The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome

Archives of Clinical Neuropsychology 22 (2007) 719–729 The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome Sandra P. Koffler a,∗ , Benjamin M. Hampstead b,c , Farzin Irani d , Jennifer Tinker d , Ralph-Thomas Kiefer e , Peter Rohr f , Robert J. Schwartzman g a b Department of Psychiatry, College of Medicine, Drexel University, Philadelphia, PA 19102, USA VA Rehabilitation R&D Center of Excellence for Aging Veterans with Vision Loss, Atlanta VA Medical Center, Decatur, GA 30033, USA c Department of Rehabilitation Medicine, Emory University, Atlanta, GA 30322, USA d Department of Psychology, Drexel University, Philadelphia, PA 19104, USA e Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls University, Tuebingen, Germany f Department of Anesthesiology, Intensive Care and Emergency Medicine, and Pain Therapy, Klinikum-Saarbruecken, Germany g Department of Neurology, College of Medicine, Drexel University, Philadelphia, PA 19102, USA Accepted 22 May 2007 Abstract BACKGROUND: Complex regional pain syndrome I (CRPS) is characterized by severe neuropathic pain that exceeds the severity of an injury and is refractory to traditional treatments. Recent experimental interventions include ketamine infusion therapy. OBJECTIVE: We sought to evaluate the physical, neurocognitive, and emotional effects of extended treatment with anesthetic doses of ketamine in refractory CRPS I patients. METHODS: Nine patients (eight females) received a neuropsychological evaluation pre- and 6 weeks post-treatment that evaluated intellectual and academic abilities, executive functioning/processing speed, attention, learning and memory, and motor functioning. Mood/affect and personality were also evaluated and patients completed an extensive pain questionnaire. RESULTS: There was a marked reduction in the report of both acute and overall pain after treatment. Brief attention and processing speed improved significantly post-treatment, whereas all other cognitive domains remained stable, with the exception of a mild decline in motor strength. CONCLUSIONS: Findings suggest that, at least at a 6-week follow up: (1) deep ketamine therapy is effective for relief of pain CRPS I and (2) there were no adverse cognitive effects of extended treatment with deep ketamine infusion. No definitive conclusions could be drawn about the relationship between mood and personality factors and the presence of CRPS I. © 2007 National Academy of Neuropsychology. Published by Elsevier Ltd. All rights reserved. Keywords: RSD; Complex regional pain syndrome; Neuropsychology; Memory; Pain; Ketamine; Ketamine infusion therapy 1. Introduction While pain is necessary for survival, the effects of chronic pain can significantly impair functioning across many aspects of daily life. Complex regional pain syndrome (CRPS) is associated with a severe neuropathic pain out of ∗ Corresponding author at: Drexel University College of Medicine, Department of Psychiatry, 245 North 15th Street, Mail Stop 341, Philadelphia, PA 19107, USA. Tel.: +1 215 762 4956; fax: +1 215 762 1537. E-mail address: (S.P. Koffler). 0887-6177/$ – see front matter © 2007 National Academy of Neuropsychology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.acn.2007.05.005 720 S.P. Koffler et al. / Archives of Clinical Neuropsychology 22 (2007) 719–729 proportion to the extent of the causal injury. Characteristics of the pain include: ordinarily non-painful stimuli evoke pain (allodynia) and this can be caused by light touch or pressure (mechanoallodynia) or changes in skin temperature (thermal allodynia), extreme sensitivity to pain (hyperalgesia), and the tendency for innocuous stimuli to become painful if exposure is repeated or prolonged (hyperpathia; Schwartzman, Alexander, & Grothusen, 2006). It is associated in varying degrees with neurogenic edema, autonomic dysregulation, movement disorder, and atrophic and dystrophic changes of the affected parts (Janig & Baron, 2003; Schwartzman & Popescu, 2002). The pain most often follows injury to soft tissue, plexi, nerve roots or directly to the peripheral nerve and frequently spreads to the contralateral side of the body in a mirror distribution, possibly encompassing the entire body (Maleki, LeBel, Bennett, & Schwartzman, 2000). Criteria for diagnosis of CRPS were derived in a special consensus conference of the International Association for the Study of Pain (IASP) (Wilson, 2004) and are as follows: (1) preceding noxious event without (CRPS I) or with obvious nerve lesion (CRPS II), (2) spontaneous pain or hyperalgesia/hyperesthesia not limited to a single nerve territory and disproportionate to the inciting event, (3) edema, skin blood flow (temperature) or pseudomotor abnormalities, motor symptoms or trophic changes are present on the affected limb, in particular at distal sites, (4) other diagnoses are excluded. The current study focuses on the CRPS I variant which was formerly known as reflex sympathetic dystrophy (RSD). CRPS I is a relatively rare condition that more commonly affects women than men and occurs more often in the upper extremities compared to the lower ones (Sandroni, Benrud-Larson, McClelland, & Low, 2003). Factors that predispose one to CRPS I have been suggested but remain controversial. Potential physical causes include a specific additional trauma caused by reduction of a displaced fracture, inadequate anesthesia during fracture reduction, poor pain relief during rehabilitation, pressure and swelling due to a tight plaster cast, and long-term administration of antiepileptic and anti-tuberculosis drugs [for a review see Zyluk, 2004]. Recent clinical and experimental evidence point to a significant role of the central nervous system in the pathophysiology and symptomatology of CRPS, with CNS lesions being causative in approximately 10% of patients (Harden & Bruehl, 2005; Janig & Baron, 2003). It has also been suggested that a variety of physiological and immune processes may be the underlying mechanisms for the initial development and maintenance of peripheral and central sensitization (Watkins & Maier, 2005; Woolf & Salter, 2000). Although controversial, psychological factors have also been proposed to be primary to the development of CRPS; however, there are limited data to support this relationship (Zyluk, 2004). For example, patients with CPRS-I demonstrated a psychological profile, as measured through clinical interview and the Minnesota Multiphasic Personality Inventory, that was highly similar to a group of patients diagnosed with conversion disorder (Shiri, Tsenter, Livai, Schwartz, & Vatine, 2003). However, prospective studies of patients undergoing total knee arthoplasty (Harden et al., 2003) or surgery for distal radial fracture (Puchalski & Zyluk, 2005), have failed to consistently demonstrate a relationship between pre-operative emotional distress and the development of CR (...truncated)