There is limited information on medical students’ perceptions of peer feedback in team-based learning (TBL), both in terms of its value and how it has affected them as they move forward in their careers. The primary goals of this study were to examine students’ perceptions about their peer feedback experiences throughout medical school and into residency and to identify areas for improvement to develop a more valuable experience. This study utilized exploratory qualitative research. A total of six focus group sessions were conducted, in which each group consisted of medical students or residents. All participants were asked for their thoughts about peer feedback using semi-structured interviews. The sessions were transcribed and thematic analysis of student responses was completed by independent reviewers. A total of 11 first-year, 12 second-year, 12 rising third-year, and 10 rising fourth-year medical students participated in the focus groups. In addition, three graduates participated in the study. Overall, four key themes were identified regarding the peer feedback experience. These included (1) preparation and training, (2) procedure and implementation, (3) evaluation of student feedback, and (4) student considerations. The participants indicated that the idea of providing and receiving effective peer feedback throughout the medical school curriculum was a valuable experience. This analysis raised awareness about several potential areas of difficulty for students in regard to the peer feedback process used in TBL. Quality improvement initiatives may include educating students about the use of constructive feedback, adding self-reflection, or using oral instead of written feedback.

Introduction:Suicide is a global health problem that health care providers must feel comfortable addressing. Unfortunately, many health care providers are not equipped to assess and treat patients at risk for suicide due to lack of training and education. Interactive resources are needed to educate health professions students about the management of suicidal patients.Methods:The suicide assessment and management team-based learning (TBL) module was developed to address the gap in suicide education. After completing the module, students were able to identify key elements for a comprehensive assessment of a patient's risk for suicide and to discuss clinical management for a suicidal patient. The activity was designed for second-year medical students during a psychopathology course, the last organ-system course prior to clerkships. This module could also be used or modified to meet the educational requirements for other health professions, including medical residents, nurse practitioner students, and physician assistant students.Results:A total of 342 students among 62 teams participated in the TBL over a period of 3 consecutive years. The class averages for the individual Readiness Assurance Test ranged from 80% to 88%. The class averages for the team Readiness Assurance Test and application questions were comparable across all 3 years. Course evaluations showed the TBL helped students think critically and integrate information to prepare them for their future careers.Discussion:Overall, this TBL was an effective educational tool that stimulated high-quality discussion, in which students remained engaged and asked thought-provoking questions.

Poster: EANM 19 / EPS-109 / Towards automated whole-body MTV/TLG calculation using artificial intelligence uptake classification by: C. A. Von Gall, D. Thomas, L. Sibille, V. Shah, B. Spottiswoode; Siemens Medical Solutions USA Inc, Knoxville, UNITED STATES OF AMERICA

Adolescents and young adults disproportionately abuse 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy'); however, since most MDMA research has concentrated on adults, the effects of MDMA on the developing brain remain obscure. Therefore, we evaluated place conditioning to MDMA (or saline) during late adolescence and assessed anxiety-like behavior and monoamine levels during abstinence. Rats were conditioned to associate 5 or 10mg/kg MDMA or saline with contextual cues over 4 twice-daily sessions. Five days after conditioning, anxiety-like behavior was examined with the open field test and brain tissue was collected to assess serotonin (5-hydroxytryptamine, 5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal raphe, amygdala, and hippocampus by high-pressure liquid chromatography (HPLC). In a separate group of rats, anxiety-like and avoidant behaviors were measured using the light-dark box test under similar experimental conditions. MDMA conditioning caused a place aversion at 10, but not at 5, mg/kg, as well as increased anxiety-like behavior in the open field and avoidant behavior in light-dark box test at the same dose. Additionally, 10mg/kg MDMA decreased 5-HT in the dorsal raphe, increased 5-HT and 5-HIAA in the amygdala, and did not alter levels in the hippocampus. Overall, we show that repeated high (10mg/kg), but not low (5mg/kg), dose MDMA during late adolescence in rats increases anxiety-like and avoidant behaviors, accompanied by region-specific alterations in 5-HT levels during abstinence. These results suggest that MDMA causes a region-specific dysregulation of the serotonin system during adolescence that may contribute to maladaptive behavior.

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its re-uptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. As mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity.

Adult Sprague-Dawley (SD) male rats were exposed for a single 3 h period to air, ozone (O-3) or O-3 followed by tobacco smoke (O-3/nTS). For pulmonary effects, bronchoalveolar lavage (BAL) cells and fluid were analyzed. Data revealed a significant increase in polymorphonuclear leukocytes (PMN), total protein and albumin concentrations in the O-3 group, reflecting inflammatory and toxic responses. A subsequent exposure to TS attenuated PMN infiltration into the airspaces and their recovery in the BAL. A similar reduction was observed for BAL protein and albumin in the O-3/nTS group, but it was not statistically significant. We also observed a significant increase in BAL total antioxidant capacity following O-3 exposure, suggesting development of protective mechanisms for oxidative stress damage from O-3. Exposure to TS attenuated the levels of total antioxidant capacity. Lung tissue protein analysis showed a significant reduction of extracellular superoxide dismutase (EC-SOD) in the O-3 or O-3/nTS group and catalase in the O-3/nTS group. TS further altered O-3-induced EC-SOD and catalase protein expression, but the reductions were not significant. For effects in the central nervous system (CNS), we measured striatal dopamine levels by HPLC with electrochemical detection. O-3 exposure produced a nonsignificant decrease in the striatal dopamine content. The effect was partially reversed in the O-3/nTS group. Overall, the results show that the toxicity of O-3 in the lung is modulated by TS exposure, and the attenuating trend, though nonsignificant in many cases, is contrary to the synergistic toxicity predicted for TS and O-3, suggesting limited cross-tolerance following such exposures.

J. Neurochem. (2012) 120, 1097–1107.AbstractMephedrone (4‐methylmethcathinone) is a β‐ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the United States and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge‐like regimen of mephedrone (4 × 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum.

J. Neurochem. (2012) 121, 974–984.AbstractNeuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive–compulsive disorder; OCD) and impulse‐control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2−/−), the initial and rate‐limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2−/− mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2−/− mice with its immediate precursor 5‐hydroxytryptophan attenuated compulsive and impulsive–aggressive behaviors. Surprisingly, in Tph2−/− mice, the lack of 5HT was not associated with anxiety‐like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.

Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure.

Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4h to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity.

J. Neurochem. (2010) 115 , 595–605. Abstract Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long‐term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH‐induced neurotoxicity, most likely as a substrate for non‐enzymatic oxidation by METH‐generated reactive oxygen species. The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long‐term depletion of 5HT stores). 5HT can also be modified by reactive oxygen species to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5‐hydroxytryptophan do not change METH‐induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p ‐chlorophenylalanine are without effect on METH toxicity, despite the fact that p ‐chlorophenylalanine largely prevents METH‐induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild‐type controls, despite showing enhanced drug‐induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH‐induced damage to DA nerve endings of the striatum.

Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the caudate-putamen (CPu) where long-term DA depletion and microglial activation are most evident. Even damage within the CPu is remarkably heterogenous with lateral and ventral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared of the damage that accompanies binge METH intoxication. Increases in cytoplasmic DA produced by reserpine, L-DOPA or clorgyline prior to METH uncover damage in the NAc as evidenced by microglial activation and depletion of DA, tyrosine hydroxylase (TH), and the DA transporter. These effects do not occur in the NAc after treatment with METH alone. In contrast to the CPu where DA, TH, and DA transporter levels remain depleted chronically, DA nerve ending alterations in the NAc show a partial recovery over time. None of the treatments that enhance METH toxicity in the NAc and CPu lead to losses of TH protein or DA cell bodies in the substantia nigra or the ventral tegmentum. These data show that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of METH to include brain structures not normally targeted for damage by METH alone. The resistance of the NAc to METH-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of METH neurotoxicity by alterations in DA homeostasis is significant in light of the important roles played by this brain structure.

Methamphetamine (METH) damages dopamine (DA) nerve endings by a process that has been linked to microglial activation but the signaling pathways that mediate this response have not yet been delineated. Cardona et al. [Nat. Neurosci. 9 (2006), 917] recently identified the microglial-specific fractalkine receptor (CX3CR1) as an important mediator of MPTP-induced neurodegeneration of DA neurons. Because the CNS damage caused by METH and MPTP is highly selective for the DA neuronal system in mouse models of neurotoxicity, we hypothesized that the CX3CR1 plays a role in METH-induced neurotoxicity and microglial activation. Mice in which the CX3CR1 gene has been deleted and replaced with a cDNA encoding enhanced green fluorescent protein (eGFP) were treated with METH and examined for striatal neurotoxicity. METH depleted DA, caused microglial activation, and increased body temperature in CX3CR1 knockout mice to the same extent and over the same time course seen in wild-type controls. The effects of METH in CX3CR1 knockout mice were not gender-dependent and did not extend beyond the striatum. Striatal microglia expressing eGFP constitutively show morphological changes after METH that are characteristic of activation. This response was restricted to the striatum and contrasted sharply with unresponsive eGFP-microglia in surrounding brain areas that are not damaged by METH. We conclude from these studies that CX3CR1 signaling does not modulate METH neurotoxicity or microglial activation. Furthermore, it appears that striatal-resident microglia respond to METH with an activation cascade and then return to a surveying state without undergoing apoptosis or migration.

Methamphetamine (METH) is well known for its ability to cause damage to dopamine (DA) nerve endings of the striatum. The mechanisms by which METH causes neurotoxicity are not fully understood, but likely candidates are increased oxidative and nitrosative stress and mitochondrial dysfunction. Microglial activation is also emerging as an important element of the METH neurotoxic cascade, and it appears that extensive cross‐talk between these cells and DA nerve endings is an early event in this process. It may seem paradoxical, but DA itself is also thought to be an essential factor in the neuronal damaging effects of METH, but issues relating to its precise role in this regard remain unanswered. We present in this overview a summary of studies that tested how alterations in the disposition of presynaptic DA (injections of reserpine, L‐DOPA, or clorgyline) modulate METH neurotoxicity. In all cases, these drugs significantly increased the magnitude of microglial activation as well as the severity of damage to striatal DA nerve endings caused by METH. The enhancement of METH effects in striatum by reserpine, L‐DOPA, and clorgyline persisted for 14 days and showed no evidence of recovery. These data establish that subtle shifts in the newly synthesized pool of DA can cause substantial changes in the severity of METH‐induced neurotoxicity. DA released into the synapse by METH is very likely the source of downstream reactants that provoke microglial activation and the ensuing damage to DA nerve endings.

The neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH-induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH-induced neurotoxicity. l-DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO-A by clorgyline increases pre-synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre-synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT, l-DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH-induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug-induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH-induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH.

We read with interest your recent review article on calciphylaxis published August 2006.1Polizzotto M.N. Bryan T. Ashby M.A. Martin P. Symptomatic management of calciphylaxis: a case series and review of the literature.J Pain Symptom Manage. 2006; 32: 186-190Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar We report a case of successful ketamine use for the control of severe pain associated with calciphylaxis in a hemodialysis patient. This case suggests that ketamine, an N-methyl-d-aspartate antagonist, is a useful adjunct/adjuvant analgesic that can be used safely in patients with renal impairment.1Polizzotto M.N. Bryan T. Ashby M.A. Martin P. Symptomatic management of calciphylaxis: a case series and review of the literature.J Pain Symptom Manage. 2006; 32: 186-190Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 2Murphy E.J. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease.Anaesth Intensive Care. 2005; 33: 311-322PubMed Google Scholar, 3Mitchell A.C. Fallon M.T. A single infusion of intravenous ketamine improves pain relief in patients with critical limb ischaemia: results of a double blind randomised controlled trial.Pain. 2002; 97: 275-281Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar A 28-year-old hemodialysis patient was referred to the palliative care team for control of pain associated with cutaneous ulcers. The patient had developed renal failure as an 8-year-old child secondary to hemolytic-uremic syndrome. He had subsequently received two kidney transplants, but was now back on dialysis with no further chance of transplantation. At time of referral, he was an inpatient, admitted for pain control, and receiving dialysis three times per week via a tunneled dialysis catheter. He had severe vascular access problems and was chronically malnourished, with a dry weight of 35 kg. His past medical history included benign intracranial hypertension, esophageal variceal hemorrhage, inferior vena cava obstruction, and parathyroidectomy for tertiary hyperparathyroidism. At time of referral, he was using a buprenorphine transdermal patch 70 μg, gabapentin 300 mg in divided doses, and short-acting oxycodone 5 mg five times daily. This analgesic combination had been titrated up over the previous week since admission. He complained of drowsiness, nausea, and uncontrolled pain. He described intense continuous “knife-like” pain in his left foot, right upper arm, and forearm. The pain centered on visible skin ulcers at all these sites, including a full thickness ulcer on is foot (Fig. 1). The working diagnosis for his ulcers was calciphylaxis, pending further investigations. The quality of the pain suggested both somatic and neuropathic components, which have been described in calciphylaxis.1Polizzotto M.N. Bryan T. Ashby M.A. Martin P. Symptomatic management of calciphylaxis: a case series and review of the literature.J Pain Symptom Manage. 2006; 32: 186-190Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar To address his pain, the buprenorphine patch was discontinued and a subcutaneous infusion was commenced via syringe driver. The infusion delivered haloperidol 1.5 mg, oxycodone 10 mg, and ketamine 20 mg over 24 hours. His nausea resolved within a day. He did not report any new side effects or symptoms, but drowsiness and pain continued. He was unable to tolerate any further increase in gabapentin dosage due to side effects. To treat both his neuropathic pain and as an opioid-sparing measure, his ketamine dose was gradually increased over the next week to 100 mg. After one week, his regimen included ketamine 100 mg/day and oxycodone 10 mg/day, with short-acting oxycodone 2.5 mg as required. His drowsiness had resolved, and his pain score had decreased from 10/10 to 6/10 in his foot; his arm pain had resolved completely. His total oxycodone requirements had halved since our initial review and commencing ketamine. At the patient's request, the syringe driver was stopped and he was converted to oral medication. He was started on ketamine 50 mg three times daily, oxycodone 5 mg twice daily, and haloperidol 2.5 mg once daily. Investigations into his skin ulcers were performed. A skin biopsy was inconclusive. A computed tomography angiogram of his lower limbs revealed a single 2 cm occlusion in his right superficial femoral artery. The distal superficial femoral artery and popliteal arteries were patent. His calcium phosphate product was persistently greater than 4.4 mmol2L2 [55 mg2/dL2]. Three days later, his pain became uncontrolled and was aggravated when holding his foot over the side of the bed. The ketamine dose was increased to 75 mg three times daily, with some improvement in pain scores reported. Following discussion with the patient and ward staff, it was apparent that his foot pain consistently increased during the evenings after he received dialysis. The exacerbation of pain and temporal relationship to hemodialysis was considered to be caused either by potential removal of analgesia (ketamine) by hemodialysis or exacerbation related to the physiological responses induced by the dialysis treatment. We were unable to measure the proportion of ketamine removed by dialysis in our laboratory, but current literature4Koppel C. Arndt I. Ibe K. Effects of enzyme induction, renal and cardiac function on ketamine plasma kinetics in patients with ketamine longterm analgosedation.Eur J Drug Metab Pharmacokinet. 1990; 15: 259-263Crossref PubMed Scopus (27) Google Scholar and discussion with colleagues in the toxicology and pharmacology departments indicated that only a small proportion of ketamine (4%–10% of dose) would be removed by hemodialysis. Therefore, the likely explanation for the increased pain was attributed to physiological changes accompanying dialysis. A fourth dose of ketamine was administered to the patient during the evenings following dialysis, with temporary improvement in pain control. His pain subsequently increased again, and the ketamine was increased to 75 mg four times daily. Several days later, the patient reported the quality of his foot pain had changed acutely. Clinical examination confirmed a cold ischemic foot for which he required a below knee amputation. He did not report any postoperative pain in his leg, and both the ketamine and oxycodone were discontinued. Interestingly, he did not report any further pain in his arm or at other sites of visible skin ulcers. Ketamine may be used to ameliorate pain from ischemia and calciphylaxis in patients with renal failure.1Polizzotto M.N. Bryan T. Ashby M.A. Martin P. Symptomatic management of calciphylaxis: a case series and review of the literature.J Pain Symptom Manage. 2006; 32: 186-190Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 2Murphy E.J. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease.Anaesth Intensive Care. 2005; 33: 311-322PubMed Google Scholar, 3Mitchell A.C. Fallon M.T. A single infusion of intravenous ketamine improves pain relief in patients with critical limb ischaemia: results of a double blind randomised controlled trial.Pain. 2002; 97: 275-281Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar It is possible that the etiology of the patient's ulcers differed. The cutaneous ulcers on the arm could have been related to calciphylaxis, whereas the foot ulcer appeared to be related to arterial insufficiency. The physiological changes that accompany hemodialysis may exacerbate underlying ischemic pain. Ketamine may be combined successfully with opioids in renally impaired patients, with the intention of reducing overall opioid use and limiting unwanted opioid side effects. In this case, ketamine was used successfully to improve the patient's pain control and reduce overall opioid requirements without any additional side effects. The interesting observation that the patient's arm pain did not return following discontinuation of ketamine, and that he did not report any postoperative leg pain, may be related to the postulated action of ketamine at N-methyl-d-aspartate receptors and the reversal of the “wind-up” phenomena.