and is unproven to have any lasting benefit. Side effects are significant, including paralysis, pneumonia, and pulmonary embolus.

Sympathetic Blocks and Sympathectomy

Sympathetic blockade, by a variety of agents and techniques, was frequently used in adults because it was thought that blocking the sympathetic overactivity would be curative. Sympathetic blocks have included guanethidine or reserpine blockades, lumbar, axillary, or stellate ganglion blocks, or sympathectomy (surgical, chemical, and radioablation). However, it was recognized not to have lasting effects and, in one report, results were felt to be good or lasting in only 7% of 273 patients treated with sympathetic blockade. In 55 adults, guanethidine blocks gave less than 10% significant long-term relief and 34% had significant side effects. There have been no specific studies of sympathetic blockade in children, but a Cochrane review found little evidence to support sympathetic blocks as standard of care in CRPS. Wilder emphasizes that sympathetic blocks should not be used to treat CRPS in children but, if used, should be in conjunction with physical therapy. Sympathetic blocks have been done for fibromyalgia and as there are individual cases of success, there are also cases of failure, such as a 14-year-old girl resistant to cortico­steroids, surgical ganglionic blockade, and sympathectomy.

Peripheral Nerve Blocks

Daudure et al. report 13 children treated with a peripheral block followed by a Bier block (intravenous regional anesthesia) and all did well at 2 months. Three patients (two children) had continuous peripheral blockade to allow for physical therapy with good results at 2 and 5 months in two patients, but one child continued receiving multiple medications. Side effects include seizures.

Epidural infusions

A variety of agents have been infused in the epidural space for treatment of amplified pain (usually CRPS), including baclofen, clonidine, morphine, ketamine, and bupivacaine. Patients in these case reports generally had unsatisfactory outcomes with minimal to moderate functional or pain benefit over repeated or prolonged (months) treatment. Untoward effects included sepsis in one child and epidural abscess in two children.

Spinal Cord Stimulators

Spinal cord stimulators are surgically implanted with leads in the epidural space at the level of the spinal cord determined by a trial procedure to decrease pain in the area of amplified pain. They are reported to transiently decrease pain but do not prevent the spread of CRPS. Wilder reported mild improvement or worsening of pain in 6 children. There is a high rate of migration of the leads as well as other complications. Olsson reported the use of spinal cord stimulators in seven children; two failed to have any benefit, one became infected, and the rest had prolonged relief and the stimulator was eventually removed. There have been no systematic reviews of spinal cord stimulators in the amplified pain syndromes; however, a Cochrane review of cancer-related pain concluded there was insufficient evidence to establish a role of spinal cord stimulators in treating refractory cancer-related pain.


Amputation has been performed in adults for intractable CRPS and although few get pain relief, the outcome is better in those with a high level of resilience. Amputation is extremely rarely indicated in children, perhaps in those with intractable infection as a complication of CRPS. The author has seen two children with CRPS with amputations; one was associated with Munchausen by proxy (Sherry D.D., personal observation).


A host of allopathic and nonallopathic therapies have been used to treat the various forms of amplified pain. There is no evidence of benefit, and none is recommended. Rodrigo found a large percentage of adults with fibromyalgia and irritable bowel syndrome to have celiac disease and reported that they improved on a gluten-free diet. Only one of 50 children with fibromyalgia was found to have celiac disease and she did not improve when on a gluten free diet. It is unlikely that amplified pain is due to a food sensitivity or dietary deficiency.


Sleep disturbance is frequently mentioned as an important aspect of childhood fibromyalgia, and good sleep hygiene ( Box 52-5 ) is always advocated; however, its value is uncertain. Low dose tricyclic antidepressant medication has been recommended to facilitate sleep initiation, but it is not helpful or needed in most children with fibromyalgia or other amplified musculoskeletal pain syndromes. It is well documented that children with fibromyalgia have altered α-δ sleep, which does not change with medication or even when they have no pain and sleep well. Increased periodic limb movements during sleep have been reported in one small series. It is the author’s experience that no specific treatment is necessary or indicated for the sleep disturbance. Even if children report not sleeping at all at night, it is rare that they fall asleep during school or during the daytime.

Jun 30, 2019 | Posted by in RHEUMATOLOGY | Comments Off on Pain Amplification Syndromes

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