Correspondence
Reflex Sympathetic Dystrophy
N Engl J Med 2000; 343:1811-1813December 14, 2000
- Article
To the Editor:
In the trial conducted by Kemler and colleagues (Aug. 31 issue),1 spinal cord stimulation plus physical therapy was compared with physical therapy alone in carefully selected patients with intractable pain due to chronic reflex sympathetic dystrophy. However, no pain-relieving effects could be expected from the exercise program, since physical therapy had already been shown to be ineffective. Hence, the control group received no effective treatment, despite intractable pain. Since spinal cord stimulation is a technique used for the relief of pain, it would be more appropriate to compare spinal cord stimulation plus optimal pain medication with optimal pain medication alone. In a study of the effects of spinal cord stimulation on pain due to ischemia in patients with chronic critical limb ischemia, it was shown that medical treatment could provide pain relief similar to that achieved with spinal cord stimulation; the same was true for the effects of treatment on the quality of life.2
2 ReferencesLuc G.Y. Claeys, M.D.
University Hospital Herne, 44625 Herne, Germany1
Kemler MA ,Barendse GA ,Van Kleef M , et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 2000;343:618-624
Full Text | Web of Science | Medline2
Klomp HM ,Spincemaille GH ,Steyerberg EW ,Habblema JD ,van Urk H . Spinal-cord stimulation in critical limb ischaemia: a randomised trial. Lancet 1999;353:1040-1044
CrossRef | Web of Science | Medline
To the Editor:
In their report on the reduction of pain with spinal cord stimulation in patients with reflex sympathetic dystrophy, Kemler and colleagues based the diagnosis of reflex sympathetic dystrophy on all the listed absolute criteria and at least three of the relative criteria shown in Table 1 of their article. The absolute criteria were all subjective measures, and three of the relative criteria (hypoesthesia, hyperalgesia, and allodynia) were subjective. Objective measures, such as edema, increased nail and hair growth, abnormal skin color, and patchy demineralization of bone, were relative criteria, not absolute criteria. The percentage of patients with any objective findings was not specified. The criteria used in this study underscore the frequent absence of objective signs on physical examination in patients who have been given the diagnosis of reflex sympathetic dystrophy, or the complex regional pain syndrome.
Daniel M. Feinberg, M.D.
Pennsylvania Hospital, Philadelphia, PA 19107To the Editor:
Schwartzman's editorial1 celebrates two reports from the Netherlands on new treatments for reflex sympathetic dystrophy, a descriptive diagnostic category that was born from empirical truths and suffers from an intrinsic fallacy.2 Reflex sympathetic dystrophy, or the complex regional pain syndrome, is presented as a matter of fact, at a time when evidence-based medicine shows otherwise.3 Any claim of scientifically ascertained mechanisms underlying this nonspecific symptom complex is problematic because of two flaws. First, patients do not undergo a critical differential diagnosis, and hence there is inadequate information for drawing conclusions. Second, placebo controls are not used, or there is unblinding because of clues elicited by the tested agent. For these reasons, as in the embarrassing case of diagnostic sympatholysis, these new treatment claims are unsustainable.
Schwartzman's editorial on the diagnosis and treatment of reflex sympathetic dystrophy misrepresents scientific findings and ignores decisive contrary evidence. The concept of “sympathetically maintained pain” has been used to argue that reflex sympathetic dystrophy is a discrete pathophysiologic entity. Schwartzman construes the elegant demonstration of acute autonomic dysregulation in one case of acute traumatic pain4 as proof of sympathetic dysfunction as a cause of reflex sympathetic dystrophy. But this case represented the opposite of sympathetically maintained pain: it was not autonomic activation, but a shutdown.
Schwartzman dismisses the critical psychiatric and behavioral contributions to reflex sympathetic dystrophy. In reality, somatoform pseudoneurologic illness is alarmingly underacknowledged, even in the neurologic clinic.5
5 ReferencesJosé Ochoa, M.D., Ph.D.
Oregon Health Sciences University, Portland, OR 972101
Schwartzman RJ . New treatments for reflex sympathetic dystrophy. N Engl J Med 2000;343:654-656
Full Text | Web of Science | Medline2
Ochoa JL . Truths, errors, and lies around “reflex sympathetic dystrophy“ and “complex regional pain syndrome.“ J Neurol 1999;246:875-879
CrossRef | Web of Science | Medline3
Max MB ,Gilron I . Sympathetically maintained pain: has the emperor no clothes? Neurology 1999;52:905-907
Web of Science | Medline4
Wasner G ,Heckmann K ,Maier C ,Baron R . Vascular abnormalities in acute reflex sympathetic dystrophy (CRPS I): complete inhibition of sympathetic nerve activity with recovery. Arch Neurol 1999;56:613-620
CrossRef | Web of Science | Medline5
Ron MA . Somatization in neurological practice. J Neurol Neurosurg Psychiatry 1994;57:1161-1164
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Claeys questions whether it would not have been more appropriate to offer all patients “optimal pain medication” instead of physical therapy. Our answer is no. With respect to the treatment of patients who have neuropathic pain caused by reflex sympathetic dystrophy, no controlled trials have substantiated the effectiveness of nonsteroidal antiinflammatory drugs, opioids, antidepressants, anticonvulsants, or vasodilators. There is no optimal pain medication for this group of patients. Nevertheless, a criterion for enrollment in our study was that all these drugs had been shown to be ineffective. Therefore, the principles of our study and the study by Klomp et al.1 are not comparable. Whereas we studied the effectiveness of spinal cord stimulation in relieving pain refractory to any other form of treatment, Klomp et al. investigated whether spinal cord stimulation had additional limb-saving value in patients with peripheral vascular disease who were receiving standard therapy with vasodilators.
Dr. Feinberg discusses the objectiveness of the diagnostic criteria used in our study. Unfortunately, we are unable to make an absolutely certain diagnosis of reflex sympathetic dystrophy. The diagnosis is based entirely on accepted clinical criteria, as established by the International Association for the Study of Pain.2 Patients who met these criteria were considered for enrollment in our study, but in addition, patients had to have impaired function and symptoms beyond the area of trauma. Thus, our diagnostic criteria were more strict than the accepted criteria for the diagnosis of this syndrome.
Dr. Ochoa denies the very existence of reflex sympathetic dystrophy but states that its cause is psychiatric, a position that offers no solution. Whatever the pathophysiology of the syndrome may be, it has an undeniably large negative effect on the health-related quality of life,3 and its incidence and costs to society are high. Evidence-based medicine has now shown, as reported in our article, that patients with chronic reflex sympathetic dystrophy can be treated effectively by spinal cord stimulation. Syndromes of unknown pathophysiology will always have believers and nonbelievers. Although the believers continue to look for clues, the nonbelievers should recall that before the discovery of magnetic resonance imaging and Helicobacter pylori, multiple sclerosis and peptic ulcers were also classified as psychosomatic disorders.
3 ReferencesMarius A. Kemler, M.D., Ph.D.
Maarten van Kleef, M.D., Ph.D.
Frans A.J.M. van den Wildenberg, M.D., Ph.D.
Maastricht University Hospital, 6202 AZ Maastricht, the Netherlands1
Klomp HM ,Spincemaille GH ,Steyerberg EW ,Habbema JD ,van Urk H . Spinal-cord stimulation in critical limb ischaemia: a randomised trial. Lancet 1999;353:1040-1044
CrossRef | Web of Science | Medline2
Merskey H, Bogduk N, eds. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. Seattle: IASP Press, 1994:40-2.
3
Kemler MA ,de Vet HC . Health-related quality of life in chronic refractory reflex sympathetic dystrophy (complex regional pain syndrome type I). J Pain Symptom Manage 2000;20:68-76
CrossRef | Web of Science | Medline
Author/Editor Response
The editorialist replies:
To the Editor: In response to Dr. Ochoa's comments: there is a huge scientific and clinical literature that buttresses the core components of reflex sympathetic dystrophy. The International Association for the Study of Pain convened a panel of experts to evaluate this symptom complex critically; they suggested that it be designated the chronic regional pain syndrome, type 1 or 2.1 This definition of the symptom complex has been accepted throughout the world. Evidence-based medicine, as demonstrated by a meta-analysis of the psychological characteristics of patients with reflex sympathetic dystrophy as compared with those of patients who have other types of severe chronic pain, has shown no differences between these two groups of patients.2
Studies in animals have shown how the sympathetic nervous system in the area of injury and at the level of the dorsal-root ganglia may sustain and drive pain in the early stages of the illness.3 The interplay between cytokines and neuropeptides has been shown, both in animals and in patients, to play an important part in the neurogenic inflammation evident in the affected area. Recent clinical studies have clearly documented that central autonomic dysregulation is part of the illness. Mechanisms underlying dystonia, tremor, weakness, and spasms have been demonstrated in animal models of neuropathic pain and in patients with reflex sympathetic dystrophy.
Perhaps the most exciting current research findings are at the molecular level. Targeted mutations of genes that control specific receptor-channel components or subunits of enzymes that are important in intracellular signaling during nociceptive behavior cause or inhibit very specific aspects of pain. In mice that carry a null mutation of the gene that encodes the neuron-specific isoform of the type I regulatory subunit (RI-beta of cyclic AMP–dependent kinase PKA), indexes of acute pain are similar to those in wild-type mice, but mice with the mutation do have decreases in behavior associated with persistent pain and in inflammation at the site of injury, as well as decreased early immediate gene expression in the dorsal horn.4 Specific types of tissue or nerve injury induce various patterns of gene expression, depending on retrogradely transported signaling molecules or trophic factors. Inflammation of peripheral tissue induces increased expression of brain-derived neurotrophic factor, mediated by nerve growth factor, in the dorsal-root ganglia and the spinal cord, which has been associated with hyperexcitable nociceptive neurons in the dorsal horn.5
5 ReferencesRobert J. Schwartzman, M.D.
MCP Hahnemann University, Philadelphia, PA 19102-11921
Merskey H, Bogduk N, eds. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. Seattle: IASP Press, 1994.
2
Lynch ME . Psychological aspects of reflex sympathetic dystrophy: a review of the adult and paediatric literature. Pain 1992;49:337-347
CrossRef | Web of Science | Medline3
McLachlan EM ,Janig W ,Devor M ,Michaelis M . Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 1993;363:543-546
CrossRef | Web of Science | Medline4
Malmberg AB ,Brandon EP ,Idzerda RL ,Liu H ,McKnight GS ,Basbaum AI . Diminished inflammation and nociceptive pain with preservation of neuropathic pain in mice with a targeted mutation of the type I regulatory subunit of cAMP-dependent protein kinase. J Neurosci 1997;17:1462-14705
Cho HJ ,Kim JK ,Zhou XF ,Rush RA . Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation. Brain Res 1997;764:269-272
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Rod S. Taylor, Jean-Pierre Van Buyten, Eric Buchser. (2006) Spinal cord stimulation for complex regional pain syndrome: A systematic review of the clinical and cost-effectiveness literature and assessment of prognostic factors. European Journal of Pain 10:2, 91-101
CrossRef2
David S Silver, Daniel J Wallace. (2002) The management of fibromyalgia-associated syndromes. Rheumatic Disease Clinics of North America 28:2, 405-417
CrossRef3
Nikolai Bogduk. (2001) Complex regional pain syndrome. Current Opinion in Anaesthesiology 14:5, 541-546
CrossRef
