Analysis of Common Single Nucleotide Polymorphisms in Complex Regional Pain Syndrome: Genome Wide Association Study Approach and Pooled DNA Strategy.

OBJECTIVE: The objective of this study was to use a genome-wide association (GWAS) approach and pooled DNA strategy to search for new genomic loci associated with complex regional pain syndrome (CRPS). DESIGN: The study cohort consisted of 230 patients with established diagnosis of CRPS. The control group consisted of 230 age- and gender-matched subjects without chronic pain. We tested the association of common single nucleotide polymorphisms (SNPs), genotyped using a high-density microarray platform, with CRPS phenotype. This was followed by individual genotyping of the most significant SNPs identified in the microarray genomic scan, in both original discovery (N = 115) and independent verification (N = 115) groups of patients with CRPS, as well as in the appropriate matched control subjects. RESULTS: The results of our study provide no support for the initial hypothesis of the existence of an association between any investigated genomic targets (including GWAS for all genomic loci available on the microarray, and focused scan of the HLA locus on chromosome 6) and CRPS phenotype. CONCLUSIONS: Despite the fact that we interrogated about 83% of all of common SNPs in the human genome, we did not find evidence that any of the investigated common SNPs may be associated with CRPS phenotype.

Establishing a relationship between bacteria in the human gut and complex regional pain syndrome.

Complex Regional Pain Syndrome (CRPS) is a serious and painful condition involving the peripheral and central nervous systems. Full comprehension of the disorder's pathophysiology remains incomplete, but research implicates the immune system as a contributor to chronic pain. Because of the impact gastrointestinal bacteria have in the development and behavior of the immune system, this study compares the GI microbial communities of 16 participants with CRPS (5 of whom have intestinal discomforts) and 16 healthy controls using 454 sequencing technology. CRPS subjects were found to have significantly less diversity than their healthy counterparts. Statistical analysis of the phylogenetic classifications revealed significantly increased levels of Proteobacteria and decreased levels of Firmicutes in CRPS subjects. Clustering analysis showed significant separation between healthy controls and CRPS subjects. These results support the hypothesis that the GI microbial communities of CRPS participants differ from those of their healthy counterparts. These variations may hold the key to understanding how CRPS develops and provide information that could yield a potential treatment.

MicroRNA modulation in complex regional pain syndrome.

BACKGROUND: Aberrant expression of small noncoding RNAs called microRNAs (miRNAs) is a common feature of several human diseases. The objective of the study was to identify miRNA modulation in patients with complex regional pain syndrome (CRPS) a chronic pain condition resulting from dysfunction in the central and/or peripheral nervous systems. Due to a multitude of inciting pathologies, symptoms and treatment conditions, the CRPS patient population is very heterogeneous. Our goal was to identify differentially expressed miRNAs in blood and explore their utility in patient stratification. METHODS: We profiled miRNAs in whole blood from 41 patients with CRPS and 20 controls using TaqMan low density array cards. Since neurogenic inflammation is known to play a significant role in CRPS we measured inflammatory markers including chemokines, cytokines, and their soluble receptors in blood from the same individuals. Correlation analyses were performed for miRNAs, inflammatory markers and other parameters including disease symptoms, medication, and comorbid conditions. RESULTS: Three different groups emerged from miRNA profiling. One group was comprised of 60% of CRPS patients and contained no control subjects. miRNA profiles from the remaining patients were interspersed among control samples in the other two groups. We identified differential expression of 18 miRNAs in CRPS patients. Analysis of inflammatory markers showed that vascular endothelial growth factor (VEGF), interleukin1 receptor antagonist (IL1Ra) and monocyte chemotactic protein-1 (MCP1) were significantly elevated in CRPS patients. VEGF and IL1Ra showed significant correlation with the patients reported pain levels. Analysis of the patients who were clustered according to their miRNA profile revealed correlations that were not significant in the total patient population. Correlation analysis of miRNAs detected in blood with additional parameters identified miRNAs associated with comorbidities such as headache, thyroid disorder and use of narcotics and antiepileptic drugs. CONCLUSIONS: miRNA profiles can be useful in patient stratification and have utility as potential biomarkers for pain. Differentially expressed miRNAs can provide molecular insights into gene regulation and could lead to new therapeutic intervention strategies for CRPS.

Enantioselective pharmacokinetics of (R)- and (S)-ketamine after a 5-day infusion in patients with complex regional pain syndrome.

INTRODUCTION: This study determined the pharmacokinetics and pharmacodynamics of (R)- and (S)-ketamine and (R)- and (S)-norketamine following a 5-day moderate dose, as a continuous (R,S)-ketamine infusion in complex regional pain syndrome (CRPS) patients. MATERIALS AND METHODS: Ketamine was titrated to 10-40 mg/h and maintained for 5 days. (R)- and (S)-Ketamine and (R)- and (S)-norketamine pharmacokinetic and pharmacodynamic studies were performed. Blood samples were obtained on Day 1 preinfusion, and at 60-90, 120-150, 180-210, and 240-300 min after the start of the infusion, on Days 2, 3, 4, 5, and on Day 5 at 60 min after the end of infusion. The plasma concentrations of (R)- and (S)-ketamine and (R)- and (S)-norketamine were determined using enantioselective liquid chromatography-mass spectrometry. RESULTS: Ketamine and norketamine levels stabilized 5 h after the start of the infusion. (R)-Ketamine clearance was significantly lower resulting in higher steady-state plasma concentrations than (S)-ketamine. The first-order elimination for (S)-norketamine was significantly greater than that of (R)-enantiomer. When comparing the pharmacokinetic parameters of the patients who responded to ketamine treatment with those who did not, no differences were observed in ketamine clearance and the first-order elimination of norketamine. CONCLUSION: The results indicate that (R)- and (S)-ketamine and (R)- and (S)-norketamine plasma concentrations do not explain the antinociceptive activity of the drug in patients suffering from CRPS.

Hsa-miR-605 regulates the proinflammatory chemokine CXCL5 in complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by inflammation and debilitating pain. CRPS patients with pain refractory to more conventional analgesics can be treated with subanesthetic doses of ketamine. Our previous studies found that poor responders to ketamine had a 22-fold downregulation of the miRNA hsa-miR-605 in blood prior to ketamine treatment. Hence, we sought to investigate the functional significance of miR-605 downregulation and its impact on target gene expression, as investigating target mRNAs of differentially expressed miRNAs can provide important insights on aberrant gene expression that may contribute to disease etiology. Using a bioinformatics prediction, we identified that miR-605 can target the proinflammatory chemokine CXCL5, which plays a role in leukocyte recruitment and activation. We hypothesized that downregulation of miR-605 in poor responders to ketamine could increase CXCL5 expression and thereby contribute to inflammation in these patients. We confirmed that miR-605 regulates CXCL5 by using a miRNA mimic and inhibitor in human primary endothelial cells. Inhibition of miR-605 increased CXCL5 secretion and migration of human monocytic cells, thereby demonstrating a functional impact of miR-605 on chemotaxis. Additionally, CXCL5 mRNA was upregulated in whole blood from poor responders to ketamine, and CXCL5 protein was increased in plasma from CRPS patients. Thus, our studies suggest that miR-605 regulation of CXCL5 can regulate inflammation.

Neuropsychological deficits associated with Complex Regional Pain Syndrome.

We sought to elucidate the existence of neuropsychological subtypes in Complex Regional Pain Syndrome (CRPS). One hundred thirty seven patients with CRPS were administered tests that assess executive control, naming/lexical retrieval, and declarative memory. A 2-step cluster analysis that does not require any a priori specification regarding the number of clusters, classified patients into three groups. Group 1 obtained scores that were in the average range on all tests (n = 48; normal CRSP group). Group 2 (n = 58; dysexecutive CRSP group) presented with mild impairment or statistically low average test performance on working memory/verbal fluency tests. Group 3 (n = 31; global CRSP group) produced scores in the statistically low average/borderline range on all tests with particularly reduced scores on naming/declarative memory tests. Between-group analyses found that the CRPS group 1 obtained higher scores than CRPS groups 2 and 3 on all tests. However, groups 2 and 3 were equally impaired on executive tests. CRPS group 3 was impaired on tests of naming/memory tests compared to the other groups. Significant neuropsychological deficits are present in 65% of patients, with many patients presenting with elements of a dysexecutive syndrome and some patients presenting with global cognitive impairment.

Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a chronic pain condition that usually arises from an injury or as a complication from a surgical procedure. CRPS can result from multiple mechanisms including active processes involving both the peripheral and the central nervous system and sickness like responses involving interactions between the immune and nervous systems. In animal models both peripheral and central sensitization as well as loss of inhibition has been implicated in neuropathic pain states. Glial cells, in particular microglia and astrocytes, are the immunocompetent cells in the central nervous system and are activated following tissue injury or inflammation. In animal studies, activated glia have been shown to be both necessary and sufficient for enhanced nociception. Using immunohistochemical techniques, this study evaluated the degree of astrocytic and microglial activation as well as neuronal loss in autopsy tissue from the cervical, thoracic and lumbar spinal cord of a patient afflicted with CRPS as compared to four control individuals. The major findings of this study are that in long standing CRPS there was significant posterior horn cell loss and activation of both microglia and astrocytes most prominently at the level of the original injury but extending throughout the entire length of the spinal cord. Our hope is that the data obtained from this and other studies of autopsy material may aid in elucidating the mechanisms involved in the pathophysiology of CRPS, which may lead to the refinement of current therapies as well as novel treatments.

Efficacy of 5-day continuous lidocaine infusion for the treatment of refractory complex regional pain syndrome.

OBJECTIVE: Chronic regional pain syndrome (CRPS) is a severe pain condition that usually results from an injury or surgical procedure. The pain in CRPS often spreads from the site of injury, and with time becomes refractory to conventional therapy. The present study was undertaken to evaluate the effects of 5-day continuous intravenous lidocaine treatment in patients afflicted with CRPS. METHODS: Intravenous lidocaine was administered in an escalating dose schedule to 49 severely affected CRPS patients in a monitored setting over 5 days. Evaluation of pain parameters and other signs and symptoms of CRPS were obtained during the infusion and at 1, 3, and 6 months following therapy. RESULTS: The majority of patients demonstrated a significant decrease in pain parameters and other symptoms and signs of CRPS. The pain reduction lasted an average of 3 months. Lidocaine may be particularly effective for thermal and mechanical allodynia. Less clinically significant effects were documented on the motor aspects of the syndrome. DISCUSSION: Intravenous lidocaine administration titrated to 5 mg/L demonstrated: 1) a significant decrease in mechanical and thermal allodynia for three months, 2) lessened associated inflammatory components of CRPS, and 3) only minimal side effects and no severe complications.

Validating an Ataxia Functional Composite Scale in spinocerebellar ataxia.

The Ataxia Functional Composite Scale (AFCS) may provide a sensitive and reproducible assessment of treatment responses in studies of the spinocerebellar ataxias (SCA). We previously assessed the effects of buspirone in a cohort of patients with SCA via the International Cooperative Ataxia Rating Scale (ICARS). At each assessment period, AFCS scores were also obtained. A strong correlation of AFCS with ICARS scores was demonstrated at all assessment periods. This study supports the validity of the AFCS as a useful assessment of ataxia in this population.

Brachial plexus traction injury: quantification of sensory abnormalities.

OBJECTIVE: Stretch injury to the brachial plexus may occur following traumatic flexion-extension of the cervical spine often seen in motor vehicle accidents or falls. Radiologic and conventional nerve conduction studies are negative in many cases. The present study was undertaken in an attempt to simplify, standardize, and quantify the positive and negative sensory abnormalities that are most often seen during the clinical examination. METHODS: Quantitation of thresholds for thermal detection and pain, vibration, pressure pain and elevated arm stress test was performed in a series of 38 patients with the clinical picture of brachial plexus traction injury as well as a group of age and sex matched control subjects. RESULTS: Significant decreases in all evoked pain thresholds, except for heat pain, along with increases in sensory detection thresholds were found in the patient group compared with controls. DISCUSSION: Quantification of sensory findings may greatly facilitate and substantiate the diagnosis of this type of injury. The data are consistent with the hypothesis that brachial plexus traction injury causes dysfunction of small sensory fiber systems and results in a form of neuropathic pain.

Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study.

OBJECTIVE: Advanced complex regional pain syndrome (CRPS) remains very difficult to treat. While subanesthetic low-dose ketamine has shown promise in early localized CRPS, its use in advanced CRPS has not been as effective. Since ketamine's analgesic potency and duration of effect in neuropathic pain are directly dose-dependant, we investigated the efficacy of ketamine in anesthetic dosage in refractory CRPS patients that had failed available standard therapies. METHODS: Twenty ASA I-III patients suffering from refractory CRPS received ketamine in anesthetic dosage over 5 days. Outcome criteria were pain relief, effect on the movement disorder, quality of life, and ability to work at baseline and up to 6 months following treatment. RESULTS: Significant pain relief was observed at 1, 3, and 6 months following treatment (93.5 +/- 11.1%, 89.4 +/- 17.0%, 79.3 +/- 25.3%; P < 0.001). Complete remission from CRPS was observed at 1 month in all patients, at 3 months in 17, and at 6 months in 16 patients. If relapse occurred, significant pain relief was still attained at 3 and 6 months (59.0 +/- 14.7%, P < 0.004; 50.2 +/- 10.6%, P < 0.002). Quality of life, the associated movement disorder, and the ability to work significantly improved in the majority of patients at 3 and 6 months. CONCLUSIONS: This open-label trial suggests benefit in pain reduction, associated CRPS symptoms, improved quality of life and ability to work following anesthetic ketamine in previously refractory CRPS patients. However, a randomized controlled trial will be necessary to prove its efficacy.

Prevalence of complex regional pain syndrome in a cohort of multiple sclerosis patients.

BACKGROUND: More than 50% of multiple sclerosis patients experience chronic pain syndrome. We set out to determine the specific type of chronic pain that was seen in our multiple sclerosis patients. METHODS: Patients with multiple sclerosis were catalogued between January 2002 and April 2006 and identified by a search of the database. Only MS patients that met the 2005 revised McDonald criteria were included. RESULTS: We determined the prevalence rate of complex regional pain syndrome in a cohort of multiple sclerosis patients. In our sample of 205 multiple sclerosis patients, the prevalence of complex regional pain syndrome was 4 cases per 205 compared to an expected age and sex-adjusted total prevalence of 0.078 cases per 205 (p < 0.0001). CONCLUSION: This study suggests that multiple sclerosis patients are at a higher risk of developing complex regional pain syndrome than the general population.

Deep cervical plexus block for the treatment of cervicogenic headache.

BACKGROUND: Cervicogenic headache descriptors include its unilateral nature, "signs and symptoms linking it to the neck," and trauma of the neck. Since the pain often occurs over the C2 or C3 nerve root, we used a modification of the deep cervical block technique for treatment of this refractory type headache. OBJECTIVE: To determine the efficacy of a modified deep cervical block for treatment of cervicogenic headache. DESIGN: Prospective case study. METHODS: Thirty-nine patients referred to our pain clinic participated in this study. All patients had undergone extensive screening/diagnostic testing. The blocks were performed unilaterally, without inducing a risk of invading the neural foramen, and repeat injection of the contra-lateral side occurred at >1 week after initial injection. Patients were followed for a 6-month period using a pain diary and questionnaire. Pain was assessed pre- and post-injection and 3 and 6 months post treatments. RESULTS: The mean treatment period was 59 +/- 61 days. The mean values for pre- and post-injection series pain scores (0-10 pain scale) were 9.54 +/- 1.53 and 6.75 +/- 3.23 respectively (p <0.001). Thirty-three percent (33%) of the patients reported pain scores of < or = 4 on the 0-10 pain scale after their last treatment. Effectiveness of the therapy following the injection procedure was rated to be 42% effective for all first injections and 40% effective for last injections (p =NS). Six months evaluations showed that return of moderate to severe pain took 6.62 +/- 8.1 weeks. At the 3 and 6 months follow up evaluations, mean pain scores had returned to 8.41 +/- 2.96 and 8.83 +/- 2.78, respectively. Ten patients (24%) had pain scores < or = 4 at the 3-month evaluation while 7 of the patients (18%) had pain scores < or = 4 at the 6-month evaluation. CONCLUSIONS: These results showed that for some patients this series of blocks provided effective pain relief for 3 months post treatment but by 6 months the pain had returned to pre-treatment levels. This block technique significantly diminished pain after the initial as well as the last treatment. These clinically significant changes in pain relief suggest that more aggressive selective therapy targeting these nerve routes might provide longer lasting relief.

miR-34a-mediated regulation of XIST in female cells under inflammation.

BACKGROUND: Evidence is overwhelming for sex differences in pain, with women representing the majority of the chronic pain patient population. There is a need to explore novel avenues to elucidate this sex bias in the development of chronic inflammatory pain conditions. Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder, and the incidence of CRPS is greater in women than in men by ~4:1. Since neurogenic inflammation is a key feature of CRPS, dysregulation of inflammatory responses can be a factor in predisposing women to chronic pain. METHODS: Our studies investigating alterations in circulating microRNAs (miRNAs) in whole blood from female CRPS patients showed significant differential expression of miRNAs between responders and poor responders to ketamine treatment. Several of these miRNAs are predicted to target the long noncoding RNA, X-inactive-specific transcript (XIST). XIST mediates X-chromosome inactivation and is essential for equalizing the expression of X-linked genes between females and males. Based on the well-established role in inflammatory process, we focused on miR-34a, one of the miRNAs predicted to target XIST, and downregulated in CRPS patients responding poorly to ketamine. RESULTS: Our in vitro and in vivo models of acute inflammation and data from patients with CRPS showed that miR-34a can regulate XIST under inflammation directly, and through pro-inflammatory transcription factor Yin-Yang 1 (YY1). XIST was significantly upregulated in a subset of CRPS patients responding poorly to ketamine. CONCLUSION: Since dysregulation of XIST can result in genes escaping inactivation or reactivation in female cells, further investigations on the role of XIST in the predominance of chronic inflammatory and pain disorders in women is warranted.

Treatment of spinocerebellar ataxia with buspirone.

Preliminary data suggest potential benefit of 5-HT receptor agonists in the treatment of ataxias. We studied the effects of buspirone in a cohort of twenty patients with spinocerebellar ataxia (SCA). Twenty patients were treated in this double-blind, placebo controlled, cross-over trial with either buspirone HCl 30 mg twice daily or placebo for 3 months. Buspirone was not shown to be superior to placebo in the treatment of patients with SCA.

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

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.

Treatment of CRPS with ECT.

BACKGROUND: Electroconvulsive therapy (ECT) is a well-established treatment method for medically refractory depression. ECT has also been used in the treatment of pain for over 50 years. The mechanism of action of ECT is still unknown, although several observations have been made regarding the effect of ECT on pain processes. It has been reported that several patients with medically refractory depression and Complex Regional Pain Syndrome who were treated with ECT for their depression were also cured of their CRPS symptoms. OBJECTIVE: We report a case of CRPS in a patient who also suffered from medically refractory depression. She was treated with ECT for her depression and subsequently was relieved of all her CRPS symptoms. CASE REPORT: A 42 year-old female patient underwent a series of 12 standard bitemporal electroconvulsive therapy treatments for medically refractory depression. Physical examination and Quantitative Sensory Testing was done before and after the patient's treatment with ECT. This standard treatment procedure for refractory depression completely resolved the patient's depressive symptoms. In addition, the patient's CRPS symptoms were also reversed. Physical examination as well as Quantitative Sensory Testing done before and after the ECT treatment correlated with her CRPS symptom improvement. CONCLUSION: ECT was effective in the treatment of severe refractory CRPS in this patient.

Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS.

Complex Regional Pain Syndrome (CRPS) Types I and II are characterized by various combinations of sensory, autonomic and motor abnormalities. Pain disproportionate to the severity and duration of the inciting event is the most devastating symptom. In animal studies, conditions resulting in exaggerated pain states demonstrate elevated pro-inflammatory cytokines. In addition, pro-inflammatory cytokines have been shown to induce or increase neuropathic and inflammatory pain. Utilizing high sensitivity enzyme linked immunosorbent assay (ELISA), we compared the levels of the pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-alpha) in the cerebrospinal fluid (CSF) of patients afflicted with CRPS to CSF levels found in other patients with and without painful conditions. The results from this study demonstrated significant increases in IL-1beta and IL-6, but not TNF-alpha in the CSF of individuals afflicted with CRPS as compared to controls. CSF cytokine levels in controls with painful conditions did not differ from levels in controls without pain. These increases showed no correlation with the patient's gender or weight. These results are consistent with studies that suggest that the pathogenesis of CRPS is due in part to central neuroimmune activation.

Diffuse cerebral air embolism treated with hyperbaric oxygen: a case report.

A 54-year-old woman presented for cardiac evaluation of atypical chest pain. Workup included coronary angiography and a left ventriculogram, during which air was inadvertently injected, resulting in the development of an acute right hemisphere syndrome. Right carotid angiography was immediately performed, yielding only a delayed diffuse venous phase without focal vessel cutoffs. Within 60 minutes, the patient underwent hyperbaric oxygen therapy for the suspected cerebral air emboli. After removal from the chamber for technical reasons, she had a generalized tonic-clonic seizure, and further hyperbaric oxygen therapy was withheld. Initial computed tomography imaging obtained approximately 8 hours after symptom onset showed signs of early right hemispheric edema. Subsequent magnetic resonance imaging studies were markedly abnormal and suggestive of diffuse bilateral but predominantly right-sided parietal lobe edema with mildly positive diffusion-weighted imaging. Follow-up magnetic resonance imaging at 6 months was normal, and the patient's neurological examination returned to normal.

Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is characterized by pain that is out of proportion to the injury and is regional in distribution. A large body of literature supports a dynamic change in the physiology and structure of central pain projecting neurons mediated through the N-methyl-D-aspartate (NMDA) receptor. A critical factor in central sensitization seems to be the release of the magnesium block on the NMDA receptor with influx of calcium and initiation of intracellular cascades. Current literature supports the effectiveness of ketamine in blocking central sensitization through its effects on the NMDA receptor. Recent treatment with anesthetic doses of ketamine in severely ill patients with generalized CRPS prompted our interest in a lower dose therapy. OBJECTIVE: To report on the efficacy of low dose outpatient ketamine infusion for the treatment of CRPS diagnosed by International Association for the Study of Pain (IASP) criteria in patients who have failed conservative treatment. DESIGN: Open label, prospective, pain journal evaluation of a 10-day infusion of intravenous ketamine in the CRPS patient. METHODS: Patients diagnosed with CRPS by a single neurologist were assigned to receive a 10-day outpatient infusion of ketamine supervised by an Anesthesiologist/Pain Management Specialist. The infusion was administered in a short procedure unit after each patient had been instructed on how to complete a pain questionnaire. Monitoring consisted of continuous ECG, pulse oximetry, and non-invasive blood pressure every 15 minutes. Patients made journal entries each day prior to the infusion of 40-80 mg of ketamine. The subjects were also asked to rate their pain intensity using a verbal analog pain scale of 0-10 and the affective component using a verbal scale of 0-4. RESULTS: There was a significant reduction in pain intensity from initiation of infusion (Day 1) to the 10th day, with a significant reduction in the percentage of patients experiencing pain by Day 10 as well as a reduction in the level of their "worst" pain. The nadirs of pain were lower by Day 10 with a significant reduction in the incidence of "punishing pain." Moreover, there was a significant improvement in the ability to initiate movement by the 10th day. CONCLUSION: A four-hour ketamine infusion escalated from 40-80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation.