Multimodal Stepped Care Approach Involving Topical Analgesics for Severe Intractable Neuropathic Pain in CRPS Type 1: A Case Report

A multimodal stepped care approach has been successfully applied to a patient with complex regional pain syndrome type 1 and severe intractable pain, not responding to regular neuropathic pain medication. The choice to administer drugs in creams was made because of the intolerable adverse effects to oral medication. With this method, peak-dose adverse effects did not occur. The multimodal stepped care approach resulted in considerable and clinically relevant decrease in pain after every step, using topical amitriptyline, ketamine, and dimethylsulphoxide

Walking with Neuropathic Pain: Paradoxical Shift from Burden to Support?

Baclofen 5% cream can be used for the treatment of neuropathic pain. We describe an unusual case of a neuropathic pain patient with spinal cord injury. A 71-year-old woman with a partial spinal cord injury lesion at L4 complained of tingling, pins and needles, and burning in her legs. She scored her pain as 6 before adding baclofen 5% cream to her pain medication (pregabalin 450 mg, acetaminophen 3000 mg, and diclofenac 150 mg daily). One month later she experienced complete pain relief, though experienced increased difficulties in walking, leading to frequent falls. Her steadier walking without stumbling and falling was more important to her than pain reduction. Thus she decided to stop using baclofen. This unusual case report discusses two important issues that relate to pain medicine and rehabilitation in patients with painful spinal cord lesions: (1) the presence of wide areas of sensory loss “covered” by the presence of painful sensations and (2) pathological sensations that can be used and integrated in the body schema to create an improved spatiovisual orientation and thus mobility. Both these aspects have to be taken into account when treating pain and design rehabilitation programs

Central Neuropathic Pain in a Patient with Multiple Sclerosis Treated Successfully with Topical Amitriptyline

Central neuropathic pain in patients with multiple sclerosis (MS) is a common debilitating symptom, which is mostly treated with tricyclic antidepressants or antiepileptics. Unfortunately, the use of these drugs is often limited due to adverse events. We investigated the analgesic effect of topical amitriptyline 5% and 10% cream in a patient with central neuropathic pain due to MS. The analgesic effect of topical amitriptyline cream on neuropathic pain was dose related. To evaluate whether this analgesic effect is due to the active compound or placebo, we conducted a double-blind placebo-controlled n-of-1 study with amitriptyline 5% cream and placebo. The instruction was to alternate the creams every week following the pattern ABAB, with an escape possibility of amitriptyline 10% cream. The result was a complete pain reduction after application of cream B, while most of the time cream A did not reduce the pain. The patient could correctly unblind both creams, determining B as active. She noted that in the week of using the active cream no allodynia was present, with a carryover effect of one day

The Association of Early Electrocardiographic Abnormalities With Brain Injury Severity and Outcome in Severe Traumatic Brain Injury

The aim of this study was to evaluate the frequency of electrocardiographic (ECG) abnormalities in the acute phase of severe traumatic brain injury (TBI) and the association with brain injury severity and outcome. In contrast to neurovascular diseases, sparse information is available on this issue. Data of adult patients with severe TBI admitted to the Intensive Care Unit (ICU) for intracranial pressure monitoring of a level-1 trauma center from 2002 till 2018 were analyzed. Patients with a cardiac history were excluded. An ECG recording was obtained within 24 h after ICU admission. Admission brain computerized tomography (CT)-scans were categorized by Marshall-criteria (diffuse vs. mass lesions) and for location of traumatic lesions. CT-characteristics and maximum Therapy Intensity Level (TILmax) were used as indicators for brain injury severity. We analyzed data of 198 patients, mean (SD) age of 40 +/- 19 years, median GCS score 3 [interquartile range (IQR) 3-6], and 105 patients (53%) had thoracic injury. In-hospital mortality was 30%, with sudden death by cardiac arrest in four patients. The incidence of ECG abnormalities was 88% comprising ventricular repolarization disorders (57%) mostly with ST-segment abnormalities, conduction disorders (45%) mostly with QTc-prolongation, and arrhythmias (38%) mostly of supraventricular origin. More cardiac arrhythmias were observed with increased grading of diffuse brain injury (p = 0.042) or in patients treated with hyperosmolar therapy (TILmax) (65%, p = 0.022). No association was found between ECG abnormalities and location of brain lesions nor with thoracic injury. Multivariate analysis with baseline outcome predictors showed that cardiac arrhythmias were not independently associated with in-hospital mortality (p = 0.097). Only hypotension (p = 0.029) and diffuse brain injury (p = 0.017) were associated with in-hospital mortality. In conclusion, a high incidence of ECG abnormalities was observed in patients with severe TBI in the acute phase after injury. No association between ECG abnormalities and location of brain lesions or presence of thoracic injury was present. Cardiac arrhythmias were indicative for brain injury severity but not independently associated with in-hospital mortality. Therefore, our findings likely suggest that ECG abnormalities should be considered as cardiac mimicry representing the secondary effect of traumatic brain injury allowing for a more rationale use of neuroprotective measures

Advances in the discovery of N-acylethanolamine acid amidase inhibitors

N-acylethanolamine acid amidase (NAAA) is a cysteine amidase that hydrolyzes saturated or monounsaturated fatty acid ethanolamides, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA has been shown to exert analgesic and anti-inflammatory effects by engaging peroxisome proliferator-activated receptor-α. Like other fatty acid ethanolamides, PEA is not stored in cells, but produced on demand from cell membrane precursors, and its actions are terminated by intracellular hydrolysis by either fatty acid amide hydrolase or NAAA. Endogenous levels of PEA and OEA have been shown to decrease during inflammation. Modulation of the tissue levels of PEA by inhibition of enzymes responsible for the breakdown of this lipid mediator may represent therefore a new therapeutic strategy for the treatment of pain and inflammation. While a large number of inhibitors of fatty acid amide hydrolase have been discovered, few compounds have been reported to inhibit NAAA activity. Here, we describe the most representative NAAA inhibitors and briefly highlight their pharmacological profile. A recent study has shown that a NAAA inhibitor attenuated heat hyperalgesia and mechanical allodynia caused by local inflammation or nerve damage in animal models of pain and inflammation. This finding encourages further exploration of the pharmacology of NAAA inhibitors

Synthesis, Structure-Activity, and Structure-Stability Relationships of 2-Substituted- N

N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator-activated receptor-α (PPAR-α). Compounds that feature an α-amino-β-lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti-inflammatory effects that are mediated through FAE-dependent activation of PPAR-α. We synthesized and tested a series of racemic, diastereomerically pure β-substituted α-amino-β-lactones, as either carbamate or amide derivatives, investigating the structure-activity and structure-stability relationships (SAR and SSR) following changes in β-substituent size, relative stereochemistry at the α- and β-positions, and α-amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the β-position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability

Chronic idiopathic axonal neuropathy and pain, treated with the endogenous lipid mediator palmitoylethanolamide: a case collection

J M Keppel Hesselink Faculty of Medicine, University Witten/Herdecke, Germany Abstract: Chronic idiopathic axonal polyneuropathy is a frequent diagnosis in patients suffering from idiopathic polyneuropathy and neuropathic pain. No guidelines exist on how to treat these patients. To date, there are no results available from randomized clinical trials, and mostly classical neuropathic analgesics are prescribed, such as amitriptyline and gabapentine. However, the usefulness of these drugs is limited, as many patients remain in pain despite treatment, or suffer debilitating side effects. Palmitoylethanolamide (PEA) is a new analgesic compound, tested in more than 4,000 patients in various clinical trials in a variety of patients suffering from various neuropathic pain states. It is available in Europe and the USA as a food supplement under the brand name PeaPure, and it is available for medical purposes in Italy and Spain under brand names Normast and Pelvilen. We present a case series of seven patients with an electrophysiological confirmed diagnosis of chronic idiopathic axonal polyneuropathy, suffering from neuropathic pains, mostly refractory to previous analgesics. In all these patients, PEA reduced pain significantly, without side effects. PEA can be administered in addition to other analgesics, without negative drug–drug interactions, or can be used as a stand-alone analgesic. Due to a favorable ratio between efficacy and safety, PEA should be considered more often as a treatment for neuropathic pain. Keywords: CIAP, polyneuropathy, treatment, neuropathi

De ziekte van Parkinson: een medisch-historische analyse van de begripsontwikkeling in verband met de ziekte van Parkinson vanaf 1817 tot 1961

Contains fulltext : mmubn000001_029049237.pdf (publisher's version ) (Open Access)Promotor : B. Schulte326 p

Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical

Jan M Keppel Hesselink Department of Pharmacology, University of Witten/Herdecke, Witten, Germany Abstract: The history of development of new concepts in pharmacology is a highly interesting topic. This review discusses scientific insights related to palmitoylethanolamide (PEA) and its progression over a period of six decades, especially in light of the work of the science sociologists, Ludwig Fleck and Thomas Kuhn. The discovery of the cannabis receptors and the nuclear peroxisome proliferator-activated receptors was the beginning of a completely new understanding of many important homeostatic physiologic mechanisms in the human body. These discoveries were necessary for us to understand the analgesic and anti-inflammatory activity of PEA, a body-own fatty amide. PEA is a nutrient known already for more than 50 years. PEA is synthesized and metabolized in animal cells via a number of enzymes and has a multitude of physiologic functions related to metabolic homeostasis. PEA was identified in the 1950s as a therapeutic principle with potent anti-inflammatory properties. Since 1975, its analgesic properties have been noted and explored in a variety of chronic pain states. Since 2008, PEA has been available as a nutraceutical under the brand names Normast® and PeaPure®. A literature search on PEA meanwhile has yielded over 350 papers, all referenced in PubMed, describing the physiologic properties of this endogenous modulator and its pharmacologic and therapeutic profile. This review describes the emergence of concepts related to the pharmacologic profile of PEA, with an emphasis on the search into its mechanism of action and the impact of failing to identify such mechanism in the period 1957–1993, on the acceptance of PEA as an anti-inflammatory and analgesic compound. Keywords: palmitoylethanolamide, sociology, science, paradigm, peroxisome proliferator-activated receptor-alpha, nutraceutica