Free
Editorial Views  |   February 2005
Complex Regional Pain Syndromes in Children and Adolescents
Author Affiliations & Notes
  • Charles B. Berde, M.D., Ph.D.
    *
  • Alyssa Lebel, M.D.
    *
  • * Department of Anesthesiology, Perioperative and Pain Medicine, Children’s Hospital, and Harvard Medical School, Boston, Massachusetts.
Article Information
Editorial Views / Central and Peripheral Nervous Systems / Neuromuscular Diseases and Drugs / Pain Medicine / Pediatric Anesthesia
Editorial Views   |   February 2005
Complex Regional Pain Syndromes in Children and Adolescents
Anesthesiology 2 2005, Vol.102, 252-255. doi:
Anesthesiology 2 2005, Vol.102, 252-255. doi:
DIAGNOSIS and treatment of complex regional pain syndromes (CRPS) I and II (also known as reflex sympathetic dystrophy  and causalgia  , respectively) continue to generate controversy among clinicians and frustration and suffering for patients.1–3 The work of Dadure et al.  4 published in this issue of Anesthesiology revisits the topic. Several case series of adults referred to specialist physicians found that prolonged pain, impairments, disability, and serious complications5,6 were common. Conversely, a more favorable clinical course was reported in a recent population-based epidemiologic study.7 Choice among therapies often seems to depend more on what type of clinician sees the patient, rather than on evidence derived from prospective controlled clinical trials. Treatments include various forms of physical therapy8,9; systemic medications10–12; regional anesthetic approaches, including sympathetic or somatic nerve block injections or neuraxial infusions13–15; spinal cord stimulation16–18; destruction of sympathetic ganglia19; and even amputation of affected extremities.20 Overall, across medical specialties, there is a growing emphasis on active physical therapy and on restoration of normal limb function as a key component of recovery. The quality of the evidence for many commonly performed procedures is relatively weak.21 Controversy persists regarding the relative importance of peripheral, autonomic, and central mechanisms in the initiation and maintenance of pain and limb dysfunction.22–24 
Complex regional pain syndromes and related disorders among children and adolescents had been described only in sporadic case reports and very small case series before the 1970s; since then, there has been a rapidly growing number of case series and clinical outcome studies.9,25–28 For purposes of this discussion, the term pediatric CRPS  refers to occurrence in both children and adolescents. Pediatric CRPS seems different from adult CRPS in several respects, as listed in table 1.
Table 1. Differences between Adult and Pediatric CRPS 
Image not available
Table 1. Differences between Adult and Pediatric CRPS 
×
In this issue of Anesthesiology, Dadure et al.  report very favorably on the combined use of intravenous regional blockade with buflomedil along with distal continuous sciatic blockade in the popliteal fossa to treat a group of pediatric patients with CRPS who had not responded to 6 months of treatment with physical therapy and cognitive–behavioral treatment. Their results seemed extremely impressive. Patients showed rapid improvement in pain scores and limb function. For patients with CRPS restricted to the foot, ankle, and lower leg, continuous distal sciatic blockade using a popliteal fossa catheter has several potential advantages compared with epidural blockade, including avoidance of contralateral sensory and motor block, urinary retention, and hypotension. Sparing of contralateral strength and sensation as well as ipsilateral upper leg motor function facilitates ambulation and participation in active physical therapy. Continuous peripheral blockade is an emerging approach for children as well as adults after many types of extremity surgery.29 
These results, although impressive, should be viewed with some caution in view of the short duration of follow-up. Their report would have been far stronger had they reported on the pain scores, limb function, and school attendance of these children at 6 months or longer after the procedure. In-person evaluations are ideal, although there are practical difficulties in getting children and their parents to travel again to a tertiary center after they have become pain free. Although there are some limitations to mail- or telephone-based questionnaires (e.g.  , absence of a physical examination), these types of follow-up would still be helpful for assessing longer-term outcomes.
A second concern with the study of Dadure et al.  relates to the study design, with a single-group, open-label, combination treatment. Without separate evaluation of intravenous regional blockade and continuous popliteal fossa blockade, it is difficult to determine which components of their treatment regimen were most important to improving outcomes. Pediatric trials are made more difficult by a number of factors, including limited numbers of patients in any single center and a general reluctance to use placebos or other control groups in the setting of chronic pain in a “vulnerable” population. Nevertheless, without some type of control condition and without separate evaluation of the two interventions being applied, conclusions about efficacy must be made with considerable caution.
Other forms of neuropathic pain also show marked differences between adults and children. Postherpetic neuralgia and trigeminal neuralgia occur only rarely in children.30 In adults with a brachial plexus injury, neuropathic pain seems quite common, severe, and persistent.31 In contrast, pain behaviors are only very rarely seen after perinatal brachial plexus injury.32,33 A recent case series found that pain behaviors and self-mutilation occurred more commonly in severely affected infants after nerve grafting procedures.33 
Animal models of nerve injury34–36 also show age-related differences in biologic consequences, in spontaneous pain-related behaviors, and in development of mechanical allodynia and hyperalgesia to mechanical or thermal stimuli. Infant rats have been studied extensively as a model for the ontogeny of pain responses. One of the more promising models for neuropathic pain in adult rats involves ligation of the tibial and peroneal branches of the sciatic nerve, with sparing of the sural nerve.37 In adult rats, this produces marked allodynia and other pain behaviors. Recent work by Howard, Fitzgerald, Beggs, and their colleagues examined the effects of these same nerve lesions in infant and adolescent rats (Simon Beggs, Research Fellow, University of Toronto, personal communication, October 2004). Remarkably, rats that underwent the tibial and peroneal nerve ligations before day 33 of life did not exhibit allodynia or hyperalgesia or related spinal cord immunohistologic changes as seen in older animals. This cutoff age in rats would correspond roughly to the age of 8 yr in humans. It is tempting to speculate that further study of the biologic bases of these age-related differences in rats might shed light on the rarity of CRPS in children before the age of 8 or 9 yr.
The role of female endocrine development in susceptibility to CRPS in childhood deserves further study. Some sex differences in pain responses in rats and humans are estrogen dependent.38 The marked lower extremity predominance in pediatric CRPS is not adequately explained. Children and adolescents commonly sustain both upper and lower extremity injuries in sports and other forms of play, but a Colles fracture at the wrist or a supracondylar fracture at the elbow only very rarely produces neuropathic pain in general, or CRPS in particular, in children and adolescents. In adults, workplace injuries and overuse syndromes are relatively common in the upper extremities, and these may be important contributing factors to the occurrence of upper extremity CRPS in these age groups.
Perhaps the most remarkable feature of most pediatric CRPS case series is that most subjects had near-complete resolution of limb dysfunction and disability, and a marked reduction in their pain scores. In many of these case series, improvement was accomplished for most patients with a regimen of active physical therapy, with or without an intensive cognitive–behavioral regimen, but without use of nerve blocking procedures or other more medically based interventions.25,27 Sherry et al.  27 have reported relatively large case series of children with CRPS (their preferred term is reflex neurovascular dystrophy  ), showing high rates of resolution of pain and recovery of limb function using a regimen with active exercises, and some psychoeducational interventions. This group makes essentially no use of medications or nerve blocks. Sherry et al.  39,40 emphasize the importance of individual and family psychological issues in the perpetuation of this condition. In the view of Sherry et al.  , nerve blocks are unnecessary and may be counterproductive because they reinforce the patient taking a passive, rather than active, role in his or her recovery. The role of psychological factors in CRPS in both adults and children is controversial.41–44 
Many of the early pediatric case series that reported good recovery using physical therapy, with or without cognitive–behavioral treatment, involved admission of the patients to an inpatient rehabilitation unit that permitted many hours daily (e.g.  , 5–6 h) of physical therapy.25,26 In the current healthcare environment, at least in the United States, pediatric inpatient rehabilitation beds are relatively scarce, and there is great difficulty getting third-party payor approval for treating patients with CRPS in this type of milieu. Our group previously conducted a randomized prospective controlled trial of outpatient physical therapy and cognitive–behavioral treatment, with two groups differing in the frequency of physical therapy sessions.9 Both groups showed good improvement in pain scores and excellent improvement in limb function scores over the 6-week intervention period and at long-term follow-up over 2–5 yr. However, in our cohort, recurrent episodes were common (25% of patients), and nearly half of the patients at some point after the 6-week controlled trial received epidural infusions, lumbar sympathetic blocks, or both to treat persistent pain.
Some of the discrepancies in outcomes between groups may relate to differences in patient populations and referral patterns among centers. For example, among the patients in case series by pediatric rheumatologists, only a minority of patients had an identifiable injury, surgery, or trauma.25,27 Conversely, nearly 90% of our patients have had a discrete traumatic event that seemed to trigger their CRPS.9,26 These differences may reflect in part the specialties involved: A high percentage of referrals to our program come from orthopedic surgeons and neurologists. Recent work by Sethna et al.  45 in our group examined quantitative sensory testing in a cohort of 55 pediatric patients with CRPS. Eighteen of these patients (33%) met criteria for CRPS II by showing sensory abnormalities in the distribution of a peripheral nerve on careful sensory and psychophysical evaluation.
Complex regional pain syndrome has remained a puzzle for more than 140 yr.46 The report of Dadure et al.  adds another potential treatment for children and adolescents with CRPS. Further mechanistic study and clinical trials may help to clarify which patients should receive which treatments, and in which sequence.3 
* Depart-ment of Anesthesiology, Perioperative and Pain Medicine, Children’s Hospital, and Harvard Medical School, Boston, Massachusetts.
References
Harden RN, Bruehl S, Galer BS, Saltz S, Bertram M, Backonja M, Gayles R, Rudin N, Bhugra MK, Stanton-Hicks M: Complex regional pain syndrome: Are the IASP diagnostic criteria valid and sufficiently comprehensive? Pain 1999; 83:211–9Harden, RN Bruehl, S Galer, BS Saltz, S Bertram, M Backonja, M Gayles, R Rudin, N Bhugra, MK Stanton-Hicks, M
Kingery WS: A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997; 73:123–39Kingery, WS
Baron R, Fields HL, Janig W, Kitt C, Levine JD: National Institutes of Health Workshop: Reflex sympathetic dystrophy/complex regional pain syndromes: State-of-the-science. Anesth Analg 2002; 95:1812–6Baron, R Fields, HL Janig, W Kitt, C Levine, JD
Dadure C, Motais F, Ricard C, Raux O, Troncin R, Capdevila X: Continuous peripheral nerve blocks at home in the treatment of recurrent complex regional pain syndrome I in children. Anesthesiology 2005; 102:387–91Dadure, C Motais, F Ricard, C Raux, O Troncin, R Capdevila, X
Oerlemans HM, Oostendorp RA, de Boo T, Goris RJ: Evaluation of three methods to rate impairment in patients with complex regional pain syndrome I of one upper extremity. Clin Rehabil 2000; 14:331–9Oerlemans, HM Oostendorp, RA de Boo, T Goris, RJ
van der Laan L, Veldman PH, Goris RJ: Severe complications of reflex sympathetic dystrophy: Infection, ulcers, chronic edema, dystonia, and myoclonus. Arch Phys Med Rehabil 1998; 79:424–9van der Laan, L Veldman, PH Goris, RJ
Sandroni P, Benrud-Larson LM, McClelland RL, Low PA: Complex regional pain syndrome type I: Incidence and prevalence in Olmsted county, a population-based study. Pain 2003; 103:199–207Sandroni, P Benrud-Larson, LM McClelland, RL Low, PA
Oerlemans HM, Oostendorp RA, de Boo T, van der Laan L, Severens JL, Goris JA: Adjuvant physical therapy versus occupational therapy in patients with reflex sympathetic dystrophy/complex regional pain syndrome type I. Arch Phys Med Rehabil 2000; 81:49–56Oerlemans, HM Oostendorp, RA de Boo, T van der Laan, L Severens, JL Goris, JA
Lee BH, Scharff L, Sethna NF, McCarthy CF, Scott-Sutherland J, Shea AM, Sullivan P, Meier P, Zurakowski D, Masek BJ, Berde CB: Physical therapy and cognitive-behavioral treatment for complex regional pain syndromes. J Pediatr 2002; 141:135–40Lee, BH Scharff, L Sethna, NF McCarthy, CF Scott-Sutherland, J Shea, AM Sullivan, P Meier, P Zurakowski, D Masek, BJ Berde, CB
Perez RS, Zuurmond WW, Bezemer PD, Kuik DJ, van Loenen AC, de Lange JJ, Zuidhof AJ: The treatment of complex regional pain syndrome type I with free radical scavengers: A randomized controlled study. Pain 2003; 102:297–307Perez, RS Zuurmond, WW Bezemer, PD Kuik, DJ van Loenen, AC de Lange, JJ Zuidhof, AJ
Kozin F, Ryan LM, Carerra GF, Soin JS, Wortmann RL: The reflex sympathetic dystrophy syndrome (RSDS): III. Scintigraphic studies, further evidence for the therapeutic efficacy of systemic corticosteroids, and proposed diagnostic criteria. Am J Med 1981; 70:23–30Kozin, F Ryan, LM Carerra, GF Soin, JS Wortmann, RL
Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE: Subanesthetic ketamine infusion therapy: A retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Medicine 2004; 5:263–75Correll, GE Maleki, J Gracely, EJ Muir, JJ Harbut, RE
Tran KM, Frank SM, Raja SN, El-Rahmany HK, Kim LJ, Vu B: Lumbar sympathetic block for sympathetically maintained pain: Changes in cutaneous temperatures and pain perception. Anesth Analg 2000; 90:1396–401Tran, KM Frank, SM Raja, SN El-Rahmany, HK Kim, LJ Vu, B
Hord AH, Rooks MD, Stephens BO, Rogers HG, Fleming LL: Intravenous regional bretylium and lidocaine for treatment of reflex sympathetic dystrophy: A randomized, double-blind study. Anesth Analg 1992; 74:818–21Hord, AH Rooks, MD Stephens, BO Rogers, HG Fleming, LL
Rauck RL, Eisenach JC, Jackson K, Young LD, Southern J: Epidural clonidine treatment for refractory reflex sympathetic dystrophy. Anesthesiology 1993; 79:1163–9Rauck, RL Eisenach, JC Jackson, K Young, LD Southern, J
Kemler MA, De Vet HC, Barendse GA, Van Den Wildenberg FA, Van Kleef M: The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: Two years’ follow-up of the randomized controlled trial. Ann Neurol 2004; 55:13–8Kemler, MA De Vet, HC Barendse, GA Van Den Wildenberg, FA Van Kleef, M
Kemler MA, Barendse GA, van Kleef M, de Vet HC, Rijks CP, Furnee CA, van den Wildenberg FA: Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 2000; 343:618–24Kemler, MA Barendse, GA van Kleef, M de Vet, HC Rijks, CP Furnee, CA van den Wildenberg, FA
Grabow TS, Tella PK, Raja SN: Spinal cord stimulation for complex regional pain syndrome: An evidence-based medicine review of the literature. Clin J Pain 2003; 19:371–83Grabow, TS Tella, PK Raja, SN
Mailis A, Furlan A: Sympathectomy for neuropathic pain. Cochrane Database Syst Rev 2003; (2):CD002918Mailis, A Furlan, A
Dielissen PW, Claassen AT, Veldman PH, Goris RJ: Amputation for reflex sympathetic dystrophy. J Bone Joint Surg Br 1995; 77:270–3Dielissen, PW Claassen, AT Veldman, PH Goris, RJ
Cepeda MS, Lau J, Carr DB: Defining the therapeutic role of local anesthetic sympathetic blockade in complex regional pain syndrome: A narrative and systematic review. Clin J Pain 2002; 18:216–33Cepeda, MS Lau, J Carr, DB
Gracely RH, Lynch SA, Bennett GJ: Painful neuropathy: Altered central processing maintained dynamically by peripheral input. Pain 1992; 51:175–94Gracely, RH Lynch, SA Bennett, GJ
Janig W, Baron R: Complex regional pain syndrome is a disease of the central nervous system. Clin Auton Res 2002; 12:150–64Janig, W Baron, R
Baron R, Maier C: Reflex sympathetic dystrophy: skin blood flow, sympathetic vasoconstrictor reflexes and pain before and after surgical sympathectomy. Pain 1996; 67:317–26Baron, R Maier, C
Bernstein BH, Singsen BH, Kent JT, Kornreich H, King K, Hicks R, Hanson V: Reflex neurovascular dystrophy in childhood. J Pediatr 1978; 93:211–5Bernstein, BH Singsen, BH Kent, JT Kornreich, H King, K Hicks, R Hanson, V
Wilder RT, Berde CB, Wolohan M, Vieyra MA, Masek BJ, Micheli LJ: Reflex sympathetic dystrophy in children: Clinical characteristics and follow-up of seventy patients. J Bone Joint Surg 1992; 74:910–9Wilder, RT Berde, CB Wolohan, M Vieyra, MA Masek, BJ Micheli, LJ
Sherry DD, Wallace CA, Kelley C, Kidder M, Sapp L: Short- and long-term outcomes of children with complex regional pain syndrome type I treated with exercise therapy. Clin J Pain 1999; 15:218–23Sherry, DD Wallace, CA Kelley, C Kidder, M Sapp, L
Dietz FR, Mathews KD, Montgomery WJ: Reflex sympathetic dystrophy in children. Clin Orthop Related Res 1990; 225–31Dietz, FR Mathews, KD Montgomery, WJ
Dadure C, Pirat P, Raux O, Troncin R, Rochette A, Ricard C, Capdevila X: Perioperative continuous peripheral nerve blocks with disposable infusion pumps in children: A prospective descriptive study. Anesth Analg 2003; 97:687–90Dadure, C Pirat, P Raux, O Troncin, R Rochette, A Ricard, C Capdevila, X
Petursson G, Helgason S, Gudmundsson S, Sigurdsson JA: Herpes zoster in children and adolescents. Pediatr Infect Dis J 1998; 17:905–8Petursson, G Helgason, S Gudmundsson, S Sigurdsson, JA
Berman JS, Birch R, Anand P: Pain following human brachial plexus injury with spinal cord root avulsion and the effect of surgery. Pain 1998; 75:199–207Berman, JS Birch, R Anand, P
Anand P, Birch R: Restoration of sensory function and lack of long-term chronic pain syndromes after brachial plexus injury in human neonates. Brain 2002; 125:113–22Anand, P Birch, R
McCann ME, Waters P, Goumnerova LC, Berde C: Self-mutilation in young children following brachial plexus birth injury. Pain 2004; 110:123–9McCann, ME Waters, P Goumnerova, LC Berde, C
Reynolds ML, Fitzgerald M: Neonatal sciatic nerve section results in thiamine monophosphate but not substance P or calcitonin gene-related peptide depletion from the terminal field in the dorsal horn of the rat: the role of collateral sprouting. Neuroscience 1992; 51:191–202Reynolds, ML Fitzgerald, M
Shortland P, Fitzgerald M: Neonatal sciatic nerve section results in a rearrangement of the central terminals of saphenous and axotomized sciatic nerve afferents in the dorsal horn of the spinal cord of the adult rat. Eur J Neurosci 1994; 6:75–86Shortland, P Fitzgerald, M
Coggeshall RE, Pover CM, Fitzgerald M: Dorsal root ganglion cell death and surviving cell numbers in relation to the development of sensory innervation in the rat hindlimb. Brain Res. Developmental Brain Res 1994; 82:193–212Coggeshall, RE Pover, CM Fitzgerald, M
Decosterd I, Woolf CJ: Spared nerve injury: An animal model of persistent peripheral neuropathic pain. Pain 2000; 87:149–58Decosterd, I Woolf, CJ
Cairns BE, Hu JW, Arendt-Nielsen L, Sessle BJ, Svensson P: Sex-related differences in human pain and rat afferent discharge evoked by injection of glutamate into the masseter muscle. J Neurophysiol 2001; 86:782–91Cairns, BE Hu, JW Arendt-Nielsen, L Sessle, BJ Svensson, P
Sherry DD, Weisman R: Psychologic aspects of childhood reflex neurovascular dystrophy. Pediatrics 1988; 81:572–8Sherry, DD Weisman, R
Sherry DD: An overview of amplified musculoskeletal pain syndromes. J Rheumatol 2000; 58:44–8Sherry, DD
Verdugo RJ, Ochoa JL: Abnormal movements in complex regional pain syndrome: Assessment of their nature. Muscle Nerve 2000; 23:198–205Verdugo, RJ Ochoa, JL
Ochoa JL, Verdugo RJ: Reflex sympathetic dystrophy: A common clinical avenue for somatoform expression. Neurol Clin 1995; 13:351–63Ochoa, JL Verdugo, RJ
Bruehl S, Husfeldt B, Lubenow TR, Nath H, Ivankovich AD: Psychological differences between reflex sympathetic dystrophy and non-RSD chronic pain patients. Pain 1996; 67:107–14Bruehl, S Husfeldt, B Lubenow, TR Nath, H Ivankovich, AD
Lynch ME: Psychological aspects of reflex sympathetic dystrophy: A review of the adult and paediatric literature. Pain 1992; 49:337–47Lynch, ME
Sethna NF, Meier P, Zurakowski D, Berde C: Cutaneous sensory abnormalities in children with CRPS types I and II. Abstracts, Combined American and Canadian Pain Societies; May 2004; Vancouver, BC, Canada
Mitchell SW, Morehouse CR, Keen WW: Gunshot Wounds and Other Injuries of the Nerves. Philadelphia, JB Lippincott, 1864Mitchell, SW Morehouse, CR Keen, WW Philadelphia JB Lippincott
Table 1. Differences between Adult and Pediatric CRPS 
Image not available
Table 1. Differences between Adult and Pediatric CRPS 
×