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Tyvin Rich,1,* Fengmin Zhao,2,* Ricardo A Cruciani,3 David Cella,4 Judith Manola,2 Michael J Fisch5 1Hampton University Proton Therapy Institute, Hampton, VA, 2Dana-Farber Cancer Institute, Boston, MA, 3Beth Israel Medical Center, New York, NY, 4Northwestern University Feinberg School of Medicine, Chicago, IL, 5The University of Texas MD Anderson Cancer Center, Houston, TX, USA *These authors contributed equally to this work Context: The biology of fatigue and depression in cancer patients is poorly understood. Hypotheses regarding cytokines and growth factors related to sickness behavior and disruption of circadian signaling have been proposed.Objectives: We prospectively examined proinflammatory cytokines (e.g., sickness behavior model) and epidermal growth factor receptor (EGFR) ligands (e.g., circadian disruption model) in the serum of cancer patients enrolled in a clinical trial testing levocarnitine for fatigue.Methods: Serum samples were collected at baseline and week 4. Cytokine/growth factor analyses were performed with a Luminex analyzer. The Brief Fatigue Index and the Center for Epidemiologic Studies Depression Index were used to measure fatigue and depression severity. The association between cytokine and symptoms was examined using logistic models.Results: Among 101 analyzable patients, all ten cytokines/growth factors examined were highly elevated at baseline and all significantly decreased at week 4 (p

Ricardo A Cruciani,1 Manuel Revuelta,2 Ella Dvorkin,3 Peter Homel,4 Pauline Lesage,5 Nora Esteban-Cruciani6 1Center for Comprehensive Pain Management and Palliative Care, Capital Institute for Neurosciences, Capital Health Medical Center, Pennington, NJ, 2Lee Memorial Hospital, Fort Myers, FL, 3Institutional Review Board, New York University, New York, NY, 4Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, NY, 5Maimonides Medical Center, Brooklyn, NY, 6Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA Background: The purpose of this study was to determine the effect of L-carnitine supplementation on fatigue in patients with terminal human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, patients who had end-stage HIV/AIDS with carnitine deficiency and fatigue received 3 g of oral L-carnitine or placebo for 2 weeks, followed by a 2-week, open-label phase with the same amount of L-carnitine for all patients. The primary outcome was the degree of fatigue according to the Brief Fatigue Inventory. Secondary outcomes included serum carnitine and lactate levels, physical, emotional, social, and functional well-being, performance status, mood, and CD4 count. Results: Eighteen patients in the treatment arm and 17 in the placebo arm completed the trial. At the end of the double-blind phase, total and free carnitine levels in the treatment arm rose from 28±9 to 48±17 nM/L (P

Hector Miranda-Grajales, Joy Hao, Ricardo A CrucianiDepartment of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, NY, USAAbstract: It has been proposed that some deaths attributed to methadone are related to prolongation of the QTc interval; however, there are no clear recommendations on electrocardiogram (ECG) monitoring in patients undergoing intravenous methadone infusion. This is a report on a patient receiving methadone intravenous patient-controlled analgesia titration for the treatment of chronic pain. Initially, her daily ECGs showed QTc intervals within normal limits; however, she experienced a rapid increase in QTc interval from 317 ms to 784 ms within a 24-hour period after methadone had been discontinued for excessive sedation. QTc interval greater than 500 ms is considered to be high risk for the fatal arrhythmia Torsades de Pointes. Daily ECGs did not detect a gradual increase in the QTc interval that would have alerted the medical staff of the need to decrease or stop the methadone before reaching a prolonged QTc interval associated with cardiotoxicity. In selected cases where aggressive methadone titration is required, more intensive monitoring, such as telemetry or ECG determinations every 12 hours, might help detect changes in QTc interval duration that might otherwise be missed by daily ECG determinations.Keywords: methadone, QTc prolongation, opioids, opioid side effects, IVPCA methadone

Helena Knotkova1,2, Ricardo Cruciani1–3, Volker M Tronnier4, Dirk Rasche41Department of Pain Medicine and Palliative Care, Research Division, Institute for Non-invasive Brain Stimulation, Beth Israel Medical Center, New York, NY, USA; 2Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; 3Department of Anesthesiology, Albert Einstein College of Medicine, Bronx, NY, USA; 4Department of Neurosurgery, University of Lübeck, GermanyAbstract: Phantom-limb pain (PLP) belongs among difficult-to-treat chronic pain syndromes. Treatment options for PLP are to a large degree implicated by the level of understanding the mechanisms and nature of PLP. Research and clinical findings acknowledge the neuropathic nature of PLP and also suggest that both peripheral as well as central mechanisms, including neuroplastic changes in central nervous system, can contribute to PLP. Neuroimaging studies in PLP have indicated a relation between PLP and the neuroplastic changes. Further, it has been shown that the pathological neuroplastic changes could be reverted, and there is a parallel between an improvement (reversal) of the neuroplastic changes in PLP and pain relief. These findings facilitated explorations of novel neuromodulatory treatment strategies, adding to the variety of treatment approaches in PLP. Overall, available treatment options in PLP include pharmacological treatment, supportive non-pharmacological non-invasive strategies (eg, neuromodulation using transcranial magnetic stimulation, visual feedback therapy, or motor imagery; peripheral transcutaneous electrical nerve stimulation, physical therapy, reflexology, or various psychotherapeutic approaches), and invasive treatment strategies (eg, surgical destructive procedures, nerve blocks, or invasive neuromodulation using deep brain stimulation, motor cortex stimulation, or spinal cord stimulation). Venues of further development in PLP management include a technological and methodological improvement of existing treatment methods, an implementation of new techniques and products, and a development of new treatment approaches.Keywords: phantom-limb pain (PLP), neuropathic pain, non-invasive treatment, invasive treatment, neuromodulation

Objectives: Chronic pain is a serious public health problem and is treated by diverse health care providers. In order to enhance policies and programs to improve pain care, we collected information about the distribution of pain patients among four major groups of pain management providers: primary care physicians (PCPs), pain physicians, chiropractors, and acupuncturists, and the variation in the attitudes and practices of these providers with respect to some common strategies used for pain., Methods: National mail survey of PCPs, pain physicians, chiropractors, and acupuncturists (ntotal = 3,000)., Results: Eight hundred seventeen responses were usable (response rate, 29%). Analyses weighted to obtain nationally representative data showed that PCPs treat approximately 52% of chronic pain patients, pain physicians treat 2%, chiropractors treat 40%, and acupuncturists treat 7%. Of the chronic pain patients seen for evaluation, the percentages subsequently treated on an ongoing basis range from 51% (PCPs) to 63% (pain physicians). Pain physicians prescribe long-acting opioids such as methadone, antidepressants or anti-convulsants, and other nontraditional analgesics approximately 50-100% more often than PCPs. Twenty-nine percent of PCPs and 16% of pain physicians reported prescribing opioids less often than they deem appropriate because of regulatory oversight concerns. Of the four groups, PCPs are least likely to feel confident in their ability to manage musculoskeletal pain and neuropathic pain, and are least likely to favor mandatory pain education for all PCPs., Conclusions: There is substantial variation in attitudes and practices of the various disciplines that treat chronic pain. This information may be useful in interpreting differences in patient access to pain care, planning studies to clarify patient outcomes in relation to different providers and treatment strategies, and designing a system that matches chronic pain patients to appropriate practitioners and treatments.

The conquest of pain would be in our mind, perhaps, the most important discovery in medicine to impact on patient suffering. In our specialty, several pancreatic diseases are characterized by severe discomfort. For instance, pancreatic cancer is one of the most painful diseases from which a human being can suffer. Chronic pancreatitis is similarly debilitating. Therefore, the field of pain research and management is of paramount importance to pancreatologists. Certainly, this area is very extensive and growing. However, as applied to pancreatic diseases, we are still in our infancy. The major problem is that, beyond the anecdotal publication, we do not know how pancreatic pain is originated and maintained. Therefore, significant efforts must be made to improve our understanding of the mechanisms of both acute and chronic pain, as well as of how we can provide our patients with a more dignified life and sometimes a more peaceful end stage of life. Thus, it is in this spirit that we are developing several articles on 'molecular pathways' focused on describing the molecular machinery underlying pancreatic pain, with the objective of both creating a better understanding of this problem as well as of generating enthusiasm for outstanding investigators to come to this emerging and critical field of pancreatology. Here, the first article will focus on the mechanism underlying the effect of morphine and opioids. It is our dearest goal that the basic scientist gets very excited about dissecting this problem, and that the clinician not only has simple, one-stop reading material, but that this reading will help him/her understand work published on pancreatic pain and hopefully also initiate clinical trials targeting this pathway., (Copyright 2008 S. Karger AG, Basel and IAP.)

Evidence is presented for the occurrence of a unique opiate alkaloid-selective, opioid peptide-insensitive binding site in N18TG2 mouse neuroblastoma cells and in late passage hybrid F-11 cells, derived from N18TG2 neuroblastoma cells and rat dorsal root ganglion cells. Those cells lacked classical opioid peptide-sensitive receptor subtypes, but contained [3H]morphine and [3H]diprenorphine binding sites with affinity for certain opiate alkaloids but not for any endogenously occurring opioid peptide or peptide analog tested, including D-ala2-D-leu5-enkephalin (DADLE), D-Ala2,N-Me-Phe4,Gly5-ol (DAGO) and dynorphin A(1-17). The binding site differed from hitherto described mu, delta and kappa neuronal opioid receptors not only on the basis of peptide insensitivity, but also on the basis of selectivity and affinities of alkaloids. Saturation experiments with [3H]morphine indicated the presence of a single site with Kd = 49 nM and Bmax = 1510 fmol/mg protein. This novel binding site was not present in F-11 hybrid cells at early passage. Instead the hybrid cells contained conventional opioid receptors (predominantly delta and also mu) capable of binding DADLE and other peptides as well as opiate alkaloids. With additional passage (cell divisions) of the hybrid cells, during which a limited change occurred in mouse chromosome number, the peptide-insensitive binding appeared and the opioid peptide-binding (delta and mu) receptors were lost reciprocally. Thus, expression of the peptide-insensitive binding normally may be repressed when conventional opioid receptors are expressed. The peptide-insensitive opiate binding site described here appears to correspond to the mu 3 receptor subtype, recently identified pharmacologically and functionally in several cell types of the immune system.(ABSTRACT TRUNCATED AT 250 WORDS)

We have examined the ion channel forming properties of magainin 2 by incorporating the peptide into artificial lipid bilayers held under voltage clamp. Magainin 2 increased lipid bilayer conductance in a concentration dependent manner with a Hill coefficient of 1.7. The magainin 2 conductance was selective for monovalent cations over anions with a ratio of 5:1 and had both voltage-sensitive and -insensitive components. Two structurally related but antibiotically less potent analogues, magainin 1 and Z-12, also increased lipid bilayer conductance with a similar ion selectivity but these peptides were less potent than magainin 2. We propose that the weak cation selectivity of the magainin channels can be accounted for by the inclusion of negatively charged lipids in the channel complex and suggest two possible structures for such a channel. The ionophoric properties of these peptides are likely to be proximal to their antibiotic activities.

The existence of multiple subtypes of kappa opioid receptors in brain and adrenal medulla, has been controversial. We have characterized opioid receptors in frozen membranes from bovine adrenal medulla by use of objective mathematical modeling. [3H]Etorphine, [3H]ethylketocyclazocine (EKC) and [3H][D-Ala2,D-Leu5]enkephalin (DADL) were utilized as labeled ligands. Self- and cross-displacement curves were constructed using the three corresponding unlabeled ligands in the presence or absence of increasing concentrations of DADL. Results indicated: (1) each of the three ligands studied individually showed the presence of heterogeneity of binding sites; (2) sites labeled by etorphine were heterogeneous: 84% of etorphine binding was displaceable by 10(-4) M DADL, while the remaining 16% was DADL non-suppressible; (3) 75% of the binding of EKC was displaceable by DADL while 25% was non-suppressible; (4) mathematical modeling showed the presence of three subtypes of kappa binding sites (a) kappa 1, showing slight selectivity for EKC relative to etorphine; (b) kappa 2, with Kd approximately equal to 1 nM for etorphine, and sufficiently high affinity for DADL (Kd approximately equal to 150 nM) so that it is suppressible by 100 microM DADL; and (c) K3, with no measurable affinity for DADL and a 27-fold selectivity for etorphine relative to EKC. The three subtypes of kappa sites were present at concentrations of 7.4, 75, and 55 fmol/mg protein, respectively. The relative affinities of a series of kappa agonists for the etorphine-binding sites were characterized. The present studies confirm the existence of three subtypes of kappa opioid receptors in bovine adrenal medulla, and indicate the utility of mathematical modeling for characterization of complex receptor systems.