Anna Quisel, MD

In last issue of the Journal of Family Practice, we discussed diagnosis of CRPS type 1 (“Complex regional pain syndrome underdiagnosed,” 2005; 54: 524–532). Once other conditions have been ruled out, a primary care practitioner can diagnose CRPS type 1 right in the office using clinical findings and the patient’s report of symptoms. Similarly, primary care practitioners can provide most of the best treatments for CRPS type 1. In fact, evidence indicates that no benefit has been proven from more invasive treatments such as sympathectomy which continue to be included in recommendations by experts.¹

Evidence for intervention less than compelling

A review of the literature on treating CRPS type 1 raises a question: is there any evidence that treatment makes a difference in outcomes that matter to patients, such as returning to work, regaining functionality of the affected limb, or resolution of pain? The large discrepancy between the high rates of CRPS type 1 documented in prospective studies of post-traumatic patients and the low rates of diagnosis of CRPS type 1 in actual practice suggests that most cases of CRPS type 1 resolve without being diagnosed and treated. This is not proven because, unfortunately, the natural history of persons diagnosed in the first 9 weeks after injury is not known.²

Are there benefits to early treatment?

From the clinician’s perspective, persons diagnosed with CRPS type 1 early appear more likely to respond to treatment. There is an “oft-quoted contention that results of early treatment will be better than those when the pain is treated late.”² Yet, the great majority of these patients may have improved just as readily without treatment. For the few cases of undiagnosed CRPS type 1 that will persist to become chronic and treatment resistant, it is unknown whether early treatment would have been preventive² or how clinicians could distinguish these cases early enough to target them for treatment.

Intriguing but limited data exist for using preventive therapies in all at-risk patients. One prospective cohort study documented a lower rate of CRPS type 1 in stroke patients who underwent early inpatient rehabilitation, compared with patients in earlier studies who rarely received early rehabilitation. This finding indirectly suggests a possible preventive effect of physical/occupational therapy (LOE: 3, cross-study comparison).³ Luckily, early inpatient rehabilitation in stroke patients has become the standard of care, which may prevent many cases of CRPS type 1 as a side effect.

It also appears that injury to a newly hemiplegic arm may contribute to the shoulder-hand syndrome; a study that alerted patients and care-takers to the risk of injury reduced the rate of shoulder hand syndrome from 27 to 8% (LOE: 2, lowerquality RCT).⁴ Among post-traumatic patients with wrist fracture, a double-blind randomized placebo controlled trial (n=115) of vitamin C 500 mg tabs initiated upon diagnosis of fracture and continued for 50 days resulted in a marked decrease of CRPS type 1 from 22% in the placebo group to 7% in the vitamin C group (relative risk=0.17) (LOE: 1, high-quality RCT).⁵ These results have not been tested in subsequent trials, however.

Guideline recommendations: Physical and psychological therapy, pain management

Many treatments for CRPS have been tried and are summarized without a systematic or evidence-based approach to the literature in a consensus statement released in 2002 by an interdisciplinary expert panel (LOE: 3, consensus guideline).¹ These guidelines suggest rapid initiation of multidisciplinary treatment with advancement to higher levels of intervention if no benefit from initial therapy occurs in 2 weeks. Simultaneous physical rehabilitation, psychological therapy, and pain management are recommended.

Rehabilitation through physical therapy and occupational therapy starts with desensitization and stress loading, progresses to increasing flexibility with gentle active range of motion and stretching, and eventually to normalization of use.

Psychological therapy starts with teaching patients that 1) pain sensations in CRPS type 1 do not indicate tissue damage, and 2) reactivation of the affected limb is important. With persistent symptoms, clinical psychological assessment is recommended, eventually followed by cognitive behavioral therapy.

Pain management starts with oral or topical medications typically used for other neuropathic pain conditions (eg, amitriptyline (Elavil), gabapentin (Neurontin), opioids, and nonsteroidal antidepressants). The guideline also recommends steroids, calcitonin, and alpha-1 adrenoceptor antagonists (terazosin [Hytrin] or phenoxybenzamine [Dibenzylene]). With persistent symptoms, intravenous regional sympathetic blocks (IRSBs) and somatic nerve blocks are recommended. According to the guideline, treatment for resistant cases may progress to epidural catheters for sympathetic blockade, spinal cord stimulation, intrathecal baclofen (Lioresal), or sympathectomy.¹

Reviews of medication trials show minimal effectiveness

Meta-analyses and systematic reviews of the literature reveal that many of the treatments recommended in the guidelines are minimally if at all effective, or have been inadequately researched.^6-12 This is particularly so concerning invasive therapies such as sympathetic ganglion block,¹³ sympathectomy,¹² and spinal cord stimulation^9,10 that introduce the possibility of adverse effects. Yet, evidence is equally sparse for common pain therapies in CRPS type 1, such as nonsteroidal anti-inflammatory drugs, antidepressants, opiates, or antiseizure medications.

Systematic review and meta-analysis of medication trials for CRPS only partially agree.^6-8,11 A 1999 systematic review concluded that oral corticosteroids demonstrated a consistent and long-term analgesic effect in CRPS.⁶ This review identified only limited data to suggest an analgesic effect from topical dimethylsulfoxide (DMSO), epidural clonidine and IRSB with ketanserin (not available in the US), and bretylium. The review concluded there was contradictory evidence of an analgesic effect from calcitonin or intravenous phentolamine and most likely no effect, and evidence against the effectiveness of guanethidine and reserpine IRSBs, and droperidol and atropine IRSBs.⁶

A 1995 systematic review of IRSBs concluded as well that overall there was no effect on pain, but a single RCT of each bretylium and ketanserin showed an analgesic effect.⁸ In a systematic review focused on upper extremity post-stroke CRPS (also known as shoulder-hand syndrome), 1 RCT was identified, and indicated that corticosteroids had an analgesic effect.¹¹ High-quality evidence for the use of intramuscular calcitonin was lacking.¹¹

Calcitonin may be one exception. A systematic review of medical treatment for CRPS type 1 identified 21 randomized trials, enough to undertake a statistical analysis of the analgesic effect of 4 types of treatment: sympathetic suppressors, guanethidine, intravenous regional blocks, and calcitonin.⁷ Of the 4, only calcitonin appeared to have a significant beneficial effect on pain.⁷

IV bisphosphonates show promise. More recently, intravenous bisphosphonates have demonstrated clinical and analgesic benefits in 2 small but high-quality RCTs.^14,15 Strikingly, short-term therapy of 3 to 10 days of IV alendronate (Fosamax) or clodronate (Bonefos) without adverse effects resulted in significant overall improvements for the duration of the 2 trials, 4 weeks¹⁴ and 180 days.¹⁵

Nonpharmacologic treatments

Nonmedical treatments that have been studied include spinal cord stimulation, physical therapy, occupational therapy, and acupuncture. Spinal cord stimulation demonstrated a modest long-term (2-year) reduction in pain and improvement in health related quality of life in 1 RCT,¹⁶ but with no improvement in patient functioning and a 34% rate of adverse occurrences.⁹ Similarly, physical therapy and occupational therapy have been studied only in 1 large RCT (n=135).

Treatment with physical therapy did decrease pain compared with occupational therapy and control therapy,¹⁷ but revealed no improvement in active range of motion with physical or occupational therapy compared with control therapy.¹⁷ Furthermore, physical therapy led only to uncertain diminishment of impairment when data were analyzed in 2 different ways, 1 of which showed a benefit of physical and occupational therapy over control treatment,¹⁸ 1 of which did not.¹⁹

Acupuncture demonstrated no improvement over sham treatment.²⁰

Applying the evidence: Medical treatment

Choose any of the therapies least likely to do harm and supported by evidence of efficacy: topical 50% DMSO cream (SOR: B), intravenous bisphosphonates (SOR: A), or limited courses of oral corticosteroids (SOR: B). Despite some contradictory findings in the literature,^6,17,18 other studies demonstrate that physical therapy^18,19 and calcitonin⁷ reduce pain, and neither is likely to cause harm (SOR: B).

Epidural clonidine injection,⁶ IRSB with bretylium,^6-8 and spinal cord stimulation^9,16 have demonstrated some efficacy, but due to the invasiveness of the treatments and the modest benefits, patients should be counseled carefully before initiating these therapies (SOR: B) (TABLE 1).

Therapies to avoid. Therapies to avoid due to lack of evidence, lack of efficacy, or likelihood of adverse outcomes include IV regional blocks with everything but bretylium,^6-8 sympathetic ganglion blocks with local anesthetics (very short duration of analgesia),¹³ systemic intravenous sympathetic inhibition,⁶ acupuncture,²⁰ and sympathectomy (SOR: B).¹²

TABLE 1
Effectiveness of treatments for CRPS type 1

Acknowledgments

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.

CORRESPONDING AUTHOR
Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: DrQuisel@comcast.net

In last issue of the Journal of Family Practice, we discussed diagnosis of CRPS type 1 (“Complex regional pain syndrome underdiagnosed,” 2005; 54: 524–532). Once other conditions have been ruled out, a primary care practitioner can diagnose CRPS type 1 right in the office using clinical findings and the patient’s report of symptoms. Similarly, primary care practitioners can provide most of the best treatments for CRPS type 1. In fact, evidence indicates that no benefit has been proven from more invasive treatments such as sympathectomy which continue to be included in recommendations by experts.¹

Evidence for intervention less than compelling

A review of the literature on treating CRPS type 1 raises a question: is there any evidence that treatment makes a difference in outcomes that matter to patients, such as returning to work, regaining functionality of the affected limb, or resolution of pain? The large discrepancy between the high rates of CRPS type 1 documented in prospective studies of post-traumatic patients and the low rates of diagnosis of CRPS type 1 in actual practice suggests that most cases of CRPS type 1 resolve without being diagnosed and treated. This is not proven because, unfortunately, the natural history of persons diagnosed in the first 9 weeks after injury is not known.²

Are there benefits to early treatment?

From the clinician’s perspective, persons diagnosed with CRPS type 1 early appear more likely to respond to treatment. There is an “oft-quoted contention that results of early treatment will be better than those when the pain is treated late.”² Yet, the great majority of these patients may have improved just as readily without treatment. For the few cases of undiagnosed CRPS type 1 that will persist to become chronic and treatment resistant, it is unknown whether early treatment would have been preventive² or how clinicians could distinguish these cases early enough to target them for treatment.

Intriguing but limited data exist for using preventive therapies in all at-risk patients. One prospective cohort study documented a lower rate of CRPS type 1 in stroke patients who underwent early inpatient rehabilitation, compared with patients in earlier studies who rarely received early rehabilitation. This finding indirectly suggests a possible preventive effect of physical/occupational therapy (LOE: 3, cross-study comparison).³ Luckily, early inpatient rehabilitation in stroke patients has become the standard of care, which may prevent many cases of CRPS type 1 as a side effect.

It also appears that injury to a newly hemiplegic arm may contribute to the shoulder-hand syndrome; a study that alerted patients and care-takers to the risk of injury reduced the rate of shoulder hand syndrome from 27 to 8% (LOE: 2, lowerquality RCT).⁴ Among post-traumatic patients with wrist fracture, a double-blind randomized placebo controlled trial (n=115) of vitamin C 500 mg tabs initiated upon diagnosis of fracture and continued for 50 days resulted in a marked decrease of CRPS type 1 from 22% in the placebo group to 7% in the vitamin C group (relative risk=0.17) (LOE: 1, high-quality RCT).⁵ These results have not been tested in subsequent trials, however.

Guideline recommendations: Physical and psychological therapy, pain management

Many treatments for CRPS have been tried and are summarized without a systematic or evidence-based approach to the literature in a consensus statement released in 2002 by an interdisciplinary expert panel (LOE: 3, consensus guideline).¹ These guidelines suggest rapid initiation of multidisciplinary treatment with advancement to higher levels of intervention if no benefit from initial therapy occurs in 2 weeks. Simultaneous physical rehabilitation, psychological therapy, and pain management are recommended.

Rehabilitation through physical therapy and occupational therapy starts with desensitization and stress loading, progresses to increasing flexibility with gentle active range of motion and stretching, and eventually to normalization of use.

Psychological therapy starts with teaching patients that 1) pain sensations in CRPS type 1 do not indicate tissue damage, and 2) reactivation of the affected limb is important. With persistent symptoms, clinical psychological assessment is recommended, eventually followed by cognitive behavioral therapy.

Pain management starts with oral or topical medications typically used for other neuropathic pain conditions (eg, amitriptyline (Elavil), gabapentin (Neurontin), opioids, and nonsteroidal antidepressants). The guideline also recommends steroids, calcitonin, and alpha-1 adrenoceptor antagonists (terazosin [Hytrin] or phenoxybenzamine [Dibenzylene]). With persistent symptoms, intravenous regional sympathetic blocks (IRSBs) and somatic nerve blocks are recommended. According to the guideline, treatment for resistant cases may progress to epidural catheters for sympathetic blockade, spinal cord stimulation, intrathecal baclofen (Lioresal), or sympathectomy.¹

Reviews of medication trials show minimal effectiveness

Meta-analyses and systematic reviews of the literature reveal that many of the treatments recommended in the guidelines are minimally if at all effective, or have been inadequately researched.^6-12 This is particularly so concerning invasive therapies such as sympathetic ganglion block,¹³ sympathectomy,¹² and spinal cord stimulation^9,10 that introduce the possibility of adverse effects. Yet, evidence is equally sparse for common pain therapies in CRPS type 1, such as nonsteroidal anti-inflammatory drugs, antidepressants, opiates, or antiseizure medications.

Systematic review and meta-analysis of medication trials for CRPS only partially agree.^6-8,11 A 1999 systematic review concluded that oral corticosteroids demonstrated a consistent and long-term analgesic effect in CRPS.⁶ This review identified only limited data to suggest an analgesic effect from topical dimethylsulfoxide (DMSO), epidural clonidine and IRSB with ketanserin (not available in the US), and bretylium. The review concluded there was contradictory evidence of an analgesic effect from calcitonin or intravenous phentolamine and most likely no effect, and evidence against the effectiveness of guanethidine and reserpine IRSBs, and droperidol and atropine IRSBs.⁶

A 1995 systematic review of IRSBs concluded as well that overall there was no effect on pain, but a single RCT of each bretylium and ketanserin showed an analgesic effect.⁸ In a systematic review focused on upper extremity post-stroke CRPS (also known as shoulder-hand syndrome), 1 RCT was identified, and indicated that corticosteroids had an analgesic effect.¹¹ High-quality evidence for the use of intramuscular calcitonin was lacking.¹¹

Calcitonin may be one exception. A systematic review of medical treatment for CRPS type 1 identified 21 randomized trials, enough to undertake a statistical analysis of the analgesic effect of 4 types of treatment: sympathetic suppressors, guanethidine, intravenous regional blocks, and calcitonin.⁷ Of the 4, only calcitonin appeared to have a significant beneficial effect on pain.⁷

IV bisphosphonates show promise. More recently, intravenous bisphosphonates have demonstrated clinical and analgesic benefits in 2 small but high-quality RCTs.^14,15 Strikingly, short-term therapy of 3 to 10 days of IV alendronate (Fosamax) or clodronate (Bonefos) without adverse effects resulted in significant overall improvements for the duration of the 2 trials, 4 weeks¹⁴ and 180 days.¹⁵

Nonpharmacologic treatments

Nonmedical treatments that have been studied include spinal cord stimulation, physical therapy, occupational therapy, and acupuncture. Spinal cord stimulation demonstrated a modest long-term (2-year) reduction in pain and improvement in health related quality of life in 1 RCT,¹⁶ but with no improvement in patient functioning and a 34% rate of adverse occurrences.⁹ Similarly, physical therapy and occupational therapy have been studied only in 1 large RCT (n=135).

Treatment with physical therapy did decrease pain compared with occupational therapy and control therapy,¹⁷ but revealed no improvement in active range of motion with physical or occupational therapy compared with control therapy.¹⁷ Furthermore, physical therapy led only to uncertain diminishment of impairment when data were analyzed in 2 different ways, 1 of which showed a benefit of physical and occupational therapy over control treatment,¹⁸ 1 of which did not.¹⁹

Acupuncture demonstrated no improvement over sham treatment.²⁰

Applying the evidence: Medical treatment

Choose any of the therapies least likely to do harm and supported by evidence of efficacy: topical 50% DMSO cream (SOR: B), intravenous bisphosphonates (SOR: A), or limited courses of oral corticosteroids (SOR: B). Despite some contradictory findings in the literature,^6,17,18 other studies demonstrate that physical therapy^18,19 and calcitonin⁷ reduce pain, and neither is likely to cause harm (SOR: B).

Epidural clonidine injection,⁶ IRSB with bretylium,^6-8 and spinal cord stimulation^9,16 have demonstrated some efficacy, but due to the invasiveness of the treatments and the modest benefits, patients should be counseled carefully before initiating these therapies (SOR: B) (TABLE 1).

Therapies to avoid. Therapies to avoid due to lack of evidence, lack of efficacy, or likelihood of adverse outcomes include IV regional blocks with everything but bretylium,^6-8 sympathetic ganglion blocks with local anesthetics (very short duration of analgesia),¹³ systemic intravenous sympathetic inhibition,⁶ acupuncture,²⁰ and sympathectomy (SOR: B).¹²

TABLE 1
Effectiveness of treatments for CRPS type 1

Acknowledgments

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.

CORRESPONDING AUTHOR
Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: DrQuisel@comcast.net

In last issue of the Journal of Family Practice, we discussed diagnosis of CRPS type 1 (“Complex regional pain syndrome underdiagnosed,” 2005; 54: 524–532). Once other conditions have been ruled out, a primary care practitioner can diagnose CRPS type 1 right in the office using clinical findings and the patient’s report of symptoms. Similarly, primary care practitioners can provide most of the best treatments for CRPS type 1. In fact, evidence indicates that no benefit has been proven from more invasive treatments such as sympathectomy which continue to be included in recommendations by experts.¹

Evidence for intervention less than compelling

A review of the literature on treating CRPS type 1 raises a question: is there any evidence that treatment makes a difference in outcomes that matter to patients, such as returning to work, regaining functionality of the affected limb, or resolution of pain? The large discrepancy between the high rates of CRPS type 1 documented in prospective studies of post-traumatic patients and the low rates of diagnosis of CRPS type 1 in actual practice suggests that most cases of CRPS type 1 resolve without being diagnosed and treated. This is not proven because, unfortunately, the natural history of persons diagnosed in the first 9 weeks after injury is not known.²

Are there benefits to early treatment?

From the clinician’s perspective, persons diagnosed with CRPS type 1 early appear more likely to respond to treatment. There is an “oft-quoted contention that results of early treatment will be better than those when the pain is treated late.”² Yet, the great majority of these patients may have improved just as readily without treatment. For the few cases of undiagnosed CRPS type 1 that will persist to become chronic and treatment resistant, it is unknown whether early treatment would have been preventive² or how clinicians could distinguish these cases early enough to target them for treatment.

Intriguing but limited data exist for using preventive therapies in all at-risk patients. One prospective cohort study documented a lower rate of CRPS type 1 in stroke patients who underwent early inpatient rehabilitation, compared with patients in earlier studies who rarely received early rehabilitation. This finding indirectly suggests a possible preventive effect of physical/occupational therapy (LOE: 3, cross-study comparison).³ Luckily, early inpatient rehabilitation in stroke patients has become the standard of care, which may prevent many cases of CRPS type 1 as a side effect.

It also appears that injury to a newly hemiplegic arm may contribute to the shoulder-hand syndrome; a study that alerted patients and care-takers to the risk of injury reduced the rate of shoulder hand syndrome from 27 to 8% (LOE: 2, lowerquality RCT).⁴ Among post-traumatic patients with wrist fracture, a double-blind randomized placebo controlled trial (n=115) of vitamin C 500 mg tabs initiated upon diagnosis of fracture and continued for 50 days resulted in a marked decrease of CRPS type 1 from 22% in the placebo group to 7% in the vitamin C group (relative risk=0.17) (LOE: 1, high-quality RCT).⁵ These results have not been tested in subsequent trials, however.

Guideline recommendations: Physical and psychological therapy, pain management

Many treatments for CRPS have been tried and are summarized without a systematic or evidence-based approach to the literature in a consensus statement released in 2002 by an interdisciplinary expert panel (LOE: 3, consensus guideline).¹ These guidelines suggest rapid initiation of multidisciplinary treatment with advancement to higher levels of intervention if no benefit from initial therapy occurs in 2 weeks. Simultaneous physical rehabilitation, psychological therapy, and pain management are recommended.

Rehabilitation through physical therapy and occupational therapy starts with desensitization and stress loading, progresses to increasing flexibility with gentle active range of motion and stretching, and eventually to normalization of use.

Psychological therapy starts with teaching patients that 1) pain sensations in CRPS type 1 do not indicate tissue damage, and 2) reactivation of the affected limb is important. With persistent symptoms, clinical psychological assessment is recommended, eventually followed by cognitive behavioral therapy.

Pain management starts with oral or topical medications typically used for other neuropathic pain conditions (eg, amitriptyline (Elavil), gabapentin (Neurontin), opioids, and nonsteroidal antidepressants). The guideline also recommends steroids, calcitonin, and alpha-1 adrenoceptor antagonists (terazosin [Hytrin] or phenoxybenzamine [Dibenzylene]). With persistent symptoms, intravenous regional sympathetic blocks (IRSBs) and somatic nerve blocks are recommended. According to the guideline, treatment for resistant cases may progress to epidural catheters for sympathetic blockade, spinal cord stimulation, intrathecal baclofen (Lioresal), or sympathectomy.¹

Reviews of medication trials show minimal effectiveness

Meta-analyses and systematic reviews of the literature reveal that many of the treatments recommended in the guidelines are minimally if at all effective, or have been inadequately researched.^6-12 This is particularly so concerning invasive therapies such as sympathetic ganglion block,¹³ sympathectomy,¹² and spinal cord stimulation^9,10 that introduce the possibility of adverse effects. Yet, evidence is equally sparse for common pain therapies in CRPS type 1, such as nonsteroidal anti-inflammatory drugs, antidepressants, opiates, or antiseizure medications.

Systematic review and meta-analysis of medication trials for CRPS only partially agree.^6-8,11 A 1999 systematic review concluded that oral corticosteroids demonstrated a consistent and long-term analgesic effect in CRPS.⁶ This review identified only limited data to suggest an analgesic effect from topical dimethylsulfoxide (DMSO), epidural clonidine and IRSB with ketanserin (not available in the US), and bretylium. The review concluded there was contradictory evidence of an analgesic effect from calcitonin or intravenous phentolamine and most likely no effect, and evidence against the effectiveness of guanethidine and reserpine IRSBs, and droperidol and atropine IRSBs.⁶

A 1995 systematic review of IRSBs concluded as well that overall there was no effect on pain, but a single RCT of each bretylium and ketanserin showed an analgesic effect.⁸ In a systematic review focused on upper extremity post-stroke CRPS (also known as shoulder-hand syndrome), 1 RCT was identified, and indicated that corticosteroids had an analgesic effect.¹¹ High-quality evidence for the use of intramuscular calcitonin was lacking.¹¹

Calcitonin may be one exception. A systematic review of medical treatment for CRPS type 1 identified 21 randomized trials, enough to undertake a statistical analysis of the analgesic effect of 4 types of treatment: sympathetic suppressors, guanethidine, intravenous regional blocks, and calcitonin.⁷ Of the 4, only calcitonin appeared to have a significant beneficial effect on pain.⁷

IV bisphosphonates show promise. More recently, intravenous bisphosphonates have demonstrated clinical and analgesic benefits in 2 small but high-quality RCTs.^14,15 Strikingly, short-term therapy of 3 to 10 days of IV alendronate (Fosamax) or clodronate (Bonefos) without adverse effects resulted in significant overall improvements for the duration of the 2 trials, 4 weeks¹⁴ and 180 days.¹⁵

Nonpharmacologic treatments

Nonmedical treatments that have been studied include spinal cord stimulation, physical therapy, occupational therapy, and acupuncture. Spinal cord stimulation demonstrated a modest long-term (2-year) reduction in pain and improvement in health related quality of life in 1 RCT,¹⁶ but with no improvement in patient functioning and a 34% rate of adverse occurrences.⁹ Similarly, physical therapy and occupational therapy have been studied only in 1 large RCT (n=135).

Treatment with physical therapy did decrease pain compared with occupational therapy and control therapy,¹⁷ but revealed no improvement in active range of motion with physical or occupational therapy compared with control therapy.¹⁷ Furthermore, physical therapy led only to uncertain diminishment of impairment when data were analyzed in 2 different ways, 1 of which showed a benefit of physical and occupational therapy over control treatment,¹⁸ 1 of which did not.¹⁹

Acupuncture demonstrated no improvement over sham treatment.²⁰

Applying the evidence: Medical treatment

Choose any of the therapies least likely to do harm and supported by evidence of efficacy: topical 50% DMSO cream (SOR: B), intravenous bisphosphonates (SOR: A), or limited courses of oral corticosteroids (SOR: B). Despite some contradictory findings in the literature,^6,17,18 other studies demonstrate that physical therapy^18,19 and calcitonin⁷ reduce pain, and neither is likely to cause harm (SOR: B).

Epidural clonidine injection,⁶ IRSB with bretylium,^6-8 and spinal cord stimulation^9,16 have demonstrated some efficacy, but due to the invasiveness of the treatments and the modest benefits, patients should be counseled carefully before initiating these therapies (SOR: B) (TABLE 1).

Therapies to avoid. Therapies to avoid due to lack of evidence, lack of efficacy, or likelihood of adverse outcomes include IV regional blocks with everything but bretylium,^6-8 sympathetic ganglion blocks with local anesthetics (very short duration of analgesia),¹³ systemic intravenous sympathetic inhibition,⁶ acupuncture,²⁰ and sympathectomy (SOR: B).¹²

TABLE 1
Effectiveness of treatments for CRPS type 1

Acknowledgments

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.

CORRESPONDING AUTHOR
Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: DrQuisel@comcast.net

Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free? The problem may be an under-recognized one—complex regional pain syndrome (CRPS) type 1, also known as reflex sympathetic dystrophy. The problem is also encountered in immobilized limbs of post-stroke patients.

Persons with persistent post-traumatic pain eventually diagnosed with CRPS type 1 often undergo unnecessary testing resulting in inappropriate or delayed treatment.¹

Signs and symptoms typical of CRPS type 1 can also occur transiently with a normally recovering immobilized limb,^2,3 so diagnosis of CRPS type 1 is based on increasing severity and duration of signs and symptoms (level of evidence [LOE]: 3; consensus guidelines)⁴:

• pain
• hyperalgesia/allodynia (pain or exaggerated response resulting from a normally painless or only slightly painful stimulus)
• joint stiffness
• swelling
• autonomic abnormalities (often sweating and temperature differences compared with the unaffected limb).

Diagnosis: Watch recovery course over first 9 weeks

Clinicians face a number of challenges in diagnosing CRPS type 1. No psychological or personality traits appear to predispose to CRPS type 1 (LOE: 2, lower-quality literature review).⁵ Fracture types and severity of injury among persons who develop CRPS type 1 are not significantly different from persons who recover normally (LOE: 2, case control studies).^6,7 The key is to remain alert to deviation from the normal course of recovery.

Studies have shown that 9 weeks post injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrist), and sweating or temperature changes in the injured limb may have CRPS type 1 (LOE: 2, case series and case control studies).^6,8 In a prospective case series (n=109), no new cases of CRPS type 1 developed beyond 9 weeks (LOE: 2, case series).⁸

Diagnostic criteria: No consensus

No one test identifies all persons with CRPS type 1. There is no objective gold standard for diagnosis.⁹ Instead, researchers and clinicians must rely on clinically derived diagnostic criteria. Unfortunately, despite the development of diagnostic criteria by the IASP in 1994 (TABLE 1),⁴ experts have not reached consensus on the best method of diagnosis, and several different sets of diagnostic criteria are used.^7,10

Initial IASP criteria.Of these, the 1994 IASP consensus-based diagnostic criteria appear to be most widely used in the litera- ture. These criteria were intended as a starting point, requiring validation through future clinical research.^4,11 In further studies using controls with neuropathic conditions, IASP criteria have demonstrated low specificity (TABLE 2 ).^11,12

Criteria refinements.Derived from 1 of these studies, Bruehl’s criteria were subsequently developed to improve the IASP criteria (TABLE 1).¹¹Several other sets of diagnostic criteria exist, but only Veldman’s criteria ( TABLE 1),¹³ which have been adopted as the standard in the Netherlands, have undergone further study.¹⁴ Studies of Bruehl’s and IASP criteria have measured specificity and sensitivity, and along with Veldman’s criteria, interobserver reliability (TABLE 2 ).^11,12,14,15 However, these numbers must be interpreted with care due to the absence of an objective and independent gold standard.

The absence of an objective gold standard does not mean CRPS type 1 is not a “real” disorder.¹² In developing diagnostic criteria for CRPS, the IASP turned to models developed for other conditions without objectively measurable findings: the International Headache Society (IHS) classification and the Diagnostic and Statistical Manual of Mental Disorders (DSM). These descriptive systems are based largely on history and self-reported symptoms rather than on clinical signs and laboratory tests. The accuracy of these types of diagnostic criteria is refined over time, through repeated, controlled validation studies using the best means available.¹¹

Specificity of criteria. Specificity has been tested using controls with neuro-pathic conditions.^11,12 In these studies, nonblinded clinicians applied CRPS type 1 diagnostic criteria, except the exclusion criterion, to patients who had either CRPS type 1 or neuropathic pain from other causes. Many persons with peripheral neuropathy met criteria for CRPS type 1. However, as stated in the IASP criteria, the diagnosis of CRPS type 1 is not considered until common causes of neuropathic pain and post-traumatic limb pain have been excluded.⁴ As long as the primary care provider considers and rules out other causes of pain, the clinically relevant specificity of these criteria is likely much higher.

Sensitivity of criteria varies.The sensitivity in these studies is based on a non-independent reference standard. Patients with CRPS type 1 were chosen for these studies using clinical criteria, and these criteria were reapplied by study clinicians to determine sensitivity.^11,12 This method does not allow any determination of whether cases of CRPS type 1 might be missed by the criteria. Sensitivity measured in this way more closely resembles interobserver reliability—the likelihood that different clinicians using the same diagnostic criteria will reach the same diagnosis— and it appears quite good, especially for IASP criteria, in these 2 studies.^11,12

However, when interobserver reliability has been directly studied, albeit in small studies of 3 and 6 observers, only Veldman’s criteria achieve good reliability; IASP and Bruehl’s criteria appear unreliable ( TABLE 3).^15,16 However, IASP and Bruehl’s criteria do fall within the range of reliability of other clinical assessments including medical fitness for a job and shoulder disorders.¹⁵

TABLE 1
Diagnostic criteria for CRPS type 1*

TABLE 2
Accuracy of diagnostic criteria for CRPS type 1

TABLE 3
Interobserver reliability of diagnostic criteria for CRPS type 1

Factors undermining objective evaluation

Despite clinically based diagnostic criteria, researchers and physicians continue to use office, laboratory, and radiographic tests to diagnose CRPS type 1,^1,10 perhaps in an attempt to provide a more objective basis for the diagnosis. However, the evaluation of these methods has been plagued by difficulties.

First, because current clinical diagnostic criteria are not yet optimized or even standardized in the literature, there is no gold standard by which to measure the accuracy of these tests.

Second, patients in different studies have been diagnosed with CRPS type 1 by varying criteria.

Third, CRPS type 1 presents differently in different people, and symptoms and signs vary over time in the same person. As a result, the sets of diagnostic criteria have been designed with various clinical findings, and CRPS patients may meet only a few at any one time.

For example, if a group of CRPS type 1 patients were tested for sweating abnormalities, only 24% at best might be expected to test positive (see TABLE 4 for representative frequency of symptoms and signs),¹⁷ resulting in an apparent sensitivity of 24% for sweating abnormalities. This is why it is important for clinicians to consider patients’ report of typical signs even when these signs are not present on exam when making a diagnosis of CRPS type 1.

TABLE 4
Frequency of symptoms and clinically observed signs in CRPS type 1

Diagnostic instrumentation adds little

Some investigators have tried using instruments to measure the clinically apparent signs included in diagnostic criteria— volumetry to measure edema, thermometry to measure skin temperature differences, and resting sweat output (RSO) to measure sweating.

Confounding nature of CRPS 1. The value of these tests is limited by factors such as the duration of CRPS type 1, time of day, relaxation of the subject, ambient temperature, body temperature, and exact placement of the measuring device,^18,19 so it is not clear that objective measurement is practical or adds precision. In fact, in a study comparing testing to clinical diagnosis, instrumentation added little to the overall accuracy of diagnosing CRPS type 1 (LOE: 2, prospective cohort study).¹⁴

Sympathetic nerve block unhelpful. Other investigators have focused on testing to improve or replace clinical diagnostic criteria. Although at one time a response to sympathetic block was considered diagnostic for CRPS type 1,⁴ subsequent studies have demonstrated there is a significant placebo response to sympathetic block, that many persons with CRPS type 1 do not respond, and that some persons with other neuropathic pain conditions do respond. A negative or positive response to sympathetic block cannot rule CRPS type 1 in or out (LOE: 2, systematic reviews with only a few high-quality studies).^20-22

Radiographic findings add nothing. Bone scanning (scintigraphy) and radiography have been used frequently in the diagnosis of CRPS type 1. Although 3phase scintigraphy looking for different uptake of radioisotope between affected and unaffected limbs has been touted as an objective and definitive test for CRPS type 1,²³ this method also suffers from the subjective interpretation of the radiologist and poor interobserver reliability.²⁴ Researchers disagree on whether the typical appearance on scintigraphy is periarticular cuffing ^25,26 or diffuse uptake of radioisotope,²⁷ and about whether delayed phase scintigraphy is adequate ²⁶ or whether 3-phase scintigraphy is necessary.²⁷

To make the interpretation of these scans more objective, quantitative analysis of bone scans has been undertaken; however, subjective interpretation was required to decide where to measure the uptake and what degree of difference between affected and unaffected limbs was considered positive for CRPS type 1.²⁷

In 1 study, without mention of whether the radiologist was blinded but using an appropriate post-traumatic control group, sensitivity of 80% and specificity of 80% were reported (LOE: 2, casecontrol design).²⁷ In a cohort of persons with upper extremity pain, also without mention of blinding, sensitivity of 73% and specificity of 86% were reported (LOE: 2, cohort design).²⁵ Using normal controls, not a clinically relevant comparison, sensitivity of 97% and specificity of 86% using bone scans have been reported (LOE: 2, case control design).²⁶

Despite the reasonable sensitivity and specificity of the bone scans in these studies, clinical assessment was used as the gold standard for diagnosis and the bone scans did not add any degree of accuracy to that clinical assessment. Based on these studies, clinicians using a bone scan to rule in or rule out CRPS type 1 instead of using a clinical assessment risk missing up to 27% of cases and over-diagnosing 20% of cases.

Older literature suggested that osteopenia/porosis demonstrated on plain radiography or dual energy x-ray absorptiometry (DEXA) scanning was important for the diagnosis of CRPS type 1, but more recent studies have revealed sensitivity for plain radiography as low as 23% (LOE: 2, exploratory cohort study with good reference standards)¹³ and for DEXA a sensitivity of 76% (LOE: 2, case-control design).²⁸ No studies were identified that used a control group post-trauma, so an adequate assessment of specificity has not been made.

Applying the evidence in practice

CRPS type 1 is often relegated to specialists. But, in fact, no special equipment or testing is required for the diagnosis of CRPS type 1, and the best treatments appear to be non-invasive and completely within the realm of family medicine.

With more attention to deviations from the normal course of recovery from trauma, the family physician will begin to recognize more cases of CRPS type 1 and can have full confidence that the treatments prescribed and monitored are in fact the treatments of choice.

Preventing CRPS 1

For persons with hemiplegia, and of course early inpatient rehabilitation of post-stroke patients with upper extremity hemiplegia. Give 500 mg of vitamin C daily to post-fracture patients in the hope of preventing CRPS type 1 (SOR: B).

Base evaluation on history and physical exam

More often, the family physician will be in the position of evaluating persistent post-traumatic pain. Given the absence of compelling evidence in the literature, rely on your experience to guide the work up.

To diagnose CRPS type 1, first rule out other diseases (FIGURE).⁴ The frequency with which other conditions occur in persons at risk for CRPS type 1 is not known because the research concerning CRPS type 1 has been undertaken in specialty care clinics; primary care physicians had already done the work of excluding many other disorders.

Physical diagnosis. The differential diagnosis for limb pain is extensive and includes fracture non-union, tendonitis, diabetic neuropathy,⁴ osteomyelitis or cellulitis,¹³ polyneuropathy, radiculopathy,¹¹ phlebothrombosis,¹³ and Raynaud’s disease.¹³ Physical exam will reveal signs of infection, focal tenderness consistent with tendonitis, erythema suggestive of cellulitis, a distribution of pain following a nerve suggestive of radiculopathy or carpal tunnel syndrome, or the stocking-glove distribution diabetic neuropathy.

Auxiliary testing. Limited testing may be helpful. Plain radiography or bone scanning may identify a poorly healed fracture or other bony lesions. A white blood cell count and inflammatory markers may identify infection or autoimmune disorders.

Using the diagnostic criteria. Once other disorders have been ruled out, evidence does support the diagnosis of CRPS type 1 based on history and physical exam without further testing (SOR: B). In the absence of clear evidence supporting 1 set of criteria over the others, clinicians may use IASP, Bruehl’s, or Veldman’s clinical criteria for diagnosis (SOR: C). While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely the literature including treatment trials. The criteria (FIGURE) can also be combined to encompass their complementary aspects (SOR: C, this author’s opinion).

ACKNOWLEDGMENTS

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.

CORRESPONDING AUTHOR
Anna Quisel, MD, Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: bretandanna@comcast.net.

Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free? The problem may be an under-recognized one—complex regional pain syndrome (CRPS) type 1, also known as reflex sympathetic dystrophy. The problem is also encountered in immobilized limbs of post-stroke patients.

Persons with persistent post-traumatic pain eventually diagnosed with CRPS type 1 often undergo unnecessary testing resulting in inappropriate or delayed treatment.¹

Signs and symptoms typical of CRPS type 1 can also occur transiently with a normally recovering immobilized limb,^2,3 so diagnosis of CRPS type 1 is based on increasing severity and duration of signs and symptoms (level of evidence [LOE]: 3; consensus guidelines)⁴:

• pain
• hyperalgesia/allodynia (pain or exaggerated response resulting from a normally painless or only slightly painful stimulus)
• joint stiffness
• swelling
• autonomic abnormalities (often sweating and temperature differences compared with the unaffected limb).

Diagnosis: Watch recovery course over first 9 weeks

Clinicians face a number of challenges in diagnosing CRPS type 1. No psychological or personality traits appear to predispose to CRPS type 1 (LOE: 2, lower-quality literature review).⁵ Fracture types and severity of injury among persons who develop CRPS type 1 are not significantly different from persons who recover normally (LOE: 2, case control studies).^6,7 The key is to remain alert to deviation from the normal course of recovery.

Studies have shown that 9 weeks post injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrist), and sweating or temperature changes in the injured limb may have CRPS type 1 (LOE: 2, case series and case control studies).^6,8 In a prospective case series (n=109), no new cases of CRPS type 1 developed beyond 9 weeks (LOE: 2, case series).⁸

Diagnostic criteria: No consensus

No one test identifies all persons with CRPS type 1. There is no objective gold standard for diagnosis.⁹ Instead, researchers and clinicians must rely on clinically derived diagnostic criteria. Unfortunately, despite the development of diagnostic criteria by the IASP in 1994 (TABLE 1),⁴ experts have not reached consensus on the best method of diagnosis, and several different sets of diagnostic criteria are used.^7,10

Initial IASP criteria.Of these, the 1994 IASP consensus-based diagnostic criteria appear to be most widely used in the litera- ture. These criteria were intended as a starting point, requiring validation through future clinical research.^4,11 In further studies using controls with neuropathic conditions, IASP criteria have demonstrated low specificity (TABLE 2 ).^11,12

Criteria refinements.Derived from 1 of these studies, Bruehl’s criteria were subsequently developed to improve the IASP criteria (TABLE 1).¹¹Several other sets of diagnostic criteria exist, but only Veldman’s criteria ( TABLE 1),¹³ which have been adopted as the standard in the Netherlands, have undergone further study.¹⁴ Studies of Bruehl’s and IASP criteria have measured specificity and sensitivity, and along with Veldman’s criteria, interobserver reliability (TABLE 2 ).^11,12,14,15 However, these numbers must be interpreted with care due to the absence of an objective and independent gold standard.

The absence of an objective gold standard does not mean CRPS type 1 is not a “real” disorder.¹² In developing diagnostic criteria for CRPS, the IASP turned to models developed for other conditions without objectively measurable findings: the International Headache Society (IHS) classification and the Diagnostic and Statistical Manual of Mental Disorders (DSM). These descriptive systems are based largely on history and self-reported symptoms rather than on clinical signs and laboratory tests. The accuracy of these types of diagnostic criteria is refined over time, through repeated, controlled validation studies using the best means available.¹¹

Specificity of criteria. Specificity has been tested using controls with neuro-pathic conditions.^11,12 In these studies, nonblinded clinicians applied CRPS type 1 diagnostic criteria, except the exclusion criterion, to patients who had either CRPS type 1 or neuropathic pain from other causes. Many persons with peripheral neuropathy met criteria for CRPS type 1. However, as stated in the IASP criteria, the diagnosis of CRPS type 1 is not considered until common causes of neuropathic pain and post-traumatic limb pain have been excluded.⁴ As long as the primary care provider considers and rules out other causes of pain, the clinically relevant specificity of these criteria is likely much higher.

Sensitivity of criteria varies.The sensitivity in these studies is based on a non-independent reference standard. Patients with CRPS type 1 were chosen for these studies using clinical criteria, and these criteria were reapplied by study clinicians to determine sensitivity.^11,12 This method does not allow any determination of whether cases of CRPS type 1 might be missed by the criteria. Sensitivity measured in this way more closely resembles interobserver reliability—the likelihood that different clinicians using the same diagnostic criteria will reach the same diagnosis— and it appears quite good, especially for IASP criteria, in these 2 studies.^11,12

However, when interobserver reliability has been directly studied, albeit in small studies of 3 and 6 observers, only Veldman’s criteria achieve good reliability; IASP and Bruehl’s criteria appear unreliable ( TABLE 3).^15,16 However, IASP and Bruehl’s criteria do fall within the range of reliability of other clinical assessments including medical fitness for a job and shoulder disorders.¹⁵

TABLE 1
Diagnostic criteria for CRPS type 1*

TABLE 2
Accuracy of diagnostic criteria for CRPS type 1

TABLE 3
Interobserver reliability of diagnostic criteria for CRPS type 1

Factors undermining objective evaluation

Despite clinically based diagnostic criteria, researchers and physicians continue to use office, laboratory, and radiographic tests to diagnose CRPS type 1,^1,10 perhaps in an attempt to provide a more objective basis for the diagnosis. However, the evaluation of these methods has been plagued by difficulties.

First, because current clinical diagnostic criteria are not yet optimized or even standardized in the literature, there is no gold standard by which to measure the accuracy of these tests.

Second, patients in different studies have been diagnosed with CRPS type 1 by varying criteria.

Third, CRPS type 1 presents differently in different people, and symptoms and signs vary over time in the same person. As a result, the sets of diagnostic criteria have been designed with various clinical findings, and CRPS patients may meet only a few at any one time.

For example, if a group of CRPS type 1 patients were tested for sweating abnormalities, only 24% at best might be expected to test positive (see TABLE 4 for representative frequency of symptoms and signs),¹⁷ resulting in an apparent sensitivity of 24% for sweating abnormalities. This is why it is important for clinicians to consider patients’ report of typical signs even when these signs are not present on exam when making a diagnosis of CRPS type 1.

TABLE 4
Frequency of symptoms and clinically observed signs in CRPS type 1

Diagnostic instrumentation adds little

Some investigators have tried using instruments to measure the clinically apparent signs included in diagnostic criteria— volumetry to measure edema, thermometry to measure skin temperature differences, and resting sweat output (RSO) to measure sweating.

Confounding nature of CRPS 1. The value of these tests is limited by factors such as the duration of CRPS type 1, time of day, relaxation of the subject, ambient temperature, body temperature, and exact placement of the measuring device,^18,19 so it is not clear that objective measurement is practical or adds precision. In fact, in a study comparing testing to clinical diagnosis, instrumentation added little to the overall accuracy of diagnosing CRPS type 1 (LOE: 2, prospective cohort study).¹⁴

Sympathetic nerve block unhelpful. Other investigators have focused on testing to improve or replace clinical diagnostic criteria. Although at one time a response to sympathetic block was considered diagnostic for CRPS type 1,⁴ subsequent studies have demonstrated there is a significant placebo response to sympathetic block, that many persons with CRPS type 1 do not respond, and that some persons with other neuropathic pain conditions do respond. A negative or positive response to sympathetic block cannot rule CRPS type 1 in or out (LOE: 2, systematic reviews with only a few high-quality studies).^20-22

Radiographic findings add nothing. Bone scanning (scintigraphy) and radiography have been used frequently in the diagnosis of CRPS type 1. Although 3phase scintigraphy looking for different uptake of radioisotope between affected and unaffected limbs has been touted as an objective and definitive test for CRPS type 1,²³ this method also suffers from the subjective interpretation of the radiologist and poor interobserver reliability.²⁴ Researchers disagree on whether the typical appearance on scintigraphy is periarticular cuffing ^25,26 or diffuse uptake of radioisotope,²⁷ and about whether delayed phase scintigraphy is adequate ²⁶ or whether 3-phase scintigraphy is necessary.²⁷

To make the interpretation of these scans more objective, quantitative analysis of bone scans has been undertaken; however, subjective interpretation was required to decide where to measure the uptake and what degree of difference between affected and unaffected limbs was considered positive for CRPS type 1.²⁷

In 1 study, without mention of whether the radiologist was blinded but using an appropriate post-traumatic control group, sensitivity of 80% and specificity of 80% were reported (LOE: 2, casecontrol design).²⁷ In a cohort of persons with upper extremity pain, also without mention of blinding, sensitivity of 73% and specificity of 86% were reported (LOE: 2, cohort design).²⁵ Using normal controls, not a clinically relevant comparison, sensitivity of 97% and specificity of 86% using bone scans have been reported (LOE: 2, case control design).²⁶

Despite the reasonable sensitivity and specificity of the bone scans in these studies, clinical assessment was used as the gold standard for diagnosis and the bone scans did not add any degree of accuracy to that clinical assessment. Based on these studies, clinicians using a bone scan to rule in or rule out CRPS type 1 instead of using a clinical assessment risk missing up to 27% of cases and over-diagnosing 20% of cases.

Older literature suggested that osteopenia/porosis demonstrated on plain radiography or dual energy x-ray absorptiometry (DEXA) scanning was important for the diagnosis of CRPS type 1, but more recent studies have revealed sensitivity for plain radiography as low as 23% (LOE: 2, exploratory cohort study with good reference standards)¹³ and for DEXA a sensitivity of 76% (LOE: 2, case-control design).²⁸ No studies were identified that used a control group post-trauma, so an adequate assessment of specificity has not been made.

Applying the evidence in practice

CRPS type 1 is often relegated to specialists. But, in fact, no special equipment or testing is required for the diagnosis of CRPS type 1, and the best treatments appear to be non-invasive and completely within the realm of family medicine.

With more attention to deviations from the normal course of recovery from trauma, the family physician will begin to recognize more cases of CRPS type 1 and can have full confidence that the treatments prescribed and monitored are in fact the treatments of choice.

Preventing CRPS 1

For persons with hemiplegia, and of course early inpatient rehabilitation of post-stroke patients with upper extremity hemiplegia. Give 500 mg of vitamin C daily to post-fracture patients in the hope of preventing CRPS type 1 (SOR: B).

Base evaluation on history and physical exam

More often, the family physician will be in the position of evaluating persistent post-traumatic pain. Given the absence of compelling evidence in the literature, rely on your experience to guide the work up.

To diagnose CRPS type 1, first rule out other diseases (FIGURE).⁴ The frequency with which other conditions occur in persons at risk for CRPS type 1 is not known because the research concerning CRPS type 1 has been undertaken in specialty care clinics; primary care physicians had already done the work of excluding many other disorders.

Physical diagnosis. The differential diagnosis for limb pain is extensive and includes fracture non-union, tendonitis, diabetic neuropathy,⁴ osteomyelitis or cellulitis,¹³ polyneuropathy, radiculopathy,¹¹ phlebothrombosis,¹³ and Raynaud’s disease.¹³ Physical exam will reveal signs of infection, focal tenderness consistent with tendonitis, erythema suggestive of cellulitis, a distribution of pain following a nerve suggestive of radiculopathy or carpal tunnel syndrome, or the stocking-glove distribution diabetic neuropathy.

Auxiliary testing. Limited testing may be helpful. Plain radiography or bone scanning may identify a poorly healed fracture or other bony lesions. A white blood cell count and inflammatory markers may identify infection or autoimmune disorders.

Using the diagnostic criteria. Once other disorders have been ruled out, evidence does support the diagnosis of CRPS type 1 based on history and physical exam without further testing (SOR: B). In the absence of clear evidence supporting 1 set of criteria over the others, clinicians may use IASP, Bruehl’s, or Veldman’s clinical criteria for diagnosis (SOR: C). While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely the literature including treatment trials. The criteria (FIGURE) can also be combined to encompass their complementary aspects (SOR: C, this author’s opinion).

ACKNOWLEDGMENTS

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.

CORRESPONDING AUTHOR
Anna Quisel, MD, Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: bretandanna@comcast.net.

Do you have a patient recovering from a limb fracture who is complaining of pain and tenderness long after most patients with a similar injury would be symptom free? The problem may be an under-recognized one—complex regional pain syndrome (CRPS) type 1, also known as reflex sympathetic dystrophy. The problem is also encountered in immobilized limbs of post-stroke patients.

Persons with persistent post-traumatic pain eventually diagnosed with CRPS type 1 often undergo unnecessary testing resulting in inappropriate or delayed treatment.¹

Signs and symptoms typical of CRPS type 1 can also occur transiently with a normally recovering immobilized limb,^2,3 so diagnosis of CRPS type 1 is based on increasing severity and duration of signs and symptoms (level of evidence [LOE]: 3; consensus guidelines)⁴:

• pain
• hyperalgesia/allodynia (pain or exaggerated response resulting from a normally painless or only slightly painful stimulus)
• joint stiffness
• swelling
• autonomic abnormalities (often sweating and temperature differences compared with the unaffected limb).

Diagnosis: Watch recovery course over first 9 weeks

Clinicians face a number of challenges in diagnosing CRPS type 1. No psychological or personality traits appear to predispose to CRPS type 1 (LOE: 2, lower-quality literature review).⁵ Fracture types and severity of injury among persons who develop CRPS type 1 are not significantly different from persons who recover normally (LOE: 2, case control studies).^6,7 The key is to remain alert to deviation from the normal course of recovery.

Studies have shown that 9 weeks post injury, persons with persistent pain, tenderness, swelling, joint stiffness (fingers and wrist), and sweating or temperature changes in the injured limb may have CRPS type 1 (LOE: 2, case series and case control studies).^6,8 In a prospective case series (n=109), no new cases of CRPS type 1 developed beyond 9 weeks (LOE: 2, case series).⁸

Diagnostic criteria: No consensus

No one test identifies all persons with CRPS type 1. There is no objective gold standard for diagnosis.⁹ Instead, researchers and clinicians must rely on clinically derived diagnostic criteria. Unfortunately, despite the development of diagnostic criteria by the IASP in 1994 (TABLE 1),⁴ experts have not reached consensus on the best method of diagnosis, and several different sets of diagnostic criteria are used.^7,10

Initial IASP criteria.Of these, the 1994 IASP consensus-based diagnostic criteria appear to be most widely used in the litera- ture. These criteria were intended as a starting point, requiring validation through future clinical research.^4,11 In further studies using controls with neuropathic conditions, IASP criteria have demonstrated low specificity (TABLE 2 ).^11,12

Criteria refinements.Derived from 1 of these studies, Bruehl’s criteria were subsequently developed to improve the IASP criteria (TABLE 1).¹¹Several other sets of diagnostic criteria exist, but only Veldman’s criteria ( TABLE 1),¹³ which have been adopted as the standard in the Netherlands, have undergone further study.¹⁴ Studies of Bruehl’s and IASP criteria have measured specificity and sensitivity, and along with Veldman’s criteria, interobserver reliability (TABLE 2 ).^11,12,14,15 However, these numbers must be interpreted with care due to the absence of an objective and independent gold standard.

The absence of an objective gold standard does not mean CRPS type 1 is not a “real” disorder.¹² In developing diagnostic criteria for CRPS, the IASP turned to models developed for other conditions without objectively measurable findings: the International Headache Society (IHS) classification and the Diagnostic and Statistical Manual of Mental Disorders (DSM). These descriptive systems are based largely on history and self-reported symptoms rather than on clinical signs and laboratory tests. The accuracy of these types of diagnostic criteria is refined over time, through repeated, controlled validation studies using the best means available.¹¹

Specificity of criteria. Specificity has been tested using controls with neuro-pathic conditions.^11,12 In these studies, nonblinded clinicians applied CRPS type 1 diagnostic criteria, except the exclusion criterion, to patients who had either CRPS type 1 or neuropathic pain from other causes. Many persons with peripheral neuropathy met criteria for CRPS type 1. However, as stated in the IASP criteria, the diagnosis of CRPS type 1 is not considered until common causes of neuropathic pain and post-traumatic limb pain have been excluded.⁴ As long as the primary care provider considers and rules out other causes of pain, the clinically relevant specificity of these criteria is likely much higher.

Sensitivity of criteria varies.The sensitivity in these studies is based on a non-independent reference standard. Patients with CRPS type 1 were chosen for these studies using clinical criteria, and these criteria were reapplied by study clinicians to determine sensitivity.^11,12 This method does not allow any determination of whether cases of CRPS type 1 might be missed by the criteria. Sensitivity measured in this way more closely resembles interobserver reliability—the likelihood that different clinicians using the same diagnostic criteria will reach the same diagnosis— and it appears quite good, especially for IASP criteria, in these 2 studies.^11,12

However, when interobserver reliability has been directly studied, albeit in small studies of 3 and 6 observers, only Veldman’s criteria achieve good reliability; IASP and Bruehl’s criteria appear unreliable ( TABLE 3).^15,16 However, IASP and Bruehl’s criteria do fall within the range of reliability of other clinical assessments including medical fitness for a job and shoulder disorders.¹⁵

TABLE 1
Diagnostic criteria for CRPS type 1*

TABLE 2
Accuracy of diagnostic criteria for CRPS type 1

TABLE 3
Interobserver reliability of diagnostic criteria for CRPS type 1

Factors undermining objective evaluation

Despite clinically based diagnostic criteria, researchers and physicians continue to use office, laboratory, and radiographic tests to diagnose CRPS type 1,^1,10 perhaps in an attempt to provide a more objective basis for the diagnosis. However, the evaluation of these methods has been plagued by difficulties.

First, because current clinical diagnostic criteria are not yet optimized or even standardized in the literature, there is no gold standard by which to measure the accuracy of these tests.

Second, patients in different studies have been diagnosed with CRPS type 1 by varying criteria.

Third, CRPS type 1 presents differently in different people, and symptoms and signs vary over time in the same person. As a result, the sets of diagnostic criteria have been designed with various clinical findings, and CRPS patients may meet only a few at any one time.

For example, if a group of CRPS type 1 patients were tested for sweating abnormalities, only 24% at best might be expected to test positive (see TABLE 4 for representative frequency of symptoms and signs),¹⁷ resulting in an apparent sensitivity of 24% for sweating abnormalities. This is why it is important for clinicians to consider patients’ report of typical signs even when these signs are not present on exam when making a diagnosis of CRPS type 1.

TABLE 4
Frequency of symptoms and clinically observed signs in CRPS type 1

Diagnostic instrumentation adds little

Some investigators have tried using instruments to measure the clinically apparent signs included in diagnostic criteria— volumetry to measure edema, thermometry to measure skin temperature differences, and resting sweat output (RSO) to measure sweating.

Confounding nature of CRPS 1. The value of these tests is limited by factors such as the duration of CRPS type 1, time of day, relaxation of the subject, ambient temperature, body temperature, and exact placement of the measuring device,^18,19 so it is not clear that objective measurement is practical or adds precision. In fact, in a study comparing testing to clinical diagnosis, instrumentation added little to the overall accuracy of diagnosing CRPS type 1 (LOE: 2, prospective cohort study).¹⁴

Sympathetic nerve block unhelpful. Other investigators have focused on testing to improve or replace clinical diagnostic criteria. Although at one time a response to sympathetic block was considered diagnostic for CRPS type 1,⁴ subsequent studies have demonstrated there is a significant placebo response to sympathetic block, that many persons with CRPS type 1 do not respond, and that some persons with other neuropathic pain conditions do respond. A negative or positive response to sympathetic block cannot rule CRPS type 1 in or out (LOE: 2, systematic reviews with only a few high-quality studies).^20-22

Radiographic findings add nothing. Bone scanning (scintigraphy) and radiography have been used frequently in the diagnosis of CRPS type 1. Although 3phase scintigraphy looking for different uptake of radioisotope between affected and unaffected limbs has been touted as an objective and definitive test for CRPS type 1,²³ this method also suffers from the subjective interpretation of the radiologist and poor interobserver reliability.²⁴ Researchers disagree on whether the typical appearance on scintigraphy is periarticular cuffing ^25,26 or diffuse uptake of radioisotope,²⁷ and about whether delayed phase scintigraphy is adequate ²⁶ or whether 3-phase scintigraphy is necessary.²⁷

To make the interpretation of these scans more objective, quantitative analysis of bone scans has been undertaken; however, subjective interpretation was required to decide where to measure the uptake and what degree of difference between affected and unaffected limbs was considered positive for CRPS type 1.²⁷

In 1 study, without mention of whether the radiologist was blinded but using an appropriate post-traumatic control group, sensitivity of 80% and specificity of 80% were reported (LOE: 2, casecontrol design).²⁷ In a cohort of persons with upper extremity pain, also without mention of blinding, sensitivity of 73% and specificity of 86% were reported (LOE: 2, cohort design).²⁵ Using normal controls, not a clinically relevant comparison, sensitivity of 97% and specificity of 86% using bone scans have been reported (LOE: 2, case control design).²⁶

Despite the reasonable sensitivity and specificity of the bone scans in these studies, clinical assessment was used as the gold standard for diagnosis and the bone scans did not add any degree of accuracy to that clinical assessment. Based on these studies, clinicians using a bone scan to rule in or rule out CRPS type 1 instead of using a clinical assessment risk missing up to 27% of cases and over-diagnosing 20% of cases.

Older literature suggested that osteopenia/porosis demonstrated on plain radiography or dual energy x-ray absorptiometry (DEXA) scanning was important for the diagnosis of CRPS type 1, but more recent studies have revealed sensitivity for plain radiography as low as 23% (LOE: 2, exploratory cohort study with good reference standards)¹³ and for DEXA a sensitivity of 76% (LOE: 2, case-control design).²⁸ No studies were identified that used a control group post-trauma, so an adequate assessment of specificity has not been made.

Applying the evidence in practice

CRPS type 1 is often relegated to specialists. But, in fact, no special equipment or testing is required for the diagnosis of CRPS type 1, and the best treatments appear to be non-invasive and completely within the realm of family medicine.

With more attention to deviations from the normal course of recovery from trauma, the family physician will begin to recognize more cases of CRPS type 1 and can have full confidence that the treatments prescribed and monitored are in fact the treatments of choice.

Preventing CRPS 1

For persons with hemiplegia, and of course early inpatient rehabilitation of post-stroke patients with upper extremity hemiplegia. Give 500 mg of vitamin C daily to post-fracture patients in the hope of preventing CRPS type 1 (SOR: B).

Base evaluation on history and physical exam

More often, the family physician will be in the position of evaluating persistent post-traumatic pain. Given the absence of compelling evidence in the literature, rely on your experience to guide the work up.

To diagnose CRPS type 1, first rule out other diseases (FIGURE).⁴ The frequency with which other conditions occur in persons at risk for CRPS type 1 is not known because the research concerning CRPS type 1 has been undertaken in specialty care clinics; primary care physicians had already done the work of excluding many other disorders.

Physical diagnosis. The differential diagnosis for limb pain is extensive and includes fracture non-union, tendonitis, diabetic neuropathy,⁴ osteomyelitis or cellulitis,¹³ polyneuropathy, radiculopathy,¹¹ phlebothrombosis,¹³ and Raynaud’s disease.¹³ Physical exam will reveal signs of infection, focal tenderness consistent with tendonitis, erythema suggestive of cellulitis, a distribution of pain following a nerve suggestive of radiculopathy or carpal tunnel syndrome, or the stocking-glove distribution diabetic neuropathy.

Auxiliary testing. Limited testing may be helpful. Plain radiography or bone scanning may identify a poorly healed fracture or other bony lesions. A white blood cell count and inflammatory markers may identify infection or autoimmune disorders.

Using the diagnostic criteria. Once other disorders have been ruled out, evidence does support the diagnosis of CRPS type 1 based on history and physical exam without further testing (SOR: B). In the absence of clear evidence supporting 1 set of criteria over the others, clinicians may use IASP, Bruehl’s, or Veldman’s clinical criteria for diagnosis (SOR: C). While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely the literature including treatment trials. The criteria (FIGURE) can also be combined to encompass their complementary aspects (SOR: C, this author’s opinion).

ACKNOWLEDGMENTS

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript, Dolores Moran and Diane Wolfe for their assistance in finding articles, and to Roger Rodrigue, MD for reviewing the manuscript. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.

CORRESPONDING AUTHOR
Anna Quisel, MD, Anna Quisel, MD, c/o Cheryl Mongillo, Family Medicine Center, 1401 Foulk Road, Wilmington, DE 19803. E-mail: bretandanna@comcast.net.

When a patient complains of pain “all over,” consider fibromyalgia, which typically causes a well-documented pattern of pain and characteristic points of tenderness observable on physical exam. Once alternative diagnoses have been ruled out, offer the patient a 2-pronged therapeutic regimen that has proven successful at moderately relieving symptoms.

First rule out concomitant or mimicking disorders

Consider the differential diagnosis carefully.¹ A person who meets the criteria for fibromyalgia may have yet another cause of chronic pain, such as rheumatoid arthritis, or may instead have a different treatable condition that mimics fibromyalgia.

Drug-induced myopathy. Pain suggestive of fibromyalgia should prompt a review of the patient’s medicines. Drug-induced myopathy may occur in persons taking colchicine, statins, corticosteroids, or antimalarial drugs.

Connective tissue, autoimmune, and rheumatologic disorders. Consider this group of disorders next. In 1 study, one fourth of persons referred to a rheumatology clinic with presumed fibromyalgia instead had a spondyloarthropathy.²

Dermatomyositis and polymyositis may present with muscle pain and tenderness but, unlike fibromyalgia, cause proximal muscle weakness.

Systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica can also lead to widespread pain.

Blood tests such as antinuclear antibody (ANA), C-reactive protein, or erythrocyte sedimentation rate (ESR) may prove helpful when a patient has a history of unexplained rashes, fever, weight loss, joint swelling, iritis, hepatitis, nephritis, or inflammatory back pain (onset before age 40, insidious onset, present for more than 3 months, associated with morning stiffness, improvement with exercise).³ In the absence of these signs, ANA, rheumatoid factor, and ESR testing in persons with fatigue and diffuse musculoskeletal pain have low positive predictive value.⁴ The rate of false-positive ANA results may be as high as 8% to 11%, especially at low titers.^5,6

Hypothyroidism. Widespread musculoskeletal pain has also been associated with hypothyroidism (level of evidence [LOE]: 2, case-control design),^7,8 supporting the inclusion of a thyroidstimulating hormone in the work-up of fibromyalgia (strength of recommendation [SOR]: B). More recent research suggests that musculoskeletal pain is more related to thyroid microsomal antibodies than to hypothyroidism,⁹ but there has been no further evaluation of antithyroid antibodies in persons with fibromyalgia.

Diagnosis: mostly by clinical judgment

Persons with fibromyalgia have widespread pain, often worst in the neck and trunk.¹ Additional symptoms include fatigue, morning stiffness, waking unrefreshed, paresthesias, and headache.^1,10-15 (See “The toll of fibromyalgia.”)

Accepted criteria

The diagnosis of fibromyalgia is based on 2 criteria:

1. A patient’s report of widespread pain (right and left sides of the body, above and below the waist, and including the axial skeleton) persisting for at least 3 months

2. The clinician’s identification of at least 11 of 18 potential tender points as specified in the American College of Rheumatology (ACR) 1990 Criteria for the Classification of Fibromyalgia (Figure) (LOE: 3, case-control design, nonindependent reference standard).¹

These criteria do not exclude persons with rheumatic diseases or other chronic pain conditions.^1,37-39

Caveats with the criteria

Despite these well-defined criteria, the diagnosis is not as clear-cut as it may appear. In 1990, the ACR convened a panel of 24 experts to define and standardize the diagnosis of fibromyalgia. The basis for this consensus was a group of 293 patients with fibromyalgia, each of whom had been assessed by one of the expert investigators according to “his or her usual method of diagnosis.” ¹

The investigators determined the unique characteristics of fibromyalgia by comparing the 293 cases to 265 controls who had other chronic pain conditions (eg, low back pain syndromes, neck pain syndromes, regional tendonitis, possible systemic lupus erythematosus, rheumatoid arthritis). The investigators considered a multitude of symptoms and signs including sleep disturbance, morning stiffness, paresthesias, irritable bowel syndrome, fatigue, and anxiety. Their conclusion was that widespread pain and tender points were the most sensitive (88.4%) and specific (81.1%) distinguishing criteria for fibromyalgia.¹

No reference standard. However, these calculations of sensitivity and specificity are less meaningful than in studies where an independent reference standard or gold standard is available. The ACR expert panel derived the criteria in a circular way using a nonindependent reference standard—ie, patients thought to have fibromyalgia compared with control patients thought not to have fibromyalgia. The expert panel essentially set the specificity of the criteria at 100%, since the specificity is based on the rate of false positives.

Furthermore, because there was no objective gold standard for determining who truly had fibromyalgia (and we do not yet have an independent biologic “test” for this condition), this panel could not determine whether additional symptoms or signs that should be considered in the diagnosis of fibromyalgia.

Biases, dubious representation? Unknown elements in this analysis are 1) how closely the reference population used to develop these criteria represents the true population of persons with fibromyalgia, and 2) the biases of the ACR experts. Finally, the positive and negative predictive values of these criteria will depend on the prevalence of fibromyalgia and other similar conditions.

Morbidity not predicted by criteria. In addition, the 1990 ACR criteria assume the number of tender points and degree of pain are directly proportional to overall morbidity; however, a person with fewer than 11 tender points may experience significant morbidity, indicating that the sensitivity of the criteria may be low.^40-42 As suggested by Wolfe in 1997, “the tender point count functions as a sedimentation rate for distress” in persons with chronic pain.⁴² Thus, the authors of the 1990 ACR study stated that ACR criteria should not be applied rigidly in diagnosing and treating fibromyalgia,⁴² leaving a large role for clinical judgment.

Subjective factors. A final difficulty with the diagnosis of fibromyalgia is its dependence on patient report and examiner technique.¹ In the 1990 ACR criteria, tender points were defined as a complaint of pain (or any more dramatic response) when an examiner applied 4 kg of pressure with the pulp of the thumb or first two or three fingers, calibrated with a dolorimeter (a device that can measure the amount and rate of pressure applied over a specified surface area).¹ It has been shown that practitioners require training to apply 4 kg of force with regularity.⁴³

However, applying exactly 4 kg of pressure may not be clinically important. Other studies have shown that finger palpation or dolorimetry identifies tender points with equal accuracy (LOE: 3, case-control design with non-independent reference standard).^44,45

Manual palpation

A controlled study of manual palpation was conducted to standardize the tender point survey described in the Figure. ⁴⁶ This method compares well with the ACR 1990 method, with a sensitivity of 88.6% and a specificity of 71.4%.⁴⁶

To speed up the examination, a particular sequence of palpating survey points was established, with the patient positioned as outlined in the Figure. Using the thumb pad of his/her dominant hand, each examiner applied 4 kg of pressure, at a rate of 1 kg per second, just once at each survey point. Examiners learned to apply the proper amount of pressure by standing a patient on a scale and watching the scale while pressing down perpendicularly on the trapezius survey point.

The examinee was seated throughout the exam, except when lying on the side for palpation of the trochanter and lying supine for palpation of the knee. A tender point was identified when the patient rated the pain resulting from palpation at least 2 out of 10 (0, no pain; 10 worst pain) (LOE: 3, case-control design, nonindependent reference standard).⁴⁶

Until a firm biologic basis for fibromyalgia is discovered and a true gold standard for testing is developed, the diagnosis of fibromyalgia will remain a matter of clinical judgment and convention (SOR: C).

Treatment

A diagnosis of fibromyalgia alone may result in health benefits. In a year-long study published in 1986, Cathey et al reported that among 81 persons diagnosed with fibromyalgia, hospitalization rates decreased in the year following diagnosis (LOE: 2, case-control design).⁴⁷

Treatments for fibromyalgia are numerous, ranging from balneotherapy (bathing) to low-energy laser therapy, and studies of interventions are often poorly designed, based on small numbers of patients, report nonstandardized outcomes, and yield conflicting results.⁴⁸

Two interventions—aerobic exercise and antidepressant therapy—appear to improve fibromyalgia.

Aerobic exercise

Though pain relief is insignificant with aerobic exercise, other positive effects are significant (SOR: A). A 2003 Cochrane review identified 7 high-quality studies of aerobic training, defined as: 1) frequency of 2 days per week; 2) intensity sufficient to achieve 40% to 85% of heart rate reserve, or 55% to 90% of predicted maximum heart rate; 3) duration of sessions 20 to 60 minutes, either continuously or intermittently throughout the day, using any mode of aerobic exercise; and 4) a total exercise period of at least 6 weeks (Table 1).⁴⁹

Improved functioning, tender-point threshold. Study subjects engaged in aerobic dancing, whole-body aerobics, stationary cycling, and walking. Persons who exercised improved in global well-being, physical function, and aerobic fitness (by about 17%), and raised the pain threshold of tender points (by about 35%).⁴⁹ Four of the studies were similar enough to be combined for meta-analysis, showing a statistically robust but modest reduction in tender-point threshold (LOE: 1).

Although it seems likely that pain or fatigue might increase at least initially with exercise, participants in the exercise groups were not deterred; the researchers pointed out that reporting of adverse effects of aerobic exercise appeared incomplete, but there was no significant difference in drop-out rates between the exercise (25.1%) and control groups (12.5%).⁴⁹

In the long-term studies (>6 months), improvements were noted up to 1 year after treatment ended but not after 4.5 years.⁴⁹ This Cochrane review further supports aerobic exercise as bring beneficial for persons with fibromyalgia.^50,51

Additional improvement measures. A similar systematic review concluded that although studies were too heterogeneous to draw final conclusions, preliminary data supported aerobic exercise (LOE: 2, with heterogeneous studies).⁵⁰ In another comprehensive meta-analysis of all treatments for fibromyalgia, heterogeneous treatment studies ranging from exercise to physical therapy were identified as physically-based treatments. The analysis revealed a positive effect on physical status (including tender-point index, grip strength, and physician global rating of pain symptoms), fibromyalgia symptoms (including self-reported fatigue and pain using visual analog scales), and psychological status (including measurements of the Hamilton Depression and Anxiety Scales), with no effect on daily functioning (including outcome measures such as the Fibromyalgia Impact Questionnaire [FIQ]) (LOE: 2, with heterogeneous studies).⁵¹

The authors noted that the magnitude of the positive effects of physically-based treatments on fibromyalgia were comparable with drug treatment judged effective for arthritis.⁵¹

TABLE 1
Aerobic exercise for fibromyalgia: the evidence

Less certain nonpharmacologic therapies

Other nonpharmacologic treatments for fibromyalgia are educational interventions, relaxation therapy, cognitive-behavioral therapy, and acupuncture. These therapies have undergone rigorous analysis, but studies have been too heterogeneous to allow for strong conclusions across the studies.⁵⁰

A recent Cochrane review concluded that although physical training plus education had a positive effect at long-term follow up, evidence is insufficient to recommend multidisciplinary rehabilitation, defined as the care of a physician plus psychological, social, and vocational interventions (SOR: C).⁵²

In contrast, other investigators have concluded that multidisciplinary treatment incorporating physically and psychologically based treatments was more successful than treatment with a single modality.⁵¹ A systematic review of acupuncture identified only 1 high-quality randomized controlled trial (Table 2), which did show some improvement in symptoms (SOR: C).⁵³

TABLE 2
Alternative nonpharmacologic therapies for fibromyalgia: the evidence

Therapy with antidepressants

Of all pharmacologic treatments, antidepressants have undergone the most thorough study. Although the optimal role of medications in fibromyalgia has not been delineated, 3 metaanalyses have reported that antidepressants, most commonly amitriptyline, reduce symptoms during treatment of a few months duration (SOR: A) (Table 3).^54,55

Any antidepressants. Pooled results from 13 studies (8 of tricyclics, 3 of selective serotonin reuptake inhibitors, 2 of s-adenosylmethionine) revealed a moderate effect on pain, sleep, and global well-being, and a mild effect on fatigue and number of trigger points.⁵⁴ The authors calculated that persons with fibromyalgia treated with antidepressants were 4 times more likely to improve than persons treated with placebo (number need to treat [NNT]=4). Adverse effects appeared insignificant but were poorly reported in the individual studies.

Tricyclics only. In another meta-analysis, 9 high-quality studies of tricyclic antidepressants (amitriptyline, dothiepin, clomipramine, maprotiline and cyclobenzaprine—classified by the authors as a tricyclic antidepressant) were analyzed for 7 outcomes (patient self-rating of pain, fatigue, stiffness, and sleep; the patient and physician global assessment of improvement; and tenderness of tender points). Significant responses were observed in 25% to 37% of patients. On meta-analysis, outcome measures improved moderately overall with tricyclic treatment, mostly in sleep and global assessment, least in stiffness and tenderness. Long-term safety (more than 8 weeks) and efficacy of tricyclic therapy for fibromyalgia have not been demonstrated.⁵⁵

Combined trials.A third meta-analysis demonstrated improvement when trials of different antidepressants were combined.⁵¹ By pooling studies of antidepressants (amitriptyline, dothiepin, fluoxetine, citalopram, and S-adenosylmethionine) improvements in physical status, fibromyalgia symptoms, and psychological status were found, with no improvement in daily functioning.⁵¹ Although the effect was smaller than physicallybased treatments, the effect size was still comparable to drug treatment for arthritis.⁵¹

Muscle relaxants (primarily cyclobenzaprine) and nonsteroidal anti-inflammatories have been studied, with no evidence of a positive effect.⁵¹ Thus, the best evidence currently supports the use of aerobic exercise and antidepressants, particularly tricyclics, for the treatment of fibromyalgia.

TABLE 3
Antidepressant therapy for fibromyalgia: the evidence

Instructions to patients, management follow-up

Persons with fibromyalgia should know that although specific symptoms, particularly pain, may be not be dramatically reduced with treatment, aerobic exercise and tricyclic antidepressants alleviate some symptoms with minimal adverse effects (SOR: A). Emphasize that these treatments have been shown to improve one’s ability to cope with fibromyalgia symptoms. The best-studied antidepressant for treating fibromyalgia is amitriptyline, usually given at 25 to 50 mg, nightly.

Exercise. Prescribe aerobic exercise, at least twice per week for 20 to 60 minutes, targeting a heart rate of 55% to 90% of the predicted maximum (180 beats per minute-age) (SOR: A). One caveat: aerobic exercise in the literature was usually supervised, so the ideal exercise regimen might be a fibromyalgia-specific program.

Medication. Consider a trial of amitriptyline, 25 to 50 mg every night, for up to 6 weeks (SOR A). A caveat: tricyclic antidepressants may also have significant side effects, which could outweigh moderate benefits. Moreover, treatment effectiveness beyond 2 months has not been proven. Therefore, longitudinal measurement of outcomes should be part of ongoing care.

Follow-up. Studies have not determined which measures are best to follow (see “Assessing treatment efficacy”), but they might include the following (SOR: C):

1. Pain (eg, visual analogue scale, pain drawings)
2. Number of tender points, and tenderness
3. Physical function (eg, cardiorespiratory fitness, self-reported physical function measured by the physical-impairment subscale of the FIQ,⁵⁶ strength)
4. Global well-being or perceived improvement (eg, physician-rated change, FIQ total score)
5. Self-efficacy (eg, Arthritis Self-efficacy Questionnaire)
6. Fatigue and sleep (eg, FIQ fatigsubscale, sleep visual analogue scale)
7. Psychological function (eg, FIQ subscales for depression and anxiety)
8. Ability to work
9. Health care consumption and costs.^47,50

Education or psychological coping strategies may also contribute positively to overall patient and family well-being. Consider education/psychological counseling (SOR: C) and acupuncture (SOR: B).

Acknowledgments

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript as well as Dolores Moran and Diane Wolf for their library assistance, and to James Newman, MD, rheumatologist, for his expert suggestions. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.of Health and Social Services, Division of Public Health.

Corresponding author
Anna Quisel, MD, c/o Cheryl Mongillo, Department of Family and Community Medicine, Christiana Care Health Systems, 1401 Foulk Road, Wilmington, DE 19803. E-mail: bretandanna@comcast.net.

When a patient complains of pain “all over,” consider fibromyalgia, which typically causes a well-documented pattern of pain and characteristic points of tenderness observable on physical exam. Once alternative diagnoses have been ruled out, offer the patient a 2-pronged therapeutic regimen that has proven successful at moderately relieving symptoms.

First rule out concomitant or mimicking disorders

Consider the differential diagnosis carefully.¹ A person who meets the criteria for fibromyalgia may have yet another cause of chronic pain, such as rheumatoid arthritis, or may instead have a different treatable condition that mimics fibromyalgia.

Drug-induced myopathy. Pain suggestive of fibromyalgia should prompt a review of the patient’s medicines. Drug-induced myopathy may occur in persons taking colchicine, statins, corticosteroids, or antimalarial drugs.

Connective tissue, autoimmune, and rheumatologic disorders. Consider this group of disorders next. In 1 study, one fourth of persons referred to a rheumatology clinic with presumed fibromyalgia instead had a spondyloarthropathy.²

Dermatomyositis and polymyositis may present with muscle pain and tenderness but, unlike fibromyalgia, cause proximal muscle weakness.

Systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica can also lead to widespread pain.

Blood tests such as antinuclear antibody (ANA), C-reactive protein, or erythrocyte sedimentation rate (ESR) may prove helpful when a patient has a history of unexplained rashes, fever, weight loss, joint swelling, iritis, hepatitis, nephritis, or inflammatory back pain (onset before age 40, insidious onset, present for more than 3 months, associated with morning stiffness, improvement with exercise).³ In the absence of these signs, ANA, rheumatoid factor, and ESR testing in persons with fatigue and diffuse musculoskeletal pain have low positive predictive value.⁴ The rate of false-positive ANA results may be as high as 8% to 11%, especially at low titers.^5,6

Hypothyroidism. Widespread musculoskeletal pain has also been associated with hypothyroidism (level of evidence [LOE]: 2, case-control design),^7,8 supporting the inclusion of a thyroidstimulating hormone in the work-up of fibromyalgia (strength of recommendation [SOR]: B). More recent research suggests that musculoskeletal pain is more related to thyroid microsomal antibodies than to hypothyroidism,⁹ but there has been no further evaluation of antithyroid antibodies in persons with fibromyalgia.

Diagnosis: mostly by clinical judgment

Persons with fibromyalgia have widespread pain, often worst in the neck and trunk.¹ Additional symptoms include fatigue, morning stiffness, waking unrefreshed, paresthesias, and headache.^1,10-15 (See “The toll of fibromyalgia.”)

Accepted criteria

The diagnosis of fibromyalgia is based on 2 criteria:

1. A patient’s report of widespread pain (right and left sides of the body, above and below the waist, and including the axial skeleton) persisting for at least 3 months

2. The clinician’s identification of at least 11 of 18 potential tender points as specified in the American College of Rheumatology (ACR) 1990 Criteria for the Classification of Fibromyalgia (Figure) (LOE: 3, case-control design, nonindependent reference standard).¹

These criteria do not exclude persons with rheumatic diseases or other chronic pain conditions.^1,37-39

Caveats with the criteria

Despite these well-defined criteria, the diagnosis is not as clear-cut as it may appear. In 1990, the ACR convened a panel of 24 experts to define and standardize the diagnosis of fibromyalgia. The basis for this consensus was a group of 293 patients with fibromyalgia, each of whom had been assessed by one of the expert investigators according to “his or her usual method of diagnosis.” ¹

The investigators determined the unique characteristics of fibromyalgia by comparing the 293 cases to 265 controls who had other chronic pain conditions (eg, low back pain syndromes, neck pain syndromes, regional tendonitis, possible systemic lupus erythematosus, rheumatoid arthritis). The investigators considered a multitude of symptoms and signs including sleep disturbance, morning stiffness, paresthesias, irritable bowel syndrome, fatigue, and anxiety. Their conclusion was that widespread pain and tender points were the most sensitive (88.4%) and specific (81.1%) distinguishing criteria for fibromyalgia.¹

No reference standard. However, these calculations of sensitivity and specificity are less meaningful than in studies where an independent reference standard or gold standard is available. The ACR expert panel derived the criteria in a circular way using a nonindependent reference standard—ie, patients thought to have fibromyalgia compared with control patients thought not to have fibromyalgia. The expert panel essentially set the specificity of the criteria at 100%, since the specificity is based on the rate of false positives.

Furthermore, because there was no objective gold standard for determining who truly had fibromyalgia (and we do not yet have an independent biologic “test” for this condition), this panel could not determine whether additional symptoms or signs that should be considered in the diagnosis of fibromyalgia.

Biases, dubious representation? Unknown elements in this analysis are 1) how closely the reference population used to develop these criteria represents the true population of persons with fibromyalgia, and 2) the biases of the ACR experts. Finally, the positive and negative predictive values of these criteria will depend on the prevalence of fibromyalgia and other similar conditions.

Morbidity not predicted by criteria. In addition, the 1990 ACR criteria assume the number of tender points and degree of pain are directly proportional to overall morbidity; however, a person with fewer than 11 tender points may experience significant morbidity, indicating that the sensitivity of the criteria may be low.^40-42 As suggested by Wolfe in 1997, “the tender point count functions as a sedimentation rate for distress” in persons with chronic pain.⁴² Thus, the authors of the 1990 ACR study stated that ACR criteria should not be applied rigidly in diagnosing and treating fibromyalgia,⁴² leaving a large role for clinical judgment.

Subjective factors. A final difficulty with the diagnosis of fibromyalgia is its dependence on patient report and examiner technique.¹ In the 1990 ACR criteria, tender points were defined as a complaint of pain (or any more dramatic response) when an examiner applied 4 kg of pressure with the pulp of the thumb or first two or three fingers, calibrated with a dolorimeter (a device that can measure the amount and rate of pressure applied over a specified surface area).¹ It has been shown that practitioners require training to apply 4 kg of force with regularity.⁴³

However, applying exactly 4 kg of pressure may not be clinically important. Other studies have shown that finger palpation or dolorimetry identifies tender points with equal accuracy (LOE: 3, case-control design with non-independent reference standard).^44,45

Manual palpation

A controlled study of manual palpation was conducted to standardize the tender point survey described in the Figure. ⁴⁶ This method compares well with the ACR 1990 method, with a sensitivity of 88.6% and a specificity of 71.4%.⁴⁶

To speed up the examination, a particular sequence of palpating survey points was established, with the patient positioned as outlined in the Figure. Using the thumb pad of his/her dominant hand, each examiner applied 4 kg of pressure, at a rate of 1 kg per second, just once at each survey point. Examiners learned to apply the proper amount of pressure by standing a patient on a scale and watching the scale while pressing down perpendicularly on the trapezius survey point.

The examinee was seated throughout the exam, except when lying on the side for palpation of the trochanter and lying supine for palpation of the knee. A tender point was identified when the patient rated the pain resulting from palpation at least 2 out of 10 (0, no pain; 10 worst pain) (LOE: 3, case-control design, nonindependent reference standard).⁴⁶

Until a firm biologic basis for fibromyalgia is discovered and a true gold standard for testing is developed, the diagnosis of fibromyalgia will remain a matter of clinical judgment and convention (SOR: C).

Treatment

A diagnosis of fibromyalgia alone may result in health benefits. In a year-long study published in 1986, Cathey et al reported that among 81 persons diagnosed with fibromyalgia, hospitalization rates decreased in the year following diagnosis (LOE: 2, case-control design).⁴⁷

Treatments for fibromyalgia are numerous, ranging from balneotherapy (bathing) to low-energy laser therapy, and studies of interventions are often poorly designed, based on small numbers of patients, report nonstandardized outcomes, and yield conflicting results.⁴⁸

Two interventions—aerobic exercise and antidepressant therapy—appear to improve fibromyalgia.

Aerobic exercise

Though pain relief is insignificant with aerobic exercise, other positive effects are significant (SOR: A). A 2003 Cochrane review identified 7 high-quality studies of aerobic training, defined as: 1) frequency of 2 days per week; 2) intensity sufficient to achieve 40% to 85% of heart rate reserve, or 55% to 90% of predicted maximum heart rate; 3) duration of sessions 20 to 60 minutes, either continuously or intermittently throughout the day, using any mode of aerobic exercise; and 4) a total exercise period of at least 6 weeks (Table 1).⁴⁹

Improved functioning, tender-point threshold. Study subjects engaged in aerobic dancing, whole-body aerobics, stationary cycling, and walking. Persons who exercised improved in global well-being, physical function, and aerobic fitness (by about 17%), and raised the pain threshold of tender points (by about 35%).⁴⁹ Four of the studies were similar enough to be combined for meta-analysis, showing a statistically robust but modest reduction in tender-point threshold (LOE: 1).

Although it seems likely that pain or fatigue might increase at least initially with exercise, participants in the exercise groups were not deterred; the researchers pointed out that reporting of adverse effects of aerobic exercise appeared incomplete, but there was no significant difference in drop-out rates between the exercise (25.1%) and control groups (12.5%).⁴⁹

In the long-term studies (>6 months), improvements were noted up to 1 year after treatment ended but not after 4.5 years.⁴⁹ This Cochrane review further supports aerobic exercise as bring beneficial for persons with fibromyalgia.^50,51

Additional improvement measures. A similar systematic review concluded that although studies were too heterogeneous to draw final conclusions, preliminary data supported aerobic exercise (LOE: 2, with heterogeneous studies).⁵⁰ In another comprehensive meta-analysis of all treatments for fibromyalgia, heterogeneous treatment studies ranging from exercise to physical therapy were identified as physically-based treatments. The analysis revealed a positive effect on physical status (including tender-point index, grip strength, and physician global rating of pain symptoms), fibromyalgia symptoms (including self-reported fatigue and pain using visual analog scales), and psychological status (including measurements of the Hamilton Depression and Anxiety Scales), with no effect on daily functioning (including outcome measures such as the Fibromyalgia Impact Questionnaire [FIQ]) (LOE: 2, with heterogeneous studies).⁵¹

The authors noted that the magnitude of the positive effects of physically-based treatments on fibromyalgia were comparable with drug treatment judged effective for arthritis.⁵¹

TABLE 1
Aerobic exercise for fibromyalgia: the evidence

Less certain nonpharmacologic therapies

Other nonpharmacologic treatments for fibromyalgia are educational interventions, relaxation therapy, cognitive-behavioral therapy, and acupuncture. These therapies have undergone rigorous analysis, but studies have been too heterogeneous to allow for strong conclusions across the studies.⁵⁰

A recent Cochrane review concluded that although physical training plus education had a positive effect at long-term follow up, evidence is insufficient to recommend multidisciplinary rehabilitation, defined as the care of a physician plus psychological, social, and vocational interventions (SOR: C).⁵²

In contrast, other investigators have concluded that multidisciplinary treatment incorporating physically and psychologically based treatments was more successful than treatment with a single modality.⁵¹ A systematic review of acupuncture identified only 1 high-quality randomized controlled trial (Table 2), which did show some improvement in symptoms (SOR: C).⁵³

TABLE 2
Alternative nonpharmacologic therapies for fibromyalgia: the evidence

Therapy with antidepressants

Of all pharmacologic treatments, antidepressants have undergone the most thorough study. Although the optimal role of medications in fibromyalgia has not been delineated, 3 metaanalyses have reported that antidepressants, most commonly amitriptyline, reduce symptoms during treatment of a few months duration (SOR: A) (Table 3).^54,55

Any antidepressants. Pooled results from 13 studies (8 of tricyclics, 3 of selective serotonin reuptake inhibitors, 2 of s-adenosylmethionine) revealed a moderate effect on pain, sleep, and global well-being, and a mild effect on fatigue and number of trigger points.⁵⁴ The authors calculated that persons with fibromyalgia treated with antidepressants were 4 times more likely to improve than persons treated with placebo (number need to treat [NNT]=4). Adverse effects appeared insignificant but were poorly reported in the individual studies.

Tricyclics only. In another meta-analysis, 9 high-quality studies of tricyclic antidepressants (amitriptyline, dothiepin, clomipramine, maprotiline and cyclobenzaprine—classified by the authors as a tricyclic antidepressant) were analyzed for 7 outcomes (patient self-rating of pain, fatigue, stiffness, and sleep; the patient and physician global assessment of improvement; and tenderness of tender points). Significant responses were observed in 25% to 37% of patients. On meta-analysis, outcome measures improved moderately overall with tricyclic treatment, mostly in sleep and global assessment, least in stiffness and tenderness. Long-term safety (more than 8 weeks) and efficacy of tricyclic therapy for fibromyalgia have not been demonstrated.⁵⁵

Combined trials.A third meta-analysis demonstrated improvement when trials of different antidepressants were combined.⁵¹ By pooling studies of antidepressants (amitriptyline, dothiepin, fluoxetine, citalopram, and S-adenosylmethionine) improvements in physical status, fibromyalgia symptoms, and psychological status were found, with no improvement in daily functioning.⁵¹ Although the effect was smaller than physicallybased treatments, the effect size was still comparable to drug treatment for arthritis.⁵¹

Muscle relaxants (primarily cyclobenzaprine) and nonsteroidal anti-inflammatories have been studied, with no evidence of a positive effect.⁵¹ Thus, the best evidence currently supports the use of aerobic exercise and antidepressants, particularly tricyclics, for the treatment of fibromyalgia.

TABLE 3
Antidepressant therapy for fibromyalgia: the evidence

Instructions to patients, management follow-up

Persons with fibromyalgia should know that although specific symptoms, particularly pain, may be not be dramatically reduced with treatment, aerobic exercise and tricyclic antidepressants alleviate some symptoms with minimal adverse effects (SOR: A). Emphasize that these treatments have been shown to improve one’s ability to cope with fibromyalgia symptoms. The best-studied antidepressant for treating fibromyalgia is amitriptyline, usually given at 25 to 50 mg, nightly.

Exercise. Prescribe aerobic exercise, at least twice per week for 20 to 60 minutes, targeting a heart rate of 55% to 90% of the predicted maximum (180 beats per minute-age) (SOR: A). One caveat: aerobic exercise in the literature was usually supervised, so the ideal exercise regimen might be a fibromyalgia-specific program.

Medication. Consider a trial of amitriptyline, 25 to 50 mg every night, for up to 6 weeks (SOR A). A caveat: tricyclic antidepressants may also have significant side effects, which could outweigh moderate benefits. Moreover, treatment effectiveness beyond 2 months has not been proven. Therefore, longitudinal measurement of outcomes should be part of ongoing care.

Follow-up. Studies have not determined which measures are best to follow (see “Assessing treatment efficacy”), but they might include the following (SOR: C):

1. Pain (eg, visual analogue scale, pain drawings)
2. Number of tender points, and tenderness
3. Physical function (eg, cardiorespiratory fitness, self-reported physical function measured by the physical-impairment subscale of the FIQ,⁵⁶ strength)
4. Global well-being or perceived improvement (eg, physician-rated change, FIQ total score)
5. Self-efficacy (eg, Arthritis Self-efficacy Questionnaire)
6. Fatigue and sleep (eg, FIQ fatigsubscale, sleep visual analogue scale)
7. Psychological function (eg, FIQ subscales for depression and anxiety)
8. Ability to work
9. Health care consumption and costs.^47,50

Education or psychological coping strategies may also contribute positively to overall patient and family well-being. Consider education/psychological counseling (SOR: C) and acupuncture (SOR: B).

Acknowledgments

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript as well as Dolores Moran and Diane Wolf for their library assistance, and to James Newman, MD, rheumatologist, for his expert suggestions. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.of Health and Social Services, Division of Public Health.

Corresponding author
Anna Quisel, MD, c/o Cheryl Mongillo, Department of Family and Community Medicine, Christiana Care Health Systems, 1401 Foulk Road, Wilmington, DE 19803. E-mail: bretandanna@comcast.net.

When a patient complains of pain “all over,” consider fibromyalgia, which typically causes a well-documented pattern of pain and characteristic points of tenderness observable on physical exam. Once alternative diagnoses have been ruled out, offer the patient a 2-pronged therapeutic regimen that has proven successful at moderately relieving symptoms.

First rule out concomitant or mimicking disorders

Consider the differential diagnosis carefully.¹ A person who meets the criteria for fibromyalgia may have yet another cause of chronic pain, such as rheumatoid arthritis, or may instead have a different treatable condition that mimics fibromyalgia.

Drug-induced myopathy. Pain suggestive of fibromyalgia should prompt a review of the patient’s medicines. Drug-induced myopathy may occur in persons taking colchicine, statins, corticosteroids, or antimalarial drugs.

Connective tissue, autoimmune, and rheumatologic disorders. Consider this group of disorders next. In 1 study, one fourth of persons referred to a rheumatology clinic with presumed fibromyalgia instead had a spondyloarthropathy.²

Dermatomyositis and polymyositis may present with muscle pain and tenderness but, unlike fibromyalgia, cause proximal muscle weakness.

Systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica can also lead to widespread pain.

Blood tests such as antinuclear antibody (ANA), C-reactive protein, or erythrocyte sedimentation rate (ESR) may prove helpful when a patient has a history of unexplained rashes, fever, weight loss, joint swelling, iritis, hepatitis, nephritis, or inflammatory back pain (onset before age 40, insidious onset, present for more than 3 months, associated with morning stiffness, improvement with exercise).³ In the absence of these signs, ANA, rheumatoid factor, and ESR testing in persons with fatigue and diffuse musculoskeletal pain have low positive predictive value.⁴ The rate of false-positive ANA results may be as high as 8% to 11%, especially at low titers.^5,6

Hypothyroidism. Widespread musculoskeletal pain has also been associated with hypothyroidism (level of evidence [LOE]: 2, case-control design),^7,8 supporting the inclusion of a thyroidstimulating hormone in the work-up of fibromyalgia (strength of recommendation [SOR]: B). More recent research suggests that musculoskeletal pain is more related to thyroid microsomal antibodies than to hypothyroidism,⁹ but there has been no further evaluation of antithyroid antibodies in persons with fibromyalgia.

Diagnosis: mostly by clinical judgment

Persons with fibromyalgia have widespread pain, often worst in the neck and trunk.¹ Additional symptoms include fatigue, morning stiffness, waking unrefreshed, paresthesias, and headache.^1,10-15 (See “The toll of fibromyalgia.”)

Accepted criteria

The diagnosis of fibromyalgia is based on 2 criteria:

1. A patient’s report of widespread pain (right and left sides of the body, above and below the waist, and including the axial skeleton) persisting for at least 3 months

2. The clinician’s identification of at least 11 of 18 potential tender points as specified in the American College of Rheumatology (ACR) 1990 Criteria for the Classification of Fibromyalgia (Figure) (LOE: 3, case-control design, nonindependent reference standard).¹

These criteria do not exclude persons with rheumatic diseases or other chronic pain conditions.^1,37-39

Caveats with the criteria

Despite these well-defined criteria, the diagnosis is not as clear-cut as it may appear. In 1990, the ACR convened a panel of 24 experts to define and standardize the diagnosis of fibromyalgia. The basis for this consensus was a group of 293 patients with fibromyalgia, each of whom had been assessed by one of the expert investigators according to “his or her usual method of diagnosis.” ¹

The investigators determined the unique characteristics of fibromyalgia by comparing the 293 cases to 265 controls who had other chronic pain conditions (eg, low back pain syndromes, neck pain syndromes, regional tendonitis, possible systemic lupus erythematosus, rheumatoid arthritis). The investigators considered a multitude of symptoms and signs including sleep disturbance, morning stiffness, paresthesias, irritable bowel syndrome, fatigue, and anxiety. Their conclusion was that widespread pain and tender points were the most sensitive (88.4%) and specific (81.1%) distinguishing criteria for fibromyalgia.¹

No reference standard. However, these calculations of sensitivity and specificity are less meaningful than in studies where an independent reference standard or gold standard is available. The ACR expert panel derived the criteria in a circular way using a nonindependent reference standard—ie, patients thought to have fibromyalgia compared with control patients thought not to have fibromyalgia. The expert panel essentially set the specificity of the criteria at 100%, since the specificity is based on the rate of false positives.

Furthermore, because there was no objective gold standard for determining who truly had fibromyalgia (and we do not yet have an independent biologic “test” for this condition), this panel could not determine whether additional symptoms or signs that should be considered in the diagnosis of fibromyalgia.

Biases, dubious representation? Unknown elements in this analysis are 1) how closely the reference population used to develop these criteria represents the true population of persons with fibromyalgia, and 2) the biases of the ACR experts. Finally, the positive and negative predictive values of these criteria will depend on the prevalence of fibromyalgia and other similar conditions.

Morbidity not predicted by criteria. In addition, the 1990 ACR criteria assume the number of tender points and degree of pain are directly proportional to overall morbidity; however, a person with fewer than 11 tender points may experience significant morbidity, indicating that the sensitivity of the criteria may be low.^40-42 As suggested by Wolfe in 1997, “the tender point count functions as a sedimentation rate for distress” in persons with chronic pain.⁴² Thus, the authors of the 1990 ACR study stated that ACR criteria should not be applied rigidly in diagnosing and treating fibromyalgia,⁴² leaving a large role for clinical judgment.

Subjective factors. A final difficulty with the diagnosis of fibromyalgia is its dependence on patient report and examiner technique.¹ In the 1990 ACR criteria, tender points were defined as a complaint of pain (or any more dramatic response) when an examiner applied 4 kg of pressure with the pulp of the thumb or first two or three fingers, calibrated with a dolorimeter (a device that can measure the amount and rate of pressure applied over a specified surface area).¹ It has been shown that practitioners require training to apply 4 kg of force with regularity.⁴³

However, applying exactly 4 kg of pressure may not be clinically important. Other studies have shown that finger palpation or dolorimetry identifies tender points with equal accuracy (LOE: 3, case-control design with non-independent reference standard).^44,45

Manual palpation

A controlled study of manual palpation was conducted to standardize the tender point survey described in the Figure. ⁴⁶ This method compares well with the ACR 1990 method, with a sensitivity of 88.6% and a specificity of 71.4%.⁴⁶

To speed up the examination, a particular sequence of palpating survey points was established, with the patient positioned as outlined in the Figure. Using the thumb pad of his/her dominant hand, each examiner applied 4 kg of pressure, at a rate of 1 kg per second, just once at each survey point. Examiners learned to apply the proper amount of pressure by standing a patient on a scale and watching the scale while pressing down perpendicularly on the trapezius survey point.

The examinee was seated throughout the exam, except when lying on the side for palpation of the trochanter and lying supine for palpation of the knee. A tender point was identified when the patient rated the pain resulting from palpation at least 2 out of 10 (0, no pain; 10 worst pain) (LOE: 3, case-control design, nonindependent reference standard).⁴⁶

Until a firm biologic basis for fibromyalgia is discovered and a true gold standard for testing is developed, the diagnosis of fibromyalgia will remain a matter of clinical judgment and convention (SOR: C).

Treatment

A diagnosis of fibromyalgia alone may result in health benefits. In a year-long study published in 1986, Cathey et al reported that among 81 persons diagnosed with fibromyalgia, hospitalization rates decreased in the year following diagnosis (LOE: 2, case-control design).⁴⁷

Treatments for fibromyalgia are numerous, ranging from balneotherapy (bathing) to low-energy laser therapy, and studies of interventions are often poorly designed, based on small numbers of patients, report nonstandardized outcomes, and yield conflicting results.⁴⁸

Two interventions—aerobic exercise and antidepressant therapy—appear to improve fibromyalgia.

Aerobic exercise

Though pain relief is insignificant with aerobic exercise, other positive effects are significant (SOR: A). A 2003 Cochrane review identified 7 high-quality studies of aerobic training, defined as: 1) frequency of 2 days per week; 2) intensity sufficient to achieve 40% to 85% of heart rate reserve, or 55% to 90% of predicted maximum heart rate; 3) duration of sessions 20 to 60 minutes, either continuously or intermittently throughout the day, using any mode of aerobic exercise; and 4) a total exercise period of at least 6 weeks (Table 1).⁴⁹

Improved functioning, tender-point threshold. Study subjects engaged in aerobic dancing, whole-body aerobics, stationary cycling, and walking. Persons who exercised improved in global well-being, physical function, and aerobic fitness (by about 17%), and raised the pain threshold of tender points (by about 35%).⁴⁹ Four of the studies were similar enough to be combined for meta-analysis, showing a statistically robust but modest reduction in tender-point threshold (LOE: 1).

Although it seems likely that pain or fatigue might increase at least initially with exercise, participants in the exercise groups were not deterred; the researchers pointed out that reporting of adverse effects of aerobic exercise appeared incomplete, but there was no significant difference in drop-out rates between the exercise (25.1%) and control groups (12.5%).⁴⁹

In the long-term studies (>6 months), improvements were noted up to 1 year after treatment ended but not after 4.5 years.⁴⁹ This Cochrane review further supports aerobic exercise as bring beneficial for persons with fibromyalgia.^50,51

Additional improvement measures. A similar systematic review concluded that although studies were too heterogeneous to draw final conclusions, preliminary data supported aerobic exercise (LOE: 2, with heterogeneous studies).⁵⁰ In another comprehensive meta-analysis of all treatments for fibromyalgia, heterogeneous treatment studies ranging from exercise to physical therapy were identified as physically-based treatments. The analysis revealed a positive effect on physical status (including tender-point index, grip strength, and physician global rating of pain symptoms), fibromyalgia symptoms (including self-reported fatigue and pain using visual analog scales), and psychological status (including measurements of the Hamilton Depression and Anxiety Scales), with no effect on daily functioning (including outcome measures such as the Fibromyalgia Impact Questionnaire [FIQ]) (LOE: 2, with heterogeneous studies).⁵¹

The authors noted that the magnitude of the positive effects of physically-based treatments on fibromyalgia were comparable with drug treatment judged effective for arthritis.⁵¹

TABLE 1
Aerobic exercise for fibromyalgia: the evidence

Less certain nonpharmacologic therapies

Other nonpharmacologic treatments for fibromyalgia are educational interventions, relaxation therapy, cognitive-behavioral therapy, and acupuncture. These therapies have undergone rigorous analysis, but studies have been too heterogeneous to allow for strong conclusions across the studies.⁵⁰

A recent Cochrane review concluded that although physical training plus education had a positive effect at long-term follow up, evidence is insufficient to recommend multidisciplinary rehabilitation, defined as the care of a physician plus psychological, social, and vocational interventions (SOR: C).⁵²

In contrast, other investigators have concluded that multidisciplinary treatment incorporating physically and psychologically based treatments was more successful than treatment with a single modality.⁵¹ A systematic review of acupuncture identified only 1 high-quality randomized controlled trial (Table 2), which did show some improvement in symptoms (SOR: C).⁵³

TABLE 2
Alternative nonpharmacologic therapies for fibromyalgia: the evidence

Therapy with antidepressants

Of all pharmacologic treatments, antidepressants have undergone the most thorough study. Although the optimal role of medications in fibromyalgia has not been delineated, 3 metaanalyses have reported that antidepressants, most commonly amitriptyline, reduce symptoms during treatment of a few months duration (SOR: A) (Table 3).^54,55

Any antidepressants. Pooled results from 13 studies (8 of tricyclics, 3 of selective serotonin reuptake inhibitors, 2 of s-adenosylmethionine) revealed a moderate effect on pain, sleep, and global well-being, and a mild effect on fatigue and number of trigger points.⁵⁴ The authors calculated that persons with fibromyalgia treated with antidepressants were 4 times more likely to improve than persons treated with placebo (number need to treat [NNT]=4). Adverse effects appeared insignificant but were poorly reported in the individual studies.

Tricyclics only. In another meta-analysis, 9 high-quality studies of tricyclic antidepressants (amitriptyline, dothiepin, clomipramine, maprotiline and cyclobenzaprine—classified by the authors as a tricyclic antidepressant) were analyzed for 7 outcomes (patient self-rating of pain, fatigue, stiffness, and sleep; the patient and physician global assessment of improvement; and tenderness of tender points). Significant responses were observed in 25% to 37% of patients. On meta-analysis, outcome measures improved moderately overall with tricyclic treatment, mostly in sleep and global assessment, least in stiffness and tenderness. Long-term safety (more than 8 weeks) and efficacy of tricyclic therapy for fibromyalgia have not been demonstrated.⁵⁵

Combined trials.A third meta-analysis demonstrated improvement when trials of different antidepressants were combined.⁵¹ By pooling studies of antidepressants (amitriptyline, dothiepin, fluoxetine, citalopram, and S-adenosylmethionine) improvements in physical status, fibromyalgia symptoms, and psychological status were found, with no improvement in daily functioning.⁵¹ Although the effect was smaller than physicallybased treatments, the effect size was still comparable to drug treatment for arthritis.⁵¹

Muscle relaxants (primarily cyclobenzaprine) and nonsteroidal anti-inflammatories have been studied, with no evidence of a positive effect.⁵¹ Thus, the best evidence currently supports the use of aerobic exercise and antidepressants, particularly tricyclics, for the treatment of fibromyalgia.

TABLE 3
Antidepressant therapy for fibromyalgia: the evidence

Instructions to patients, management follow-up

Persons with fibromyalgia should know that although specific symptoms, particularly pain, may be not be dramatically reduced with treatment, aerobic exercise and tricyclic antidepressants alleviate some symptoms with minimal adverse effects (SOR: A). Emphasize that these treatments have been shown to improve one’s ability to cope with fibromyalgia symptoms. The best-studied antidepressant for treating fibromyalgia is amitriptyline, usually given at 25 to 50 mg, nightly.

Exercise. Prescribe aerobic exercise, at least twice per week for 20 to 60 minutes, targeting a heart rate of 55% to 90% of the predicted maximum (180 beats per minute-age) (SOR: A). One caveat: aerobic exercise in the literature was usually supervised, so the ideal exercise regimen might be a fibromyalgia-specific program.

Medication. Consider a trial of amitriptyline, 25 to 50 mg every night, for up to 6 weeks (SOR A). A caveat: tricyclic antidepressants may also have significant side effects, which could outweigh moderate benefits. Moreover, treatment effectiveness beyond 2 months has not been proven. Therefore, longitudinal measurement of outcomes should be part of ongoing care.

Follow-up. Studies have not determined which measures are best to follow (see “Assessing treatment efficacy”), but they might include the following (SOR: C):

1. Pain (eg, visual analogue scale, pain drawings)
2. Number of tender points, and tenderness
3. Physical function (eg, cardiorespiratory fitness, self-reported physical function measured by the physical-impairment subscale of the FIQ,⁵⁶ strength)
4. Global well-being or perceived improvement (eg, physician-rated change, FIQ total score)
5. Self-efficacy (eg, Arthritis Self-efficacy Questionnaire)
6. Fatigue and sleep (eg, FIQ fatigsubscale, sleep visual analogue scale)
7. Psychological function (eg, FIQ subscales for depression and anxiety)
8. Ability to work
9. Health care consumption and costs.^47,50

Education or psychological coping strategies may also contribute positively to overall patient and family well-being. Consider education/psychological counseling (SOR: C) and acupuncture (SOR: B).

Acknowledgments

The authors would like to express their appreciation to Cheryl Mongillo, Peggy Lardear, and Brian Pellini for their assistance in preparing the manuscript as well as Dolores Moran and Diane Wolf for their library assistance, and to James Newman, MD, rheumatologist, for his expert suggestions. Funding for this project was provided by a grant from the Delaware Department of Health and Social Services, Division of Public Health.of Health and Social Services, Division of Public Health.

Corresponding author
Anna Quisel, MD, c/o Cheryl Mongillo, Department of Family and Community Medicine, Christiana Care Health Systems, 1401 Foulk Road, Wilmington, DE 19803. E-mail: bretandanna@comcast.net.