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Electroconvulsive Therapy in Complex Regional Pain Syndromes William W. McDaniel, MD Abstract Three cases are presented in which electroconvulsive therapy (ECT) for depression led to the relief of comorbid complex regional pain syndrome as well as depression. In one of the cases, concomitant fibromyalgia was not relieved during 2 separate series of ECT. The literature regarding the role of ECT in the management of chronic pain is reviewed and discussed in light of recent findings about ECT and changes in neurotransmission associated with seizures. Key Words: ECT, CRPS, complex regional pain syndrome, fibromyalgia, depression
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I
Received August 5, 2002; accepted July 3, 2003. From the Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA. Reprints: William McDaniel, Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 710, Norfolk, VA 23507 (e-mail:
[email protected]). Copyright © 2003 by Lippincott Williams & Wilkins
t is common knowledge that chronically painful conditions are often accompanied by clinically significant depression.1 The relationship is manifold but includes the effect of suffering on mood, neurochemical adaptations to pain that share common pathways with depression, and social effects of chronic pain limiting the sufferer’s activities and social contacts.1,2 Complex regional pain syndrome (CRPS) is a chronically painful condition that may arise in the site of an earlier injury or operation to a limb, resulting in changes in circulation; coldness and discoloration; and pain and stiffness progressing to joint contractures in the most severe cases.2 Like all chronically painful conditions, it is associated with depressed mood. This diagnostic category encompasses the older categories of reflex sympathetic dystrophy and causalgia. Both diagnoses described chronic pain with neuropathically mediated circulation changes with peripheral neuropathy and similar autonomic dysfunction after injury. They are now thought to represent the same process, and
both conditions are subsumed under the same diagnostic formulation, CRPS.2 Depression responds to medications and/or psychotherapy in most cases. Electroconvulsive therapy (ECT), the oldest modern antidepressant treatment, provides relief in the great majority of the nonresponders.3,4 ECT has been reported to relieve depression associated with regional pain syndromes and at the same time reverse the signs and symptoms of regional pain syndrome.5–7 I report here three more cases in which ECT for depression resulted in resolution of a comorbid CRPS.
CASE REPORTS Ms. A was a 53-year-old Caucasian woman who had been treated with a wide variety of antidepressant medications for 12 years for depression. She attained partial, temporary relief with several regimens only to experience exacerbations. At the time of the decision to refer her for ECT, she had a recurrence of depression with suicidal ideation and melancholic neurovegetative symptoms despite a regimen of amitriptyline 200 mg daily and methylphenidate. She had never had any signs or symptoms of mania. Her medical history was remarkable for hypothyroidism, although she was now euthyroid with thyroid hormone replacement therapy. Her right arm had been injured in a motor vehicle accident 5 years earlier, and although the multiple fractures had healed, she developed severe CRPS and her dominant right hand was crippled by joint contractures. She listed the pain and disability as the most im-
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portant stressors contributing to the depression. She was hospitalized with suicide precautions. Her ineffective antidepressant medications were discontinued. She was treated with a series of 12 treatments of ECT with bitemporal electrode placement under anesthesia with methohexital 80 mg and succinylcholine 80 mg. Her ECT was performed using the MECTA SR-1 using a dose titration protocol with the dose set just above the seizure threshold. The treatments were welltolerated, and she demonstrated improvement in mood beginning by about the third treatment. Her immobile right hand began to move after the fifth treatment, and physical therapy was initiated. By the 10th treatment, the pain, stiffness, discoloration, and coldness had resolved. By the 12th treatment, the remission in her depressive symptoms seemed stable, with normal sleep, appetite, and concentration, and treatments were discontinued. There was no recurrence of either depression or pain during the following 6 months. The patient was lost to follow-up when she moved to another state. Ms. B was a 28-year-old Caucasian woman with bipolar disorder who had responded to ECT during an episode of depression 3 years earlier. She was referred for ECT again during an episode of depression that had occurred despite therapy with divalproex 1500 mg per day, and fluoxetine 60 mg daily. She was hospitalized after a suicide attempt by overdosing on several medications and transferred to our facility when medically stable. She requested ECT, remembering how well she had done before. She had suffered a fracture of the left humerus during an episode of mania 1 year earlier and underwent open reduction and internal fixation. The fracture healed slowly, and she developed CRPS in the arm. She reported the arm and hand were so stiff and painful that she could not use them but that she had not developed contractures. She had a long history of migraine headaches, which had been aggravated during her earlier course of ECT, as well as fibromyalgia, which had neither improved nor worsened. Propofol anesthe-
sia, as well as right unilateral stimulation, had lessened the frequency of post-ECT headache during a previous course of ECT, and were used again. The patient underwent a series of eight treatments of ECT using the MECTA SR-1 with unilateral electrode placement. Stimulus dose was set at approximately twice seizure threshold. She sustained a complete remission of both depression and CRPS. Four years later, there has been no reappearance of CRPS, despite recurrences of depression and discovery of a peripheral nerve entrapment by the hardware used at open reduction and internal fixation of the fracture. Surgery to remove the hardware relieved local pain caused by the entrapment. She continued to suffer from fibromyalgia. Mr. C was a 46-year-old Caucasian male who had three different psychiatric hospitalizations due to suicide attempts by hanging in a 6-month period during a reportedly compliant trial of bupropion 150 mg/day with paroxetine 30 mg/day plus quetiapine 600 mg/day for auditory hallucinations that commanded suicide. In any case, he was failing to improve on his third course of medications. Contributory stressors included a recent fracture of his right lower leg in a fall and chronic pain in the same limb from an old workrelated injury. The chronic pain problem had been diagnosed as reflex sympathetic dystrophy, or under the new nomenclature, CRPS. Most of the limb was of course enclosed in his cast, but his toes were cold and discolored, and he complained of such pain that we initially feared he was developing a compartment syndrome. His orthopedic surgeon who had followed his case through the development of the regional pain syndrome reevaluated him in consultation and was able to clarify the diagnosis. Due to his severe, lifethreatening, and unremitting psychotic depression, the patient was offered ECT, and he accepted. He received anesthesia with propofol, requiring a relatively high dose of 150 mg to achieve anesthesia, and succinylcholine 100 mg for seizure modification. After
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the third treatment, the patient developed a right hemifacial palsy most consistent with Bell’s palsy. ECT was halted while neurologic consultation was obtained and an MRI performed. The brain imaging study was unremarkable. The neurologist’s diagnosis was Bell’s palsy, and this was treated with pulse prednisone. ECT was resumed without further incident. The patient received a total of 16 treatments of ECT with bilateral electrode placement using the MECTA spECTrum 5000Q unit using a 20% supra-threshold stimulus. With propofol anesthesia, however, the threshold was so high, it was frequently difficult to obtain a seizure for the patient even with maximal energy settings. The last eight treatments were performed with more success using thiopental anesthesia. Mr. C obtained a partial remission from his psychotic depression, with relief of the severe depression and suicidal ideation that compelled his hospitalization. He continued to suffer from mild depression and auditory hallucinations, although these were adequately controlled by medication. His CRPS remitted completely. He was discharged to a nursing home for continued care, where his leg fracture healed.
DISCUSSION The utility of ECT in relief of chronic pain associated with depression has been known for more than 50 years. ECT therapy has been reported to relieve regional pain syndromes before this.5–9 It has also been reported to relieve phantom limb pain, whose mechanism is mysterious, but possibly related to CRPS.8 Conditions that have been reported to respond to ECT include trigeminal neuralgia,9,10 and pain probably consistent with reflex-sympathetic dystrophy.5,6,10 ECT was advocated for eye pain associated with depression and “monosymptomatic hypochondriasis.12 Disappointing results were reported in some cases.11 A trial of ECT for thalamic pain was disappointing.13 The pain syndromes that seem to appear most often in case reports advocating ECT are neuropathic © 2003 Lippincott Williams & Wilkins
pain and complex regional pain syndromes.1,5–11,14,15 The use of ECT in chronic pain is considered experimental by most authors when major depression is not present.14,15 Some authors have begun to advocate the use of ECT for CRPS even in the absence of depression.16 The mechanism of the effect of ECT on chronic pain is fascinating but difficult to elucidate. Increases in CNS enkephalin levels and in enkephalin receptors have been demonstrated in both rats and humans during electroconvulsive stimulation, an effect that is specific to brain region.17 Moreover, antagonists to delta-enkephalin, but not to muenkephalin, blocked the antinociceptive effect of electroconvulsive stimuli.17 Similar focal changes in concentration and binding of neuropeptide transmitters after seizures has been demonstrated in the case of Substance P,18 neuropeptide Y,19 somatostatin,20 thyrotropin-releasing hormone,21 corticotropin-releasing hormone,22,23 as well as central benzodiazepine and mu-opioid receptors.23 This is consistent with the theory that ECT has its therapeutic effect by emptying transmitters from synaptic vesicles into the synapses, thereby inducing changes in postsynaptic receptors. The fact that all of these neuropeptides have some implied role in mood disorders, modulation or mediation of pain, and/or control of seizure threshold suggests the findings about enkephalins in ECT should be regarded as a beginning. This information suggests electroconvulsive stimulation studies may provide a way to systematically study the role of the various neuropeptides in mood disorders and their treatment. Two relatively recent reports of CRPS resolving during ECT for depression speculated that bilateral electrode placement might be required for this effect if stimulation of the thalami is required to effect relief of chronic pain.5,24 One of the cases reported here responded with remission of complex regional pain syndrome during unilateral ECT, arguing against this hypothesis. It is interesting that Ms. B, who suffered from chronic pain from
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both fibromyalgia and CRPS, obtained no relief from the former condition during unilateral ECT yet experienced complete and lasting relief of CRPS pain even before the nerve entrapment was identified and reduced. Recent work by Fukui et al.16,24 suggests that the end-organ for the effect of ECT on chronic pain is indeed the thalamus. In two elegant studies on patients suffering from all types of neuropathic pain and from CRPS, pain was associated with reduced ipsilateral thalamic regional cerebral blood flow (rCRBF) on single-photon emission tomography. Pain was relieved during ECT for comorbid depression, and pain relief was associated with normalization of rCRBF. Bitemporal stimulation was used in these studies of ECT for chronic pain. Fukui et al propose that ECT may be considered for complex regional pain syndromes that have failed more traditional approaches, even when no mood disorder is present.24 Other authors consider this to be still an experimental approach.14,15
CONCLUSIONS There is a mutually amplifying effect when depressed mood coexists with physical suffering; relieving depression should break this vicious cycle1. At the same time, complex regional pain syndromes are often resistant to antidepressant medications.3 Electroconvulsive therapy should be considered for treatment of depression that coexists with a regional pain syndrome. REFERENCES 1. Bradley JJ. Severe localized pain associated with the depressive syndrome. Br J Psychiatry. 1963;109: 741–745. 2. Baron R, Wasner G. Complex regional pain syndrome. Curr Headache Pain Rep. 2001;5:114–123. 3. Parker G, Roy K, Wilhelm K, et al. Assessing the comparative effectiveness of antidepressant therapies: a prospective clinical practice study. J Clin Psychiatry. 2001;62:117–125. 4. Sackeim HA. the antidepressant efficacy of highdose nondominant long-distance parietotemporal and bitemporal electroconvulsive therapy. Convuls Ther. 1994;10:43–52. 5. King JH, Nuss S. Reflex sympathetic dystrophy treated by electroconvulsive therapy: intractable pain, depression, and bilateral electrode ECT. Pain. 1993;55:393–396.
6. Mandel MR. Electroconvulsive therapy for chronic pain associated with depression. Am J Psychiatry. 1975;132:632–636. 7. Van Hagen K. Chronic intolerable pain. Report of eight cases treated with electric shock. JAMA. 1957; 165:773–777. 8. Pisetsky J. the disappearance of painful phantom limbs after electric shock treatment. Am J Psychiatry. 1946;102:599–601. 9. Janjigian ER. Report of three cases of trigeminal neuralgia apparently cured by electroshock therapy. Am J Psychiatry. 1949;106:143. 10. Weiss DM, Bloomber W, Drew JH. The use of electroshock as therapy for atypical and intractable pain. Trans Am Neurol Assoc. 1957;82:166–168. 11. Hampf G, Kuoppasalmi K, Henricksson M, et al. Chronic pain together with severe depression is responsive to electroconvulsive therapy: a case report. Acta Odontol Scand. 1992;50:129–132. 12. Bebbington PE. Monosymptomatic hypochondriasis, abnormal illness behavior and suicide. Brit J Psychiatry. 1976;128:475–478. 13. Salmon JB, Hanna MH, Williams M, et al. Thalamic pain—the effect of electroconvulsive therapy (ECT). Pain. 1988;33:67–71. 14. Bloomstein JR, Rummans TA, Maruta T, Lin SC, Pilegi TS. The use of electroconvulsive therapy in pain patients. Psychosomatics. 1996;37:374–379. 15. Rasmussen KG, Rummans TA. Electroconvulsive therapy in the management of chronic pain. Curr Pain Headache Rep. 2002;6:17–22. 16. Fukui S, Shigemori S, Yoshimura A, et al. Chronic pain with beneficial response to electroconvulsive therapy and regional cerebral blood flow changes assessed by single photon emission computed tomography. Reg Anesth Pain Med. 2002;27:211–213. 17. Holaday JW, Tortella FC, Meyerhoff JL, et al. Electroconvulsive shock activates endogenous opioid systems: behavioral and biochemical correlates. Ann N Y Acad Sci. 1986;467:249–255. 18. Martin JL, Sloviter RS. Focal inhibitory interneuron loss and principal cell hyperexcitability in the rat hippocampus after microinjection of a neurotoxic conjugate of saporin and a peptidase-resistant analog of Substance P. J Comp Neurol. 2001;436:127–152. 19. Madsen TM, Greisen MH Nielsen SM, Bolwig TG, Mikkelsen JD. Electroconvulsive stimuli enhance both neuropeptide Y receptor Y1 and Y2 messenger RNA expression and levels of binding in the rat hippocampus. Neuroscience. 2000;98:33–39. 20. Vezzani A, Hoyer D. Brain somatostatin: a candidate inhibitory role in seizures and epileptogenics. Eur J Neurosci. 1999;11:3767–3776. 21. Yamashita K, Mori A, Otsuki S. Changes in brain thyrotropin-releasing hormone (TRH) of seizureprone El mice. Exp Neurol. 1990;108:71–75. 22. Baram TZ, Mitchell WG, Brunson K, et al. Infantile spasms: hypothesis-driven therapy and pilot human infant experiments using corticotropin-releasing hormone receptor antagonists. Dev Neurosci. 1999; 21:281–289. 23. Duncan JS. Positron emission tomography receptor studies. Adv Neurol. 1999;79:893–899. 24. Fukui S, Shigemori S, Nosaka S. Changes in regional cerebral blood flow in the thalamus after electroconvulsive therapy for patients with complex regional pain syndrome type 1 (preliminary case series). Reg Anesth Pain Med. 2002;27:529–532.
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