A Delphi consensus statement of the Neuropathic Pain Special Interest Group of the Italian Neurological Society on pharmacoresistant neuropathic pain.

To improve patient care and help clinical research, the Neuropathic Pain Special Interest Group of the Italian Neurological Society appointed a task force to elaborate a consensus statement on pharmacoresistant neuropathic pain. The task force included 19 experts in neuropathic pain. These experts participated in a Delphi survey consisting of three consecutive rounds of questions and a face-to-face meeting, designed to achieve a consensus definition of pharmacoresistant neuropathic pain. In the three rounds of questions, the participants identified and described the main distinguishing features of pharmacoresistance. In the face-to-face meeting the participants discussed the clinical features determining pharmacoresistance. They finally agreed that neuropathic pain is pharmacoresistant when "the patient does not reach the 50% reduction of pain or an improvement of at least 2 points in the Patient Global Impression of Change, having used all drug classes indicated as first, second, or third line in the most recent and widely agreed international guidelines, for at least 1 month after titration to the highest tolerable dose." Our consensus statement might be useful for identifying eligible patients for invasive treatments, and selecting patients in pharmacological trials, thus improving patient care and helping clinical research.

Is 2-Hydroxypropyl-ß-cyclodextrin a Suitable Carrier for Central Administration of Δ9 -Tetrahydrocannabinol? Preclinical Evidence.

Preclinical Research Δ9 -Tetrahydrocannabinol (THC) is a hydrophobic compound that has a potent antinociceptive effect in animals after intrathecal (IT) or intracerebroventricular (ICV) administration. The lack of a suitable solvent precludes its IT administration in humans. 2-Hydroxypropyl-ß-cyclodextrin (HPßCD) increases the water solubility of hydrophobic drugs and is approved for IT administration in humans. To investigate whether HPßCD might be a suitable carrier for ICV administration of THC in rats, two formulations containing THC complexed with HPßCD (30 and 135 µg of THC per animal) and vehicle were administered to Wistar rats. The antinociceptive effect (using the tail flick test), locomotor activity, and body temperature were evaluated. ICV injection of 135 µg of THC/HPßCD complex increased tail flick latency, reduced locomotor activity, and had a dual effect on body temperature. The 30 µg THC/HPßCD formulation only produced a hyperthermic effect. All animals appeared healthy, with no difference between the groups. These results were similar to those obtained in other preclinical studies in which THC was administered centrally using solvents that are unsuitable for IT administration in humans because of their toxicity. Our findings suggest that HPßCD may be a useful carrier for IT administration of THC in humans. Drug Dev Res 78 : 411-419, 2017. © 2017 Wiley Periodicals, Inc.

Oxytocin nasal spray in fibromyalgic patients.

Fibromyalgia is a pain disorder associated with frequent comorbid mood, anxiety, and sleep disorders. Despite the frequent use of a complex, poly-drug pharmacotherapy, treatment for fibromyalgia is of limited efficacy. Oxytocin has been reported to reduce the severity of pain, anxiety, and depression, and improve the quality of sleep, suggesting that it may be useful to treat fibromyalgia. To evaluate this hypothesis, 14 women affected by fibromyalgia and comorbid disorders, assuming a complex pharmacotherapy, were enrolled in a double-blind, crossover, randomized trial to receive oxytocin and placebo nasal spray daily for 3 weeks for each treatment. Order of treatment (placebo-oxytocin or oxytocin-placebo) was randomly assigned. Patients were visited once a week. At each visit, the following instruments were administered: an adverse drug reaction record card, Visual Analog Scale of Pain Intensity, Spielberger State Anxiety Inventory, Zung Self-rating Depression Scale, and SF-12. Women self-registered painkiller assumption, pain severity, and quality of sleep in a diary. Unlikely, oxytocin nasal spray (80 IU a day) did not induce positive therapeutic effects but resulted to be safe, devoid of toxicity, and easy to handle.

Long-term efficacy of onabotulinum toxin in treating persistent myofascial pain and masticatory muscles hypertone in an adolescent with bruxism. A 7-year follow-up case report.

BACKGROUND: Temporomandibular disorders (TMDs) represent a common chronic complaint, which includes myofascial pain (MP). Although several therapeutical options have been proposed to control bruxism-related muscle hyperactivity, there is not enough evidence to define a standard approach. The present article describes the case of a 14-year old male patient with a history of painful mandibular close lock. CASE REPORT: The patient was diagnosed with persistent myofascial pain in the left masseter, bilateral disc displacement with reduction, and retrodiscitis and capsulitis in the left temporomandibular joint. Awake and sleep bruxism were also present. Since first line treatments failed in managing the disorders, injections of onabotulinum toxin (BoNT-A ) were performed. After one month the pain decreased significantly and the jaw movements were restored. The patient was recommended to avoid hard and/or rubbery food, wide movements of the jaws and teeth clenching and to wear orthodontic appliance during the night since the joint damage was moderate. We report the 7-year follow-up demonstrating the long-term efficacy of a single injection of onabotulinum toxin in masseters and temporalis muscles in order to treat masticatory pain and dysfunctions. CONCLUSION: The authors suggest that BoNT-A could be an optimum treatment for persistent MP and bruxism in young adolescents when first-line therapies fail.

Sudden death in epilepsy: an experimental animal model.

INTRODUCTION: The physiopathogenetic mechanisms possibly involved in sudden unexplained epileptic death (SUDEP), were investigated in the hemispherectomized rat. METHODS: For this purpose, paroxysmal activity, vagal nerve firing, systemic blood pressure (BP), pulmonary artery pressure, and ECG were simultaneously recorded in an experimental animal model of epilepsy. Recordings were performed in basal conditions and during paroxysmal activity induced by topical application of penicillin-G at hypothalamic and mesencephalic level. During the experiment were also performed hemogas analysis and at end, samples of lung tissue were processed for histology. RESULTS: Activation of hypothalamic (HEF) and mesencephalic (MEF) epileptic foci induced a significant increase of spontaneous vagal nerve firing that was strictly correlated to ECG impairments and hypotension. When paroxysmal activity extinguished, vagal nerve activity and cardiovascular parameters returned to basal conditions. However, in 25% of the animals, co-activation of HEF and MEF always triggered a vagal hypertone which was temporally correlated to cardiac arrhythmias, but also to hyperkalemia, acidosis, pulmonary hypertension and to animal death. Histological control in lungs of deceased animals showed an alveolar and perivessel oedema with an oedematous infiltration in the alveolar and bronchial spaces and mucous secretion. During ictal activity, comparison between survived and deceased animals showed significant differences in the incidence of ECG impairment of pulmonary artery pressures, pO2, and pCO2 pressures, and [K+], [HCO3-], and [pH], concentrations. DISCUSSION: A possible explanation of the above observations is discussed in relationship to SUDEP physiopathogenesis.

What to Do, and What Not to Do, When Diagnosing and Treating Breakthrough Cancer Pain (BTcP): Expert Opinion.

Clinical management of breakthrough cancer pain (BTcP) is still not satisfactory despite the availability of effective pharmacological agents. This is in part linked to the lack of clarity regarding certain essential aspects of BTcP, including terminology, definition, epidemiology and assessment. Other barriers to effective management include a widespread prejudice among doctors and patients concerning the use of opioids, and inadequate assessment of pain severity, resulting in the prescription of ineffective drugs or doses. This review presents an overview of the appropriate and inappropriate actions to take in the diagnosis and treatment of BTcP, as determined by a panel of experts in the field. The ultimate aim is to provide a practical contribution to the unresolved issues in the management of BTcP. Five 'things to do' and five 'things not to do' in the diagnosis and treatment of BTcP are proposed, and evidence supporting said recommendations are described. It is the duty of all healthcare workers involved in managing cancer patients to be mindful of the possibility of BTcP occurrence and not to underestimate its severity. It is vital that all the necessary steps are carried out to establish an accurate and timely diagnosis, principally by establishing effective communication with the patient, the main information source. It is crucial that BTcP is treated with an effective pharmacological regimen and drug(s), dose and administration route prescribed are designed to suit the particular type of pain and importantly the individual needs of the patient.

The brainstem cardioarrhythmogenic triggers and their possible role in sudden epileptic death.

The cardiovascular effects of simultaneous activation of hypothalamic and mesencephalic cardioarrhythmogenic triggers were studied in hemispherectomized rats. Paroxysmal activity of hypothalamic neurons (HEF), elicited by topical application of penicillin G on the thalamus, triggered short-lasting bradyarrhythmic episodes, up to a maximum of 6 s, and alterations in repolarization. In the hypothalamic neurons, an additional penicillin G epileptic focus at mesencephalic level (MEF) induced the enhancement of paroxysmal activity by a recruitment of new units and potentiation of their background activity. HEF+MEF triggered second-degree 2:1-8:1 atrioventricular (A-V) blocks, impairment of the A-V conduction, alterations in the recovery phase and bundle branch blocks. After HEF, the arterial blood pressure decreased by 4-6%. HEF+MEF induced a further reduction of 17% in systolic pressure only. It is possible that the enhancement of the HEF following MEF could depend on MEF spreading upward. The HEF, in turn, by spreading downward could influence the MEF and so activate, between HEF and MEF, a circuitry with reciprocal co-excitation that could explain the more serious cardiovascular alterations observed during HEF+MEF compared with those observed during HEF only or during MEF only. However, this cardiovascular impairment, which must be neurogenic in origin as it was observed in animals with normal acid-base and blood parameter values, did not induce heart death. Thus, additional concomitances must be considered, such as metabolic derangement which can occur during seizures, to explain sudden death in epileptic patients. Some aspects of metabolic complications in cardiac activity during epilepsy are also discussed.

Autonomic nervous system activity and life threatening arrhythmias in experimental epilepsy.

In the present study the possible derangement of the autonomic system and its influence in life threatening arrhythmias were analysed during paroxysmal activity. In hemispherectomized rats a paroxysmal activation of the hypothalamic and mesencephalic cardioarrhythmogenic triggers was performed by topical application of penicillin-G. Blood gas parameters and electrical activity of the thalamus, hypothalamus, vagal nerve fibre, ECG and arterial blood pressure were simultaneously monitored in basal conditions and repeated after the appearance of paroxysmal activity. Temporal correlation analysis was carried out. Results showed that during activation of these triggers, the spontaneous vagal nerve fibre activity significantly increased and triggered the appearance of cardiac arrhythmias which could become life threatening and induce animal death when blood gas and electrolytic parameters were simultaneously impaired. These experiments suggest that fatal evolution of the heart impairment is related not only to an autonomic cardiac trigger, but also to a concomitant metabolic derangement, which most likely shares the same autonomic origin.

[Percutaneous neurolysis of the celiac plexus under CT guidance in the invasive treatment of visceral pain caused by cancer]. / Neurolisi percutanea del plesso celiaco sotto guida TC nel trattamento invasivo del dolore viscerale da cancro.

To verify the effectiveness and the incidence of complication in the transcutaneal celiac plexus block with CT-guided in the patient with intractable upper abdominal cancer, using alcoholic solutions to different concentrations (50% and 96%), previous insertion of the peridural catheter. From December 1997 to June 2002, studies were carried out on 24 patients with CT-guided percutaneous coeliac plexus neurolysis including 17 men and 7 women with inoperable abdominal malignancy and two with chronic pancreatitis. The patients were affected by very intense pain controllable only with high doses of analgesic narcotics. Before the procedure a catheter was installed in the peridurale space between L1-T12. To avoid general anesthesia, 40 mL of marcaine 0.5% was injected to relieve the back pain sometimes reported after the neurolysis, caused by the diffusion of alcohol in the coeliac plexus. This technique requires a posterior percutaneous procedural transaortic approach CT scan guided, to determine the correct position of the needle tips and the spread of neurolytic solution (40 mL of 96% + 3 mL of contrast medium) around the origin of the coeliac trunk's anatomical center of the plexus. The first 10 patients have received 40 mL of 50% ethyl alcohol + 3 mL of contrast medium. To evaluate the rate of the analgesia relief, a visual analogue pain score (VAS) was used before and 48 hours after the neurolysis. The percutaneous neurolysis of the celiac plexus is useful to relieve the pain in patients affected by cancer developing in upper abdomen. The CT-scan guide of the needle allows an omogeneous distribution of the contrast medium. The insertion of the peridural catheter made a complete analgesia and reduced the incidence of complications. Our method provided an excellent control of the pain in all patients. In our experience the pain relief was almost complete in patients treated with 96% ethyl alcohol solution (VAS from 8 before the treatment to 1, 48 hours after the treatment). The alcohol administered in elevated concentrations (96%), does not increase the incidence of complications.

Hypothesis and development of a minimally invasive approach for percutaneous transmyocardial revascularization with holmium laser.

BACKGROUND: Percutaneous transluminal myocardial revascularization (PTMR) is a new procedure to improve perfusion of the ventricular wall for patients with intractable angina and untreatable by surgery or conventional catheter-based intervention. Actually PTMR requires femoral approach to utilize 8F-9F system device. We now report the feasibility study of PTMR using a laser delivered through a novel Eclipse system and new 6F and 7F guiding catheters that allow to perform PTMR even in patients with peripheral vascular disease and particularly suitable for alternative small vascular access. METHODS: Percutaneous vascular access for PTMR treatment was obtained via the femoral or radial artery. A 6F or 7F mono-directional catheter carrying flexible fiber optics was used with a Holmium laser (Eclipse system) and was placed across the aortic valve into the left ventricular cavity to create channels of 5 mm in depth from the endocardial surface into the myocardial tissue. From June 1999 to September 2000, 39 patients (28 males, 11 females, mean age 72 +/- 8 years, range 58-86 years) underwent PTMR with the Eclipse system. Preoperative mean Canadian Cardiovascular Society (CCS) angina class was 3.5 +/- 0.5 and previous myocardial procedures had been performed in 39 patients (18 coronary artery bypass graft and 31 coronary angioplasty). RESULTS: The procedure was well tolerated and a procedural success was obtained in all patients (100%). We performed a mean of 19 +/- 7 channels in a mean fluoroscopy time of 21 +/- 9 min. We report only one procedural complication: one embolic stroke (2.4%). No hospital major adverse cardiac events were observed. The average length of hospital stay was 3.1 days. The mean CCS angina class at entry was 3.5 and it declined from 3.5 +/- 0.5 to 1.25 +/- 0.8 at discharge. At the follow-up of 8.2 +/- 3.9 months the mean CCS was 1.5 +/- 0.7. CONCLUSIONS: This experience confirmed the safety and technical feasibility of PTMR with this mini-invasive approach with a reduction in operative and fluoroscopy time. The PTMR with the 6F or 7F guiding catheter is feasible in high risk patients even when the femoral approach is contraindicated. Immediate and short-term results confirm that a clinical improvement is obtained in most patients.

[Acute myocardial infarction during labor: report of a case and review of the literature]. / Infarto miocardico acuto durante travaglio di parto: descrizione di un caso e revisione della letteratura.

Acute myocardial infarction in pregnancy is a rare condition with substantial risk of maternal and fetal death. There is very little information about the use in this setting of percutaneous coronary interventional therapy. Together with literature review on this topic, we present the case of a 33-year-old 39-week pregnant woman who sustained during labor an acute transmural anterior myocardial infarction. Immediately after successful cesarean section, she was treated by primary percutaneous coronary angioplasty and direct stenting of the left anterior descending coronary artery with maternal and fetal excellent outcome.

Epileptic discharge of cortical, subcortical and spinal neurons in penicillin induced experimental epilepsy.

The sensitivity and electrophysiological patterns of paroxysmal activity induced in different brain structures by topical application of penicillin-G were evaluated in the rat. Recordings were carried out in five groups of animals, in telencephalon, diencephalon, mesencephalon, rombencephalon and spinal cords. The following analysis were carried out: frequency distribution histograms, latency and time course duration of paroxysmal activity, duration and amplitude of epileptic bursts. The results obtained showed that the nervous structures tested with penicillin-G had a different epileptogenic sensitivity and response pattern which significantly changed along the cerebral cortex-spinal cord axis. The highest epileptic sensitivity was observed in somatosensory cortex (SI) at 500-600 microns depth; in the other cortical layers, a significant lenghtening in latency was observed. Among the other structures, the spinal cord seemed to be the most sensitive target to the epileptogenic action of penicillin-G, whereas in the remaining structures, sensitivity significantly decreased in rostro-caudal direction. As far as the features of the paroxysmal activity are concerned, significant differences among tested structures were observed. In particular, within the SI cortex, the main differences were represented by the gradual increase in burst frequency and voltage from the surface to the IVth layer and by their subsequent decrease in deeper layers (V-VI). In the diencephalon, the paroxysmal activity was similar to that observed in more superficial and deeper cortical layers even though epileptic bursts showed a lower amplitude. Mesencephalon and rombencephalon displayed a paroxysmal activity with a distinctive feature, characterized by long lasting bursts of low amplitude, although bulbar outbursts showed a shorter duration than the mesencephalic ones. In the spinal cord, the epileptiform activity displayed a different paroxysmal pattern, characterized by the longest duration and the highest amplitude. The different sensitivities of the investigated brain structures to penicillin-G and the characteristics of the induced paroxysmal activity have been extensively discussed.

Trigeminal neuralgia and pain related to multiple sclerosis.

Although many patients with multiple sclerosis (MS) complain of trigeminal neuralgia (TN), its cause and mechanisms are still debatable. In a multicentre controlled study, we collected 130 patients with MS: 50 patients with TN, 30 patients with trigeminal sensory disturbances other than TN (ongoing pain, dysaesthesia, or hypoesthesia), and 50 control patients. All patients underwent pain assessment, trigeminal reflex testing, and dedicated MRI scans. The MRI scans were imported and normalised into a voxel-based, 3D brainstem model that allows spatial statistical analysis. The onset ages of MS and trigeminal symptoms were significantly older in the TN group. The frequency histogram of onset age for the TN group showed that many patients fell in the age range of classic TN. Most patients in TN and non-TN groups had abnormal trigeminal reflexes. In the TN group, 3D brainstem analysis showed an area of strong probability of lesion (P<0.0001) centred on the intrapontine trigeminal primary afferents. In the non-TN group, brainstem lesions were more scattered, with the highest probability for lesions (P<0.001) in a region involving the subnucleus oralis of the spinal trigeminal complex. We conclude that the most likely cause of MS-related TN is a pontine plaque damaging the primary afferents. Nevertheless, in some patients a neurovascular contact may act as a concurring mechanism. The other sensory disturbances, including ongoing pain and dysaesthesia, may arise from damage to the second-order neurons in the spinal trigeminal complex.

[Percutaneous cervical cordotomy in the therapy of incidence pain]. / La cordotomia cervicale percutanea nella terapia del dolore incident.

BACKGROUND: Incident pain does not respond to opioid treatment and it is not easily relieved with other therapeutic strategies (local intrapleural or spinal analgesia, phenol blocks etc.). For this reason cervical percutaneous cordotomy at C(1)-C(2) interspace is the only effective antalgic therapy in patients whose life expectancy is more than three to six months. METHODS: This study is a rectrospective review of 22 patients with cancer and incident pain from brachial, lumbar-sacral plexus injury and gluteal ulcer. RESULTS: Cordotomy provided excellent contralateral side pain relief in 21 patients; pain relief was maintained up to death and to the moment of last observation in living patients. In one deaf patient it was impossible to carry out the procedure due to incomplete co-operation and pain returned after 48 hours. Ventilatory depression caused death in one patient. Other complications recorded included ataxia, headache, motor deficit, dysesthesia and orthostatic hypotension. CONCLUSIONS: The conclusion is drawn that percutaneous cordotomy should, in carefully selected cases, be considered the only technique to relieve incident pain.

Disposition of propofol between red blood cells, plasma, brain and cerebrospinal fluid in rabbits.

The disposition of propofol in the blood and brain of New Zealand rabbits was studied in three groups of six rabbits. One group received a single anaesthetic dose; a second group received a 1-h infusion; and a third group was studied after the rabbits were judged to have recovered from a 1-h infusion. There was a high concentration of propofol in the red blood cell fraction and in the brain, however, the red blood cell concentration largely exceeded the one found in the brain in all groups of animals. This is consistent with the high fat solubility of diisopropylphenol. The possible effects of propofol sequestered in red blood cells is discussed.

Acute and mid-term results of phosphorylcholine-coated stents in primary coronary stenting for acute myocardial infarction.

The aim of this pilot study was to evaluate the safety and efficacy of the BiodivYsio phosphorylcholine-coated stent in the primary treatment of acute myocardial infarction. The BiodivYsio stent (Biocompatible) is a balloon-expandable stent, laser etched from a 316 L stainless steel tube. This device is coated with phosphorylcholine, a synthetic, hemocompatible phospholipid polymer that has been shown in experimental studies to reduce platelet and protein adhesion to the surface of the metal. One hundred consecutive patients within 24 hr of symptoms of onset of acute MI, treated with primary PTCA, were enrolled. After PTCA, stenting was attempted in all eligible lesions (reference diameter > or = 2.5 mm; no bend lesion > 45 degrees ). Poststenting regimens contained ticlopidine (500 mg/day) and aspirin (325 mg/day) and 6-12 hr of heparin infusion. Procedural success (TIMI > or = II and residual stenosis < 30%) was obtained in 70/74 cases (95%). TIMI grade III was restored in 90% of cases. In the patient group with procedural success (70 cases), 70 BiodivYsio stents were placed. After stenting, diameter stenosis decreased from 96% +/- 11% to 22% +/- 12% (P < 0.01) and minimal luminal diameter increased from 0.13 +/- 0.29 to 2.47 +/- 0.43 (P < 0.01). Nominal stent diameter was between 3.0 and 4.0 mm (mean, 3.5 +/- 0.4 mm). Stent length was between 11 and 28 mm (mean, 17 +/- 4.5 mm). Clinical follow-up was obtained in all patients; angiographic follow-up was performed in 65/70 (93%). No acute or subacute thrombosis was reported. Two in-hospital major adverse cardiac events (MACE) were reported due to a nontreated left main disease that required coronary artery bypass graft (CABG) surgery. At follow-up, MACE were found in 9 of 68 patients (13%), target lesion revascularization (TLR) in 6%, and CABG in the remaining 6%. Primary stenting with phosphorylcholine-coated stent leads to excellent short- and mid-term clinical outcomes and is associated with a restenosis rate of 12%.