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The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome. 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. Keywords. RSD; Complex regional pain syndrome; Neuropsychology; Memory; Pain; Ketamine; Ketamine infusion therapy.
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 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, 2. It is associated in varying degrees with neurogenic edema, autonomic dysregulation, movement disorder, and atrophic and dystrophic changes of the affected parts (Janig & Baron, 2. Schwartzman & Popescu, 2. 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, Le.
Bel, Bennett, & Schwartzman, 2. Criteria for diagnosis of CRPS were derived in a special consensus conference of the International Association for the Study of Pain (IASP) (Wilson, 2. 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, Mc. Clelland, & Low, 2. 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, 2. 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 1. Harden & Bruehl, 2. Janig & Baron, 2.
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, 2. Woolf & Salter, 2.
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, 2. 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, 2. However, prospective studies of patients undergoing total knee arthoplasty (Harden et al., 2.
Puchalski & Zyluk, 2. CRPS following surgery. Such results are consistent with De Good and colleagues’ finding that patients with CRPS expressed less emotional distress than patients with other forms of chronic pain (De Good, Cundiff, Adams, & Shutty, 1. Thus, there appears to be little prospective evidence to support the relationship between premorbid psychological distress (e. CRPS 1. Treatment for CRPS I can be pathophysiologically oriented (steroids, sympathetic blocks, radical scavengers), symptomatically oriented (antidepressants, antiepileptics, opioids), or non- drug based (physical therapy, transcutaneous electrical nerve stimulation) [for a review see Birklein, 2. Because these treatments tend to have only modest therapeutic benefits, novel therapeutic interventions, such as ketamine infusion therapy, have recently been attempted in this patient population.
Ketamine is a non- barbituate anesthetic that is recognized for its dissociative, analgesic, and psychedelic properties (Hirota & Lambert, 1. It has been described as an “ideal” anesthetic agent due to its rapid onset, absence of cardiorespiratory depressant effects, and benign effect on muscle tone and protective airway reflexes (Ceber & Salihoglu, 2.
Aside from its use in chronic pain, there is a growing body of research that is examining the utility of ketamine in patients with treatment- refractory depression (Zarate et al., 2. There is clinical and experimental evidence for the importance of the N- methyl- d- aspartate (NMDA) receptor in many neuropathic pain conditions, including CRPS (Correll, Maleki, Gracely, Muir, & Harbut, 2. Jorum, Warncke, & Stubhaug, 2.
Sheng & Kim, 2. Ushida et al., 2. Ketamine has potent NMDA receptor- blocking properties and was first used successfully to treat an adult female who had had CRPS I for 9 years (Harbut & Correll, 2. This treatment was administered as an inpatient subanesthetic (i. Following this infusion, the patient obtained complete relief of her lower extremity CRPS and remained pain free for 1.
A few more CRPS I patients have been successfully treated ( Correll et al., 2. Kiefer et al., 2.
Kiefer et al., 2. However, there has been little research performed on the effectiveness of ketamine treatment at a group level, especially when using anesthetic doses of the drug.