Article

sec-Butylpropylacetamide (SPD), a New Amide Derivative of Valproic Acid for the Treatment of Neuropathic and Inflammatory Pain

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect ∼20% of the world’s population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study we defined the pharmacokinetic parameters of SPD in rat and mouse, and then evaluated its antinociceptive potential in neuropathic and acute inflammatory pain models. In the sciatic nerve ligation (SNL) model of neuropathic pain, SPD was equipotent to gabapentin and more potent than its parent compound VPA. SPD also showed either higher or equal potency to VPA in the formalin, carrageenan and writhing tests of inflammatory pain. SPD showed no effects on compound action potential properties in a sciatic nerve preparation, suggesting that its mechanism of action is distinct from local anesthetics and membrane stabilizing drugs. SPD’s activity in both neuropathic and inflammatory pain warrants its development as a potential broad-spectrum anti-nociceptive drug.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... The desired product 3a was obtained in excellent yield with outstanding diastereoselectivity (96% yield and 97:3 d.r., see Scheme 1). On the other hand, the amide functional group commonly exists in many bioactive natural products and medicinal molecules [68,69]. With the intention of preparing amide-containing spirocyclopropanes, benzyl or PMB substituted amidic sulfonium salts 4a and 4b were prepared for further investigation. ...
... Further studies of the cyclopropanation of cyclic enone 1 and sulfonium salts 4 a . On the other hand, the amide functional group commonly exists in many bioactive natural products and medicinal molecules [68,69]. With the intention of preparing amide-containing spirocyclopropanes, benzyl or PMB substituted amidic sulfonium salts 4a and 4b were prepared for further investigation. ...
Article
Full-text available
A highly diastereoselective cyclopropanation of cyclic enones with sulfur ylides was developed under catalyst-free conditions, producing multifunctional spirocyclopropanes in generally excellent yields (up to 99% yield and >99:1 d.r.). The asymmetric version of this method was realized by using an easily available chiral sulfur ylide, affording products with moderate to good stereoselectivity.
... Kaufmann et al. studied the antiallodynic activity of range of VPA related compounds in SNL model and found SPD to be as effective as Gabapentin in countering neuropathic pain with ED 50 values of 49 mg/kg along with mild sedation observed at dose of 80 mg/kg [78]. ...
Article
Full-text available
Citation: Mishra, M.K.; Kukal, S.; Paul, P.R.; Bora, S.; Singh, A.; Kukreti, S.; Saso, L.; Muthusamy, K.; Hasija, Y.; Kukreti, R. Insights into Structural Modifications of Valproic Acid and Their Pharmacological Profile. Molecules 2022, 27, 104. https:// Abstract: Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.
... Moreover, the administration of dilute acetic acid produces a characteristic writhing response in mice, which is representative of peritoneovisceral inflammatory pain [30]. This test detects peripheral analgesic activity, and antiepileptic drugs with various mechanisms of action also show activity in this test [31][32][33][34][35][36]. ...
Article
Full-text available
The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione and thiophene rings in the structure as potential anticonvulsant and antinociceptive agents. For this purpose, we obtained a series of new compounds and evaluated their anticonvulsant activity in animal models of epilepsy (maximal electroshock (MES), psychomotor (6 Hz), and subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine the mechanism of action of the most active anticonvulsant compounds (3, 4, 6, 9), their influence on the voltage-gated sodium and calcium channels as well as GABA transporter (GAT) was assessed. The most promising compound 3-(3-methylthiophen-2-yl)-1-(3-morpholinopropyl)pyrrolidine-2,5-dione hydrochloride (4) showed higher ED50 value than those of the reference drugs: valproic acid (VPA) and ethosuximide (ETX) (62.14 mg/kg vs. 252.7 mg/kg (VPA) in the MES test, and 75.59 mg/kg vs. 130.6 mg/kg (VPA) and 221.7 mg/kg (ETX) in the 6 Hz test, respectively). Moreover, in vitro studies of compound 4 showed moderate but balanced inhibition of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Additionally, the antinociceptive activity of the most active compounds (3, 4, 6, 9) was also evaluated in the hot plate test and writhing tests, and their hepatotoxic properties in HepG2 cells were also investigated. To determine the possible mechanism of the analgesic effect of compounds 3, 6, and 9, the affinity for the TRPV1 receptor was investigated.
... Вместе с тем до сих пор остается открытым вопрос о целесообразности применения этой методики у детей с эпилепсией, принимающих препараты вальпроевой кислоты, из-за потенциального риска геморрагических осложнений (эпидуральная гематома) [16,17,[23][24][25]. Кроме того, нет однозначного мнения об использовании нейроаксиальной блокады у пациентов с гидроцефалией, в том числе компенсированной установкой ликворошунтирующего механизма, ввиду отсутствия достаточных данных о риске развития осложнений, связанном с повышением внутричерепного давления при выполнении эпидуральной аналгезии [22,26]. ...
... On the other hand, lamotrigine and gabapentin inhibited only the late phase formalin behaviors (Laughlin et al. 2002). Recently, it has been reported that valproic acid at a dose of 300 mg/kg showed a significant reduction in the acute and inflammatory phases , but at a dose of 100 mg/kg, it reduced significantly the licking time only in the inflammatory phase (Kaufmann et al. 2016). The first phase of the formalin test is connected with acute chemical pain, whereas the second one is defined as tonic nociception involving central sensitization of dorsal horn neurons of the spinal cord or inflammation-induced hyperactivity of afferent nociceptors or combination of both (Laughlin et al. 2002;Ximenes et al. 2013). ...
Article
Full-text available
The purpose of the present study was to examine the analgesic activity of six novel hybrid molecules, which demonstrated in the previous research anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure (scPTZ) tests in mice. The antinociceptive properties were estimated in three models of pain in mice-the hot plate test, the formalin test, and in the oxaliplatin-induced neuropathy. Moreover, extended anticonvulsant studies were carried out and the antiseizure activity was investigated in the 6-Hz test. Considering drug safety evaluation, the influence of compounds on locomotor activity and contextual memory were checked. Furthermore, chosen molecules were tested in vitro for potential hepatotoxicity. To explain the probable mechanism of action, the radioligand binding assays were performed. In both phases of formalin test, analgesic activity demonstrated compounds 4, 8, and 9. These agents relieved also mechanical allodynia in oxaliplatin-induced model of neuropathic pain. At active doses, they did not influence locomotor activity of mice. Moreover, for compounds 8 and 9, no deleterious effect on memory was observed, but compound 4 might induce memory deficits. All tested compounds (4, 5, 8, 9, 15, and 16) inhibited psychomotor seizures with the ED50 values = 24.66-47.21 mg/kg. The binding studies showed that compound 4 only at the high concentrations revealed the effective binding to the neuronal sodium channels and moderately binding to the L-type calcium (verapamil site) channels and NMDA receptors. The present preclinical results proved that novel hybrid molecules demonstrate very promising anticonvulsant and analgesic activity.
Article
Full-text available
Introduction : The use of the pharmacophoric approach is a promising direction for modifying the chemical structure of 2-propylpentanoic (valproic) acid in order to obtain new drugs. Materials and methods : In the experiments on mice, acute toxicity, neurotoxicity, antiepileptic activity and analgesic effect of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide (valprazolamide) were evaluated. LD 50 was determined by probit analysis. Neurotoxicity was determined in a rotarod test and a bar test in mice. The effects of valprazolamide on the exploratory behavior of mice in open field test and in a light/dark transition test were evaluated. Its antiepileptic activity was tested in mice against seizures induced by maximal electroshock, pentylenetetrazole (scPTZ); isoniazid, thiosemicarbazide, pilocarpine, and camphor. The analgesic effect was studied in a hot plate test. Results and discussion : N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide was obtained by introducing pharmacophores into the structure of 2-propylpentanoic acid: a substituted amide group and an electron-donor domain of 1,3,4-thiadiazole. The LD 50 value for intraperitoneal administration of a new 2-propylpentanoic acid: derivative to mice was 924.8 mg/kg, and the TD 50 value in the rotarod test and the bar test were 456.7 mg/kg and 546.7 mg/kg, respectively. The suppression of orienting responses in the animals was noted when it was administered in neurotoxic doses. Valprazolamide showed the most antiepileptic activity on models of MES, scPTZ and isoniazid antagonism tests. The ED 50 values were 138.4 mg/kg, 74.5 mg/kg, and 126.8 mg/kg, respectively. The therapeutic indices for these models of epilepsy were 6.7; 12.4; 7.3, and protective index – 3.3; 6.1 and 3.6, respectively. In the hot plate test, valprazolamide increased the latency period before a defensive response to a thermal stimulus (ED 50 165 mg/kg). Conclusion : N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide is a new 1,3,4-thiadiazolylamide derivative of 2-propylpentanoic acid with antiepileptic and analgesic activities, which belongs to the group of low-toxic agents. Graphic abstract N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-propylpentanamide (3D) LD 50 =924.8 mg/kg (mice, intraperitoneally) TD 50 =456.7 mg/kg (rotarod, mice, intraperitoneally) ED 50 =138.4 mg/kg (MES, mice, intraperitoneally) ED 50 =74.5 mg/kg (scPTZ, mice, intraperitoneally)
Article
The objective of this study was to evaluate analgesic and antiallodynic activity of four new 3-benzhydryl-pyrrolidine-2,5-dione derivatives, which demonstrated previously anticonvulsant activity in the seizure tests in mice. Analgesic activity was examined in acute (the hot plate test), tonic (the formalin test), as well as neuropathic (the oxaliplatin-induced peripheral neuropathy) pain models in mice. Moreover, potential sedative properties and hepatotoxicity were evaluated. To establish the plausible mechanism of action, in vitro assays were carried out. All tested compounds RS 34, RS 37, RS 48, and RS 49, similarly to pregabalin, were active in the second phase of formalin test, a model of tonic pain. The most promising effect was observed for compounds RS 34, RS 48, and RS 49, which in a statistically significant way attenuated the nocifensive response at all tested doses 1, 10, and 30 mg/kg. Furthermore, all compounds at a dose of 30 mg/kg revealed antiallodynic activity in neuropathic pain related to chemotherapy-induced peripheral neuropathy in mice. In experimental tests on three compounds RS 34, RS 37 and RS 48 at active doses no sedative properties were registered. In the in vitro assay the selected molecule RS 34 did not induce cytotoxic effect on hepatoma cells. The binding and functional studies did not provide firm evidence on possible mechanism of action of these derivatives. In conclusion, the tested pyrrolidine-2,5-dione derivatives with antiseizure activity exerted also analgesic and antiallodynic effects in mouse models of pain.
Article
This paper contains five contributions which were presented as part of the novel therapies section of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures. These illustrate recent advances being made in the management and therapy of status epilepticus. The five contributions concern: genetic variations in Na + channel genes and their importance in status epilepticus; the European Reference Network for rare and complex epilepsies EpiCARE; the North American Pediatric Status Epilepticus Research Group (pSERG); Fenfluramine as a potential therapy for status epilepticus’ and the valproate derivatives, valnoctamide and sec-butylpropylacetamide (SPD), as potential therapies for status epilepticus. This article is part of the Special Issue “Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures”
Article
The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes.
Article
Full-text available
Background: Though migraine is disabling and affects 12%-15% of the population, there are few drugs that have been developed specifically for migraine prevention. Valproic acid (VPA) is a broad-spectrum antiepileptic drug (AED) that is also used for migraine prophylaxis, but its clinical use is limited by its side effect profile. sec-Butylpropylacetamide (SPD) is a novel VPA derivative, designed to be more potent and tolerable than VPA, that has shown efficacy in animal seizure and pain models. Methods: We evaluated SPD's antimigraine potential in the cortical spreading depression (CSD) and nitroglycerin (NTG) models of migraine. To evaluate SPD's mechanism of action, we performed whole-cell recordings on cultured cortical neurons and neuroblastoma cells. Results: In the CSD model, the SPD-treated group showed a significantly lower median number of CSDs compared to controls. In the NTG-induced mechanical allodynia model, SPD dose-dependently reduced mechanical sensitivity compared to controls. SPD showed both a significant potentiation of GABA-mediated currents and a smaller but significant decrease in NMDA currents in cultured cortical neurons. Kainic acid-evoked currents and voltage-dependent sodium channel currents were not changed by SPD. Conclusions: These results demonstrate SPD's potential as a promising novel antimigraine compound, and suggest a GABAergic mechanism of action.
Article
Full-text available
Study design:Systematic review and effectiveness analysis.Objectives:Assess the effectiveness of anticonvulsants for the management of post spinal cord injury (SCI) neuropathic pain.Setting:Studies from multiple countries were included.Methods:CINAHL, Cochrane, EMBASE and MEDLINE were searched up to April 2013. Quality assessment was conducted using the Jadad and the Downs and Black tools. Effect sizes and odds ratios were calculated for primary and secondary outcome in the included studies.Results:Gabapentinoids, valproate, lamotrigine, levetiracetam and carbamazepine were examined in the 13 included studies, ten of which are randomized controlled trials. Large effect size (0.873-3.362) for improvement of pain relief was found in 4 of the 6 studies examining the effectiveness of gabapentin. Pregabalin was shown to have a moderate to large effect (0.695-3.805) on improving neuropathic pain post SCI in 3 studies. Valproate and levetiracetam were not effective in improving neuropathic pain post SCI, while lamotrigine was effective in reducing neuropathic pain amongst persons with incomplete lesions and carbamazepine was found effective for relief of moderate to intense pain.Conclusion:Gabapentin and pregabalin are the two anticonvulsants which have been shown to have some benefit in reducing neuropathic pain.Spinal Cord advance online publication, 3 December 2013; doi:10.1038/sc.2013.146.
Article
Full-text available
The sucrose-gap technique has been widely used as a convenient tool for recording of the membrane activities from myelinated or unmyelinated nerves and muscle preparations (such as smooth and cardiac muscles). The quantitative measurements of membrane and action potentials in preparations with electrical coupling between their compartments are made much easier by this technique; the recorded potentials are rather similar to those recorded with a microelectrode. Recording of the membrane activities is of great value to experimenters studying the nervous system due to the simplicity and ease of use of this technique and the broad spectrum of sensitivity to agents influencing the electrical activity. This paper is focused on the set-up procedure and operation of the sucrose-gap technique, which provides an inexpensive, practical, and effective method for the investigation of the effects of drugs on the membrane activities of nerves and muscles in vitro.
Article
Full-text available
Transient receptor potential ankyrin 1 (TRPA1) is an ion channel involved in thermosensation and nociception. TRPA1 is activated by exogenous irritants and also by oxidants formed in inflammatory reactions. However, our understanding of its role in inflammation is limited. Here, we tested the hypothesis that TRPA1 is involved in acute inflammatory edema. The TRPA1 agonist allyl isothiocyanate (AITC) induced inflammatory edema when injected intraplantarly to mice, mimicking the classical response to carrageenan. Interestingly, the TRPA1 antagonist HC-030031 and the cyclo-oxygenase (COX) inhibitor ibuprofen inhibited not only AITC but also carrageenan-induced edema. TRPA1-deficient mice displayed attenuated responses to carrageenan and AITC. Furthermore, AITC enhanced COX-2 expression in HEK293 cells transfected with human TRPA1, a response that was reversed by HC-030031. This study demonstrates a hitherto unknown role of TRPA1 in carrageenan-induced inflammatory edema. The results also strongly suggest that TRPA1 contributes, in a COX-dependent manner, to the development of acute inflammation.
Article
Full-text available
ATP, acting via P2 purinergic receptors, is a known mediator of inflammatory and neuropathic pain. There is increasing evidence that the ATP-gated P2X4 receptor (P2X4R) subtype is a locus through which activity of spinal microglia and peripheral macrophages instigate pain hypersensitivity caused by inflammation or by injury to a peripheral nerve. The present article highlights the recent advances in our understanding of microglia-neuron interactions in neuropathic pain by focusing on the signaling and regulation of the P2X4R. We will also develop a framework for understanding converging lines of evidence for involvement of P2X4Rs expressed on macrophages in peripheral inflammatory pain.
Article
Full-text available
In the last decade the number of bioscience journals has increased enormously, with many filling specialised niches reflecting new disciplines and technologies. The emergence of open-access journals has revolutionised the publication process, maximising the availability of research data. Nevertheless, a wealth of evidence shows that across many areas, the reporting of biomedical research is often inadequate, leading to the view that even if the science is sound, in many cases the publications themselves are not “fit for purpose”, meaning that incomplete reporting of relevant information effectively renders many publications of limited value as instruments to inform policy or clinical and scientific practice [1–21]. A recent review of clinical research showed that there is considerable cumulative waste of financial resources at all stages of the research process, including as a result of publications that are unusable due to poor reporting [22]. It is unlikely that this issue is confined to clinical research [2–14,16–20].
Article
Full-text available
Immune cells and glia interact with neurons to alter pain sensitivity and to mediate the transition from acute to chronic pain. In response to injury, resident immune cells are activated and blood-borne immune cells are recruited to the site of injury. Immune cells not only contribute to immune protection but also initiate the sensitization of peripheral nociceptors. Through the synthesis and release of inflammatory mediators and interactions with neurotransmitters and their receptors, the immune cells, glia and neurons form an integrated network that coordinates immune responses and modulates the excitability of pain pathways. The immune system also reduces sensitization by producing immune-derived analgesic and anti-inflammatory or proresolution agents. A greater understanding of the role of the immune system in pain processing and modulation reveals potential targets for analgesic drug development and new therapeutic opportunities for managing chronic pain.
Article
Full-text available
The experiments were done on frog sciatic nerves, using a sucrose-gap recording technique. The aim of our study was to investigate and to compare the tonic and phasic conduction blocking potency of tramadol and lidocaine on whole nerve and their interactions with Ca(2+). The concentration of a tramadol solution producing the same amount of tonic and phasic conduction blocks was three and six times higher than that needed for lidocaine, respectively. Increasing the Ca(2+) concentration in the test solution enhanced the conduction blocking potency of tramadol, but decreased that of lidocaine. It is concluded that tramadol blocks nerve conduction like a local anesthetic but with a weaker effect than that of lidocaine. Interactions of Ca(2+) and these drugs suggested that these drugs might have either different binding sites or different action mechanisms.
Article
Full-text available
Pain can be an adaptive sensation, an early warning to protect the body from tissue injury. By the introduction of hypersensitivity to normally innocuous stimuli, pain may also aid in repair after tissue damage. Pain can also be maladaptive, reflecting pathological function of the nervous system. Multiple molecular and cellular mechanisms operate alone and in combination within the peripheral and central nervous systems to produce the different forms of pain. Elucidation of these mechanisms is key to the development of treatments that specifically target underlying causes rather than just symptoms. This new approach promises to revolutionize pain diagnosis and management.
Article
Full-text available
The conduction of action potential in peripheral nerves requires the coordinated opening and closing of Na(+) and K(+) channels. In the present study, we used the sucrose-gap recording technique to determine the electrophysiological changes of the regenerating nerves after sciatic nerve injury by using 4-aminopyridine (4-AP) and tetraethylammonium (TEA), and lidocaine. 4-AP enhanced the amplitude and duration of the compound action potentials (CAPs) of regenerating sciatic nerve 15 days post crush (15 dpc), and elicited delayed depolarizations (Del-dep) in 38 dpc and intact groups. Hyperpolarizing afterpotentials elicited by 4-AP were completely removed by TEA in both 15 and 38 dpc. Lidocaine effectively blocked the CAP amplitude. This blockage was more pronounced in 15 dpc than 38 dpc. This agent also exhibited a partial blockage on the Del-dep amplitude. These results may indicate that the changes in the activities of 4-AP- and TEA-sensitive K(+) channels and slow Na(+) channels may play critical roles in nerve excitability and conduction.
Article
Full-text available
The purpose of the present studies was to compare anticonvulsant drugs with diverse mechanisms of action in a persistent pain model, the formalin test. In addition, the anticonvulsant effects of the compounds were determined in the threshold electroshock tonic seizure test and the 6-Hz limbic seizure test. The effects of the compounds were also determined on locomotor activity. Carbamazepine, oxcarbazepine, lamotrigine, gabapentin and ethosuximide all produced statistically significant analgesic effects in the formalin test whereas phenytoin, topiramate, zonisamide, phenobarbital, tiagabine, valproate and levetiracetam did not. All compounds were anticonvulsant. In addition, morphine and phenobarbital increased locomotor activity while ethosuximide had no effect and all other compounds decreased locomotor activity. For those compounds that were analgesic, the doses required to produce analgesia were larger in magnitude than the anticonvulsant ED50 values in the threshold electroshock and 6-Hz tests, as well as larger than doses that altered locomotor activity. The present results demonstrate that the anticonvulsant and analgesic effects of clinically used antiepileptic drugs do not necessarily correlate and therefore suggest that the anticonvulsant and analgesic efficacy of these drugs may be due to different pharmacologic mechanisms.
Article
Full-text available
During the past two decades, an important focus of pain research has been the study of chronic pain mechanisms, particularly the processes that lead to the abnormal sensitivity - spontaneous pain and hyperalgesia - that is associated with these states. For some time it has been recognized that inflammatory mediators released from immune cells can contribute to these persistent pain states. However, it has only recently become clear that immune cell products might have a crucial role not just in inflammatory pain, but also in neuropathic pain caused by damage to peripheral nerves or to the CNS.
Article
Neuropathic pain is caused by disease or injury of the nervous system and includes various chronic conditions that, together, affect up to 8% of the population. A substantial body of neuropathic pain research points to several important contributory mechanisms including aberrant ectopic activity in nociceptive nerves, peripheral and central sensitization, impaired inhibitory modulation, and pathological activation of microglia. Clinical evaluation of neuropathic pain requires a thorough history and physical examination to identify characteristic signs and symptoms. In many cases, other laboratory investigations and clinical neurophysiological testing may help identify the underlying etiology and guide treatment selection. Available treatments essentially provide only symptomatic relief and may include nonpharmacological, pharmacological, and interventional therapies. Most extensive evidence is available for pharmacological treatment, and currently recommended first-line treatments include antidepressants (tricyclic agents and serotonin-norepinephrine reuptake inhibitors) and anticonvulsants (gabapentin and pregabalin). Individualized multidisciplinary patient care is facilitated by careful consideration of pain-related disability (eg, depression and occupational dysfunction) as well as patient education; repeat follow-up and strategic referral to appropriate medical/surgical subspecialties; and physical and psychological therapies. In the near future, continued preclinical and clinical research and development are expected to lead to further advancements in the diagnosis and treatment of neuropathic pain. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
Article
Diabetes is a worldwide epidemic, and associated neuropathy is its most costly and disabling complication. Given the rising prevalence of painful diabetic neuropathy, it is increasingly important that we understand the best ways to diagnose and treat this condition. Diagnostic tests in this field are evolving rapidly. These include the use of skin biopsies to measure small unmyelinated fibers, as well as even newer techniques that can measure both small unmyelinated fibers and large myelinated fibers in the same biopsy. The main treatments for painful diabetic neuropathy remain management of the underlying diabetes and drugs for the relief of pain. However, emerging evidence points to major differences between type 1 and type 2 diabetes, including the ability of glycemic control to prevent neuropathy. Enhanced glucose control is much more effective at preventing neuropathy in patients with type 2 diabetes than in those with type 1 disease. This dichotomy emphasizes the need to study the pathophysiologic differences between the two types of diabetes, because different treatments may be needed for each condition. The impact of the metabolic syndrome on neuropathy in patients with type 2 diabetes may account for the difference between the two types of diabetes and requires further study. Finally, neuropathic pain is under-recognized and undertreated despite an ever evolving list of effective drugs. Evidence exists to support several drugs, but the optimal sequence and combination of these drugs are still to be determined.
Article
Antiepileptic drugs (AEDs) are used to treat various nonepileptic central nervous system (CNS) disorders, both in neurology and psychiatry. Most AEDs have multiple mechanisms of action (MOAs), which include modulation of γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission, and alteration of voltage-gated ion channels or intracellular signaling pathways. These MOAs may explain the efficacy of AEDs in the treatment of bipolar disorder and neuropathic pain. Bipolar disorder and epilepsy have some common features, such as their episodic nature and associated kindling phenomena, which led to the regulatory approval and use of the AEDs carbamazepine (CBZ), valproic acid (VPA), and lamotrigine (LTG) in the treatment of bipolar disorder. A major limitation for the development of drugs with improved mood-stabilizing activity is the lack of knowledge on the mechanism of treatment for bipolar disorder. In contrast to epilepsy, no animal models in bipolar disorder are universally accepted and no model is able to exhibit the characteristic mood swings. Although most AEDs have now been investigated for their mood-stabilizing effects, only three (e.g., VPA, CBZ, and LTG) demonstrated clinical efficacy in patients. This suggests that the mechanism of drug action in mood disorder and in epilepsy only partially overlaps. Peripheral nerve damage leads to the initiation of cellular and molecular changes in the nervous system resulting in ectopic, repetitive firing perceived as chronic pain. Epileptic seizures are also characterized by hyperexcitability of neurons in the brain. The spontaneous electrogenesis in neuropathic pain has similarities to that of epilepsy. Alteration in sodium channels expression suggests that the mechanism underlying epileptic hyperexcitability may be similar to those underlying neuropathic pain. The AEDs gabapentin (GBP) and pregabalin (PGB) have become the mainstay of treatment for various neuropathic pain syndromes, owing to their ability to inhibit neuronal hyperactivity along the pain pathways. One explanation for how GBP and PGB relieve neuropathic pain is that they bind selectively to the Ca(+2) -channel subunit α2-δ in muscle tissue and brain. With 16 new AEDs having entered the market since 1990 the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2012 to the pharmaceutical industry, even though the clinical needs of refractory epilepsy remain unmet. Due to this situation, the future design of new AEDs must also include a potential in nonepileptic CNS disorders, such as bipolar disorder and neuropathic pain. The global market size of each of these two indications is similar to that of epilepsy, whereas they both currently have fewer approved drugs for treatment than epilepsy. Therefore, a new AED with additional approved indications in bipolar disorder and neuropathic pain might have a potential market size three times larger than that of epilepsy alone.
Article
A comparison was made of the spontaneous nociceptive behaviors elicited by s.c. injection into the rat hind paw of the following 8 irritants: acetic acid, carrageenan, formalin, kaolin, platelet-activating factor, mustard oil (given topically), serotonin, and yeast. Two distinct quantifiable behaviors indicative of pain were identified: flinching/shaking of the paw and hindquarters and licking/biting of the injected paw. These behaviors were prolonged and intense after formalin and acetic acid. Formalin-induced flinching was biphasic across time, a finding potentially useful for the study of both acute and tonic pain. Of the remaining test agents, only yeast caused significant spontaneous behavioral activity, which was of low intensity but long duration. Different time-courses for nociceptive behavior and development of edema were demonstrated for formalin, acetic acid and yeast. It is therefore unlikely that these endpoints are causally related. Overall, the present data strongly support the use of formalin as a noxious stimulus in tonic pain research.
Article
Chronic pain is a widespread public health issue that has many effects on physical, emotional and cognitive functions. An estimated 10-55% of all adults are thought to have chronic pain. Chronic pain is a multifactorial condition, caused by the complex interplay of nociceptive, neuropathic or mixed pathogenic mechanisms. Chronic pain is associated with specific and non-specific medical conditions such as cancer, HIV/AIDS, rheumatoid arthritis, fibromyalgia, osteoarthritis, low back pain or spinal stenosis and is broadly categorized as cancer pain and non-cancer pain. Evaluation of chronic pain requires a clear understanding of the nature of the pain and its underlying pathophysiology. Adequate assessment of pain, using validated tools, is an essential prerequisite of successful pain management. Unidimensional scales are useful for the measurement of pain intensity, while multidimensional scales measure both pain intensity and the extent to which pain interferes with life activity and emotional functioning. Patients should be reassessed and followed up in order to monitor progress and measure improvements in pain.
Article
The role of microglia and their contribution to the development and maintenance of pain states has emerged as an attractive field of study. Sensitization of central nociceptors and interneurons is thought to be responsible for the symptoms of chronic neuropathic pain states. Microglia interact with these neurons at the site of injury or disease as well as remotely. Microglia can be activated by phagocytosis or through the activation of a number of constitutively expressed cell surface molecules. Once activated, microglia participate in both innate and adaptive immune responses and remain active indefinitely. Activated microglia contribute to pain states through the production of pro-inflammatory cytokines, chemokines and extracellular proteases. Activated microglia also exhibit a modulated cell surface receptor and ion channel profile. The activation of several intracellular pathways in microglia has also been implicated in pain states. Attenuation of microglia activity is being presented as a viable therapeutic approach with regard to not only the reduction of pain symptoms but also in preventing the development of chronic pain states.
Article
sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a central nervous system (CNS)-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The study reported herein evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death. The anticonvulsant activity of SPD was evaluated in several rodent seizure and epilepsy models, including maximal electroshock (MES), 6-Hz psychomotor; subcutaneous (s.c.) metrazol-, s.c. picrotoxin, s.c. bicuculline, and audiogenic, corneal, and hippocampal kindled seizures following intraperitoneal administration. Results obtained with SPD are discussed in relationship to those obtained with VPA and VCD. SPD was also evaluated for its ability to block benzodiazepine-resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N-methyl-D-aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE-induced hippocampal cell death using FluoroJade B staining. The cognitive function of SPD-treated rats that were protected against pilocarpine-induced convulsive SE was examined 10-14 days post-SE using the Morris water maze (MWM). The relationship between the pharmacokinetic profile of SPD and its efficacy against soman-induced SE was evaluated in two parallel studies following SPD (60 mg/kg, i.p.) administration in the soman SE rat model. SPD was highly effective and displayed a wide protective index (PI = median neurotoxic dose/median effective dose [TD(50)/ED(50)]) in the standardized seizure and epilepsy models employed. The wide PI values of SPD demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also displayed anticonvulsant activity in the rat pilocarpine model of SE. Thirty minutes after the induction of SE, the calculated rat ED(50) for SPD against convulsive SE in this model was 84 mg/kg. SPD was not neuroprotective in the organotypic hippocampal slice preparation; however, it did display hippocampal neuroprotection in both SE models and cognitive sparing in the MWM, which was associated with its antiseizure effect against pilocarpine-induced SE. When administered 20 and 40 min after SE onset, SPD (100-174 mg/kg) produced long-lasting efficacy (e.g., 4-8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD ED(50) values in guinea pigs were 67 and 92 mg/kg when administered at SE onset or 40 min after SE onset, respectively. Assuming linear pharmacokinetics (PK), the PK-PD (pharmacodynamic) results (rats) suggests that effective SPD plasma levels ranged between 8 and 40 mg/L (20 min after the onset of soman-induced seizures) and 12-50 mg/L (40 min after the onset of soman-induced seizures). The time to peak (t(max)) pharmacodynamic effect (PD-t(max)) occurred after the PK-t(max), suggesting that SPD undergoes slow distribution to extraplasmatic sites, which is likely responsible for antiseizure activity of SPD. The results demonstrate that SPD is a broad-spectrum antiseizure compound that blocks SE induced by pilocarpine and soman and affords in vivo neuroprotection that is associated with cognitive sparing. Its activity against SE is superior to that of diazepam in terms of rapid onset, potency, and its effect on animal mortality and functional improvement.
Article
Chronic neuropathic and inflammatory pain is a major public health problem. Nociceptors undergo sensitization, first in peripheral tissues then in the central nervous sytem, via neuroimmune interactions linking neurons, glial cells (microglia and astrocytes), and immune cells. These interactions may either exacerbate or attenuate the pain and inflammation, which normally reach a state of equilibrium. With more powerful or longer lasting stimuli, specific profiles of microglial and, subsequently, astrocytic activation in the dorsal horn play a key role in neuronal plasticity and transition to chronic pain. Recent insights into the interactions between the nervous system and the immune system suggest a large number of potential therapeutic targets that could be influenced either by targeted inhibition or by directing the neuroimmune response toward the antiinflammatory and analgesic end of its spectrum.
Article
Inflammatory bowel disease and the irritable bowel syndrome are conditions characterized by chronic pain that generates persistent, hyperalgesic states in many regions of the body. It is difficult to explain the pain of conditions such as inflammatory bowel disease and irritable bowel syndrome by extrapolating directly from what is known about the mechanisms of somatic pain. Visceral and somatic pain show many differences not only in the psychophysics of the sensation, but also in the neurobiological mechanisms that mediate the sensory process. The activation and sensitization of visceral nociceptors are heavily influenced by the secretory and motor properties of the microenvironment where the sensory receptors are located. In some cases, epithelial cells can play a direct role in the activation of primary sensory neurons. Subclinical alterations of the epithelium can contribute to enhanced visceral sensitivity. Central hypersensitivity induced by visceral activation also shows differences with its somatic counterpart. Mobilization of AMPA receptors from the cytosol to the membrane of nociceptive neurons has been identified as a mechanism of sensitization of visceral pain pathways. Finally, functional pain syndromes, such as irritable bowel syndrome could be triggered or maintained by hormonal alterations, particularly those involving sex hormones such as estrogen.
Article
In a large proportion of individuals nervous system damage may lead to a debilitating chronic neuropathic pain. Such pain may now be considered a neuro-immune disorder, since recent data indicate a critical involvement of innate and adaptive immune responses following nerve injury. Activation of immune and immune-like glial cells in the injured nerve, dorsal root ganglia and spinal cord results in the release of both pro- and anti-inflammatory cytokines, as well as algesic and analgesic mediators, the balance of which determines whether pain chronicity is established. This review will critically examine the role of the immune system in modulating chronic pain in animal models of nervous system injury, and highlight the possible therapeutic opportunities to intervene in the development and maintenance of neuropathic pain.
Article
Valproic acid (VPA, 1) is a major broad spectrum antiepileptic and central nervous system drug widely used to treat epilepsy, bipolar disorder, and migraine. VPA's clinical use is limited by two severe and life-threatening side effects, teratogenicity and hepatotoxicity. A number of VPA analogues and their amide, N-methylamide and urea derivatives, were synthesized and evaluated in animal models of neuropathic pain and epilepsy. Among these, two amide and two urea derivatives of 1 showed the highest potency as antineuropathic pain compounds, with ED(50) values of 49 and 51 mg/kg for the amides (19 and 20) and 49 and 74 mg/kg for the urea derivatives (29 and 33), respectively. 19, 20, and 29 were equipotent to gabapentin, a leading drug for the treatment of neuropathic pain. These data indicate strong potential for the above-mentioned novel compounds as candidates for future drug development for the treatment of neuropathic pain.
Article
Chronic pain is one of the most prevalent, costly and disabling conditions in both clinical practice and the workplace, yet often remains inadequately treated. Moreover, chronic pain commonly co-occurs with depression, anxiety and somatoform disorders, and adversely affects response of these conditions to psychiatric treatments. This article provides an evidence-based approach to the pharmacotherapy of chronic pain. This narrative review is derived largely from meta-analyses and systematic reviews published since 2005. For a few medications, findings from multiple recent trials are synthesized if a systematic review had not yet been published. Classes of medications are first reviewed, followed by an overview of four common pain disorders: neuropathic pain, low back pain, fibromyalgia and osteoarthritis. A stepped care approach based upon existing evidence includes (1) simple analgesics (acetaminophen or nonsteroidal anti-inflammatory drugs); (2) tricyclic antidepressants (if neuropathic, back or fibromyalgia pain) or tramadol; (3) gabapentin, duloxetine or pregabalin if neuropathic pain; (4) cyclobenzaprine, pregabalin, duloxetine, or milnacipran for fibromyalgia; (5) topical analgesics (capsaicin, lidocaine, salicylates) if localized neuropathic or arthritic pain; and (6) opioids. Disease-specific recommendations for neuropathic, low back, fibromyalgia and osteoarthritis pain are reviewed. A number of medications have proven effective in chronic pain disorders and their use individually or in combination should improve the management of chronic pain.
Article
Ionotropic gamma-aminobutyric acid (GABA(A)) receptors control the relay of nociceptive signals at several levels of the neuraxis. Experiments with systemically applied benzodiazepines, which enhance the action of GABA at these receptors, have suggested both anti- and pronociceptive effects. The interpretation of such experiments has been notoriously difficult because of confounding sedation. Here, we have used genetically engineered mice, which carry specific benzodiazepine-insensitive GABA(A) receptor subunits, to test whether diazepam, a frequently used classical benzodiazepine, exerts antihyperalgesia after systemic administration in the formalin test, a model of tonic nociception. In wild-type mice, systemic diazepam (3-30 mg/kg, p.o.) dose-dependently reduced the number of formalin-induced flinches during both phases of the test by about 40-70%. This antinociception was reversed by the benzodiazepine site antagonist flumazenil (10mg/kg, i.p.), but fully retained in GABA(A) receptor alpha1 point-mutated mice, which were resistant against the sedative action of diazepam. Experiments carried out in mice with two diazepam-insensitive subunits (alpha1/alpha2, alpha1/alpha3 and alpha1/alpha5 double point-mutated mice) allowed addressing the contribution of alpha2, alpha3 and alpha5 subunits to systemic diazepam-induced antihyperalgesia in the absence of sedation. The relative contributions of these subunits were alpha2 approximately alpha3>alpha5, and thus very similar to those found for intrathecal diazepam (0.09 mg/kg). Accordingly, SL-651498 (10mg/kg, p.o.), an "anxioselective" benzodiazepine site agonist with preferential activity at alpha2/alpha3 subunits, significantly reduced formalin-induced flinching in wild-type mice. We conclude that systemic diazepam exerts a genuine antihyperalgesic effect, which depends on spinal GABA(A) receptors containing alpha2 and/or alpha3 subunits.
Article
Recent studies show that peripheral injury activates both neuronal and nonneuronal or glial components of the peripheral and central cellular circuitry. The subsequent neuron-glia interactions contribute to pain hypersensitivity. This review will briefly discuss novel findings that have shed light on the cellular mechanisms of neuron-glia interactions in persistent pain. Two fundamental questions related to neuron-glia interactions in pain mechanisms have been addressed: what are the signals that lead to central glial activation after injury and how do glial cells affect central nervous system neuronal activity and promote hyperalgesia? Evidence indicates that central glial activation depends on nerve inputs from the site of injury and release of chemical mediators. Hematogenous immune cells may migrate to/infiltrate the brain and circulating inflammatory mediators may penetrate the blood-brain barrier to participate in central glial responses to injury. Inflammatory cytokines such as interleukin-1beta released from glia may facilitate pain transmission through its coupling to neuronal glutamate receptors. This bidirectional neuron-glia signaling plays a key role in glial activation, cytokine production and the initiation and maintenance of hyperalgesia. Recognition of the contribution of the mutual neuron-glia interactions to central sensitization and hyperalgesia prompts new treatment for chronic pain.
Article
Voltage clamp experiments were carried out on Rana catesbiana nodes of Ranvier in order to test predictions regarding the relationship between local anesthetic lipid solubility and the rate of development of and recovery from frequency-dependent increments of sodium channel block. Contrary to expectations, the drugs of greater lipid solubility than lidocaine showed slower rates of development of frequency-dependent block and, in addition, induced longer rather than shorter memories for recent frequency-depent increments in channel block. Relaxation time constants for bupivacaine (50 micrometer), etidocaine (15 micrometer) and tetracaine (0.7 micrometer) measured 50, 8 and 8 sec, respectively, compared to shorter time constant of 2 sec for lidocaine (250 micrometer). Rate constants were calculated for binding to channels in both open and closed states. Open channels displayed a 130- to 6000-fold greater affinity for the local anesthetics than did closed channels, verifying an important feature of the "modulated receptor" hypothesis. In addition, binding to closed channels was enhanced by holding the membrane at more depolarizing potentials, which favored the development of inactive channel states. The exceptionally large binding constants of lidocaine for interactions with both closed and open channels cannot be attributed to its lipid solubility characteristics alone.
Article
The mild analgesic activities of aspirin, phenacetin and acetaminophen have been compared in the trypsin, kaolin and carrageenan hyperalgesic assays as well as in the acetic acid writhing test. The trypsin and kaolin hyperalgesic assays were designed to be unaffected by drugs with anti-inflammatory activity. Aspirin and acetaminophen were inactive in these two tests at dose levels devoid of side effects. Phenacetin was active in the trypsin and kaolin assays with oral ED50's of 114 +/- 36.2 and 107 +/- 11.5 mg/kg, respectively. Non-steroidal anti-inflammatory drugs as well as phenacetin and acetaminophen were active in the acetic acid writhing and carrageenan hyperalgesic assays. This led to evaluation of phenacetin and acetaminophen as anti-inflammatory agents. Both of these latter drugs were active in the carrageenan pleurisy and adjuvant arthritis models of inflammation. In all studies phenacetin was equipotent to or more potent than acetaminophen. The data suggest that the analgesia produced by aspirin and acetaminophen results from their anti-inflammatory activity whereas the analgesia produced by phenacetin has two components, one dependent on and one independent of anti-inflammatory activity.
Article
We attempted to develop an experimental animal model for peripheral neuropathic pain. Under sodium pentobarbital anesthesia, both the L5 and L6 spinal nerves (group 1) or the L5 spinal nerve alone (group 2) of one side of the rat were tightly ligated. For comparison, a parallel study was conducted with another group of rats (group 3) which received a partial tight sciatic nerve ligation, a paradigm developed previously as a neuropathy model. Withdrawal latencies to application of radiant heat to the foot were tested for the next 16 weeks in all 3 groups. Sensitivity of the hind paw to mechanical stimulation was tested with von Frey filaments. The general behavior of each rat was noted during the entire test period. Results suggested that the surgical procedure in all 3 groups produced a long-lasting hyperalgesia to noxious heat (at least 5 weeks) and mechanical allodynia (at least 10 weeks) of the affected foot. In addition, there were behavioral signs of the presence of spontaneous pain in the affected foot. Therefore, we believe we have developed an experimental animal model for peripheral neuropathy using tight ligations of spinal nerves. The model manifests the symptoms of human patients with causalgia and is compatible with a previously developed neuropathy model. The present model has two unique features. First, the surgical procedure is stereotyped. Second, the levels of injured and intact spinal segments are completely separated, allowing independent experimental manipulations of the injured and intact spinal segments in future experiments to answer questions regarding mechanisms underlying causalgia.
Article
The formalin test for nociception, which is predominantly used with rats and mice, involves moderate, continuous pain generated by injured tissue. In this way it differs from most traditional tests of nociception which rely upon brief stimuli of threshold intensity. In this article we describe the main features of the formalin test, including the characteristics of the stimulus and how changes in nociceptive behaviour may be measured and interpreted. The response to formalin shows an early and a late phase. The early phase seems to be caused predominantly by C-fibre activation due to the peripheral stimulus, while the late phase appears to be dependent on the combination of an inflammatory reaction in the peripheral tissue and functional changes in the dorsal horn of the spinal cord. These functional changes seem to be initiated by the C-fibre barrage during the early phase. In mice, the behavioural response in the late phase depends on the ambient temperature. We argue that the peripheral tissue temperature as well as other factors influencing the peripheral inflammation may affect the response, possibly confounding the results obtained with the test. Furthermore, we discuss the methods of recording the response and the value of observing more than one aspect of behaviour. Scoring of several behavioural variables provides a means of assessing motor or sensorimotor function as possible causes for changes in behaviour. In conclusion, the formalin test is a valuable addition to the battery of methods available to study nociception.
Article
The pharmacokinetics of a single 400 mg oral dose of valnoctamide (VCD) has been investigated in seven healthy, adult, male volunteers. VCD was not biotransformed rapidly to its corresponding acid valnoctic acid (VCA), unlike its isomer valpromide (VPD). It had a mean residence time of 13.2 h and a terminal half-life of 9.3 h. Throughout the study, only low plasma levels of VCA could be detected. Thus, unlike VPD, which is a pro-drug of the corresponding acid, (valproic acid, VPA). VCD appears to act as a drug in its own right, and it does not undergo similar hydrolysis. The pharmacokinetic difference may account for the different pharmacological activities of the two isomers.
Article
Experiments were done to assess the relationship of the chemical properties of local anesthetics to their ability to block neuronal impulse conduction, using a series of hitherto unavailable homologs of lidocaine. These molecules varied in the number and arrangement of alkyl groups attached to the tertiary amine nitrogen. Each compound was applied to desheathed sciatic nerves of frogs (Rana pipiens) mounted in a sucrose gap recording chamber. Compound action potentials (AP) were recorded at room temperature (20-23 degrees C) and the potency of each anesthetic determined from the concentration required to produce a 40% reduction in the amplitude of the AP at low-frequency stimulation: 1 min-1. This reduction was called Bt. An additional Bt was measured from the further decrease in amplitude of the AP during high-frequency stimulation (10 and 40 Hz). Tonic and phasic blocking potencies were analyzed as functions of the calculated drug partition coefficients, and the known molecular weights, molecular configurations and pKa values. Potency for Bt increased with increasing length of n-alkyl groups attached to the terminal amine, whereas it decreased as the length of the alkyl group connecting the amide bond to the terminal amine was increased. However, when considered in terms of their physicochemical properties, the homologs showed a potency for Bt that increased uniformly with increasing partition coefficient. This analysis revealed a strong positive correlation between tonic potency and partitioning into octanol for both neutral and protonated anesthetic species but little correlation with molecular weight or pKa. However, Bt did not depend uniquely on hydrophobicity, as predicted if lipophilic partitioning alone determined potency.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The quantitative relation between the concentration of local anesthetic (LA), the length of nerve exposed, and severity of conduction blockade was studied with use of a chamber where exposure length was varied as the concentration of lidocaine was held constant. Recordings of the compound action potential and of single axons established that small variations in the length of nerve exposed to LA strongly modulate conduction block even at exposure lengths in excess of 2 cm. Therefore, exposure length is a significant factor in determining blocking potency, and only at very high concentrations of LA, where voltage-dependent Na conductance is almost completely blocked, is the critical exposure length less than three nodes of Ranvier. The concentration required for 50% block of impulses in single fibers (that is, where 50% of the impulses would fail to propagate through the exposed region of the nerve) diminished as the exposed length of nerve increased, approximately halving as exposure length was changed from 6 mm to 15-25 mm. Conduction latency increased with the exposure length becoming sharply more variable as the critical exposure length for conduction block was approached. The results are consistent with the hypothesis of decremental conduction, where a partial active response in nodes exposed to marginal blocking concentrations extends the decay of the action potential along the axon, and do not support the interpretation that lengths of several centimeters affect blocking concentration because such distances increase the probability that three nodes will be blocked in succession. This study contradicts the broader common assumption that beyond three nodes, the length of nerve exposed is not a factor in nerve block with local anesthetics.
Evaluation of new non-steroidal anti-inflammatory drugs (NSAIDs) must compare efficacy and toxicity with existing compounds. Real progress involves maintaining effectiveness while decreasing toxicity. It is relatively easy to assess the effects of NSAIDs in animal models, and to determine gastrointestinal toxicity. However, although the ratio of active and toxic doses in animals can be extrapolated to man, the approach is limited and the NSAID needs to be assessed in a clinical setting as early as possible. In France, a national survey system has reported a wide range of adverse effects related to NSAIDs and shown important differences between compounds. Overdosage may be one of the factors responsible for toxicity, therefore pharmacokinetic evaluation is useful. In some disease states e.g. rheumatoid arthritis, there is a higher possibility of saturation pharmacokinetics with some drugs. Other pharmacokinetic parameters of interest are half-life, functions limiting activity, and hepatotoxicity. Furthermore, different pharmacokinetic parameters are required for different forms of disease. In acute states, the NSAID should have a short half-life and low protein binding and vice versa in chronic states. An important goal is to develop more selective NSAIDs regarding mechanisms of action or distribution into diseased tissues.
Article
Interspecies differences in regard to the teratogenicity of drugs can be the result of differing pharmacokinetic processes that determine the crucial concentration-time relationships in the embryo. Maternal absorption, as well as distribution, of the drugs does not usually show great species differences. The first-pass effect after oral application is often more pronounced in animals than man (e.g., valproic acid, 13-cis-retinoic acid), although in some cases the reverse was found (e.g., hydrolysis of valpromide). Existing differences can be adjusted by appropriate choice of the administration route and measurements of drug levels. Many variables determine the placental transfer of drugs: developmental stage, type of placenta, properties of the drug. Even closely related drugs (e.g., retinoids) may differ greatly in regard to placental transfer. Maternal protein binding is an important determinant of placental transfer, since only the free concentration in maternal plasma can equilibrate with the embryo during organogenesis; this parameter differs greatly across species (e.g., valproic acid: five times higher free fractions in mouse and hamster than in monkey and man). The metabolic pattern has not yet been demonstrated to be a major cause of species differences, although recent evidence on phenytoin and thalidomide support the hypothesis that some species differences can be the result of differing activation/deactivation pathways. Laboratory animals usually have a much higher rate of drug elimination than man. Drastic drug level fluctuations are therefore present during teratogenicity testing in animals, but not to the same degree in human therapy. It must, therefore, be investigated if peak concentrations (such as for valproic acid and possibly caffeine) or the area under the concentration-time curve (AUC) (such as for cyclophosphamide and possibly retinoids) correlate with the teratogenic response. Only then is a rational and scientific basis for interspecies comparison possible. It is concluded that the prediction of the human response based on animal studies can be improved by consideration of the appropriate pharmacokinetic determinants.
Article
A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
Article
The formalin test in mice is a valid and reliable model of nociception and is sensitive for various classes of analgesic drugs. The noxious stimulus is an injection of dilute formalin (1% in saline) under the skin of the dorsal surface of the right hindpaw. The response is the amount of time the animals spend licking the injected paw. Two distinct periods of high licking activity can be identified, an early phase lasting the first 5 min and a late phase lasting from 20 to 30 min after the injection of formalin. In order to elucidate the involvement of inflammatory processes in the two phases, we tested different classes of drugs in the two phases independently. Morphine, codeine, nefopam, and orphenadrine, as examples of centrally acting analgesics, were antinociceptive in both phases. In contrast, the non-steroid anti-inflammatory drugs indomethacin and naproxen and the steroids dexamethasone and hydrocortisone inhibited only the late phase, while acetylsalicylic acid (ASA) and paracetamol were antinociceptive in both phases. The results demonstrate that the two phases in the formalin test may have different nociceptive mechanisms. It is suggested that the early phase is due to a direct effect on nociceptors and that prostaglandins do not play an important role during this phase. The late phase seems to be an inflammatory response with inflammatory pain that can be inhibited by anti-inflammatory drugs. ASA and paracetamol seem to have actions independent of their inhibition of prostaglandin synthesis and they also have effects on non-inflammatory pain.
Article
This paper describes the responses of peripheral and central visceral nociceptive systems to acute injury and discusses these observations in relation to the concept of 'pre-emptive analgesia'. Visceral nociceptors are known to respond to injury but are also known to become sensitized to non-noxious stimuli during the inflammatory process that follows intense noxious stimulation. The afferent barrages triggered in visceral nociceptors by the acute injury and the enhanced responses evoked in sensitized nociceptors during the repair process can, in turn, increase the excitability of central nociceptive systems. The maintenance of central hypersensitivity is, however, dependant on the continuing presence of afferent volleys from sensitized nociceptors because the central changes cannot be sustained in the absence of a peripheral drive. Therefore it is proposed that the concept of 'pre-emptive analgesia', as such, has no neurophysiological basis. Any analgesic procedure aimed at reducing postoperative pain must not only prevent the arrival in the CNS of the initial afferent barrage evoked in nociceptive endings but also reduce or eliminate the persistent discharges of sensitized nociceptors during the inflammatory repair process that are critically important for the maintenance of the central pain state.
Article
Zusammenfassung Beschreibung einer neuen Methode, die es gestattet, mit Aussenelektroden die wahre Grösse der Membranpotentialschwankungen, die durch den Einfluss von hyper- oder hypopolarisierenden Substanzen oder durch die Erregung in markhaltigen Nervenfasern erzeugt werden, zu registrieren.
Article
Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. Combined use of NSAIDs and opioids has been indicated for achieving better analgesia with reduced side effects. The present study was aimed at evaluating the combination of different NSAIDs, which inhibit cyclooxygenase (COX) enzymes and tramadol against acetic acid-induced writhing in mice. The expected beneficial effect of combination regimen was analyzed by isobolographic analysis. The oral and intrathecally administered tramadol, a mu-opioid and naproxen, a nonselective COX inhibitor produced dose-dependent antinociception, however, rofecoxib, a selective COX-2 inhibitor lacked analgesic efficacy in writhing test. Isobolographic analysis showed synergistic or supra-additive interactions for the combinations of naproxen and tramadol after oral and intrathecal administration. However, similar interaction was not observed when tramadol was combined with rofecoxib. Pretreatment with naloxone partially reversed the antinociceptive effect of tramadol per se and its combination with naproxen without modifying the per se effect of NSAID. The results demonstrated marked synergistic interaction between naproxen and tramadol and such interaction involved opioid as well as non-opioid mechanisms of tramadol and inhibition of COX-1 but not COX-2 by naproxen.
Article
Although there are several animal models of epilepsy, the extrapolation of antiepileptic drug (AEDs) performance to epileptic patients from anticonvulsant activity results in animals is not straightforward. Consequently, the aim of this work was to perform a correlation analysis between therapeutic daily doses (D) and average steady-state plasma concentrations (Css,av) of AEDs and their activity in common anticonvulsant animal models. AED activity in anticonvulsant animal models was expressed as maximal electroshock seizure (MES) test ED50 values in mice and rats and ED50 values in audiogenic seizure-susceptible mice (AGS ED50). Data were examined, by use of linear and logarithmic approaches, for an association between Css,av (mg/L or micromol/L) and D (mg or mmol) for each AED in epileptic patients as the dependent variable (Y) and its MES ED50 in mice and rats and AGS ED50 in mice (mg/kg or micromol/kg) as the independent variable (X). Linear correlation analyses between Css,av (mg/L) and ED50 (mg/kg) for 11 AEDs gave the following correlation coefficients (R2): 0.68 (mice, MES); 0.73 (rat, MES); 0.64 (AGS). Switching the units from milligrams to micromoles improved the correlation significantly and gave the following R2 values: 0.88 (mice, MES); 0.90 (rat, MES); 0.76 (AGS). The linear correlation between Css,av and ED50 was better than that between D and ED50. The results of this analysis suggest that the relationship between Css,av and ED50 is useful in predicting target concentration ranges in humans. The Y intercepts of the Css,av-versus-ED50 and D-versus- ED50 plots were similar in all three animal models and ranged between 12 and 17 mg/L and between 570 and 890 mg, respectively, indicating that for all AEDs analyzed except valproic acid and ethosuximide, the therapeutic plasma concentration is in the range 10-20 mg/L.
Article
Antiepileptic drugs (AEDs) are often utilized in the treatment of neuropathic pain. The major AED valproic acid (VPA) is of particular interest as it is thought to engage a variety of different neural mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but life-threatening side effects: teratogenicity and hepatotoxicity. We synthesized VPA's corresponding amide: valpromide (VPD), two of VPAs isomers and their corresponding amides; valnoctic acid (VCA), valnoctamide (VCD), diisopropyl acetic acid (DIA), diisopropylacetamide (DID), and VPD's congener: N-methyl-VPD (MVPD). VCD, DID and VPD are nonteratogenic, potentially nonhepatotoxic, and exhibit better anticonvuslant potency than VPA. In this study, we assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation model of neuropathic pain (SNL, Chung model). VCA and MVPD were inactive. However, VPD (20–100 mg kg− 1), VCD (20–100 mg kg− 1) and DID (20–90 mg kg− 1) produced dose-related reversal of tactile allodynia with ED50 values of 61, 52 and 58 mgkg− 1, respectively. All the amides were more potent than VPA (ED50=269 mgkg− 1). The antiallodynic effect of VPA, VPD, VCD and DID was obtained at plasma concentrations of 125, 24, 18 and 7 mg l− 1, respectively, with a good pharmacokinetic–pharmacodynamic correlation and a minimal lag response. VCD and DID were found to have minimal motor and sedative side effects at analgesic doses, and were equipotent to GBP, currently the leading drug in neuropathic pain treatment. Consequently, VCD and DID have potential to become new drugs for the treatment of neuropathic pain. British Journal of Pharmacology (2005) 146, 198–208. doi:10.1038/sj.bjp.0706310
Article
Contemporary standard pharmacological care for the treatment of noncancer pain includes the use of opioid medications. The responsiveness of neuropathic pain to opioids has long been an area of controversy. Evidence from multiple randomized controlled trials indicates that opioids can relieve pain in a variety of neuropathic pain syndromes. Opioids are typically reserved for moderate to severe pain that cannot be relieved by the nonsteroidal anti-inflammatory drugs (NSAIDs). Opioids are often used in combination with other adjuvants or other analgesic agents. The advantage of opioids is the lack of a ceiling effect of the pure mu opioid agonists. The disadvantages of these drugs are a series of mechanism-based opioids-related side effects (e.g., nausea, drowsiness, constipation) and the potential issue of their abuse and misuse. Each patient needs to undergo a comprehensive evaluation and receive education on the treatment. The physician must be well conversant with the differential diagnosis and definitions of physical dependence, tolerance, pseudotolerance, aberrant behaviors, addiction, and pseudoaddiction. No specific opioid drug is intrinsically ''better'' than the others. Opioid rotation refers to the switch from one opioid to another when the degree of analgesia obtained is limited by the persistence of adverse effects or the occurrence of clinically relevant tolerance. This approach is based on the observation that a patient's response varies from opioid to opioid. At present, after 1) appropriate selection of patients and 2) longitudinal patient care with routine assessment of degree of analgesia, functional daily activities, adverse events and aberrant behaviors is carried out, opioid therapy can be the safest and most effective treatment measure for quality of life improvement in the chronic pain patient.
Article
Antiepileptic drugs (AEDs) are widely utilized in the management of neuropathic pain. The AED valproic acid (VPA) holds out particular promise as it engages a variety of different anticonvulsant mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but potentially life-threatening side effects: teratogenicity and hepatotoxicity. We have synthesized several tetramethylcyclopropyl analogues of VPA amides that are non-teratogenic, and are likely to be non-hepatotoxic, and that exhibit good antiepileptic efficacy. In the present study we have assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation (SNL) model of neuropathic pain. TMCA (2,2,3,3-tetramethylcyclopropanecarboxylic acid, 100-250 mg/kg), TMCD (2,2,3,3-tetramethylcyclopropanecarboxamide, 40-150 mg/kg), MTMCD (N-methyl-TMCD, 20-100 mg/kg), and TMCU (2,2,3,3-tetramethylcyclopropanecarbonylurea, 40-240 mg/kg) all showed dose-related reversal of tactile allodynia, with ED(50) values of 181, 85, 41, and 171 mg/kg i.p., respectively. All were more potent than VPA (ED(50)=269 mg/kg). An antiallodynic effect was obtained for TMCD, MTMCD and TMCU at plasma concentrations as low as 23, 6 and 22 mg/L, respectively. MTMCD was found to be non-toxic, non-sedative and equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. Tetramethylcyclopropyl analogues of VPA amides have potential to become a new series of drugs for neuropathic pain treatment.
Article
The in vivo effect of inhibitors of fatty acid amide hydrolase (FAAH) upon oedema volume and FAAH activity was evaluated in the carrageenan induced hind paw inflammation model in the mouse. Oedema was measured at two time points, 2 and 4 h, after intraplantar injection of carrageenan to anaesthetised mice. Intraperitoneal (i.p.) injections of the FAAH inhibitor URB597 (0.1, 0.3, 1 and 3 mg kg−1) 30 min prior to carrageenan administration, dose-dependently reduced oedema formation. At the 4 h time point, the ED50 for URB597 was ∼0.3 mg kg−1. Indomethacin (5 mg kg−1 i.p.) completely prevented the oedema response to carrageenan. The antioedema effects of indomethacin and URB597 were blocked by 3 mg kg−1 i.p. of the CB2 receptor antagonist SR144528. The effect of URB597 was not affected by pretreatment with the peroxisome proliferator-activated receptor γ antagonist bisphenol A diglycidyl ether (30 mg kg−1 i.p.) or the TRPV1 antagonist capsazepine (10 mg kg−1 i.p.), when oedema was assessed 4 h after carrageenan administration. The CB1 receptor antagonists AM251 (3 mg kg−1 i.p.) and rimonabant (0.5 mg kg−1 i.p.) gave inconsistent effects upon the antioedema effect of URB597. FAAH measurements were conducted ex vivo in the paws, spinal cords and brains of the mice. The activities of FAAH in the paws and spinal cords of the inflamed vehicle-treated mice were significantly lower than the corresponding activities in the noninflamed mice. PMSF treatment almost completely inhibited the FAAH activity in all three tissues, as did the highest dose of URB597 (3 mg kg−1) in spinal cord samples, whereas no obvious changes were seen ex vivo for the other treatments. In conclusion, the results show that in mice, treatment with indomethacin and URB597 produce SR144528-sensitive anti-inflammatory effects in the carrageenan model of acute inflammation. British Journal of Pharmacology (2005) 146, 467–476. doi:10.1038/sj.bjp.0706348
Article
Neuropathic pain treatment remains unsatisfactory despite a substantial increase in the number of trials. This EFNS Task Force aimed at evaluating the existing evidence about the pharmacological treatment of neuropathic pain. Studies were identified using first the Cochrane Database then Medline. Trials were classified according to the aetiological condition. All class I and II controlled trials (according to EFNS classification of evidence) were assessed, but lower-class studies were considered in conditions that had no top level studies. Only treatments feasible in an outpatient setting were evaluated. Effects on pain symptoms/signs, quality of life and comorbidities were particularly searched for. Most of the randomized controlled trials included patients with postherpetic neuralgia (PHN) and painful polyneuropathies (PPN) mainly caused by diabetes. These trials provide level A evidence for the efficacy of tricyclic antidepressants, gabapentin, pregabalin and opioids, with a large number of class I trials, followed by topical lidocaine (in PHN) and the newer antidepressants venlafaxine and duloxetine (in PPN). A small number of controlled trials were performed in central pain, trigeminal neuralgia, other peripheral neuropathic pain states and multiple-aetiology neuropathic pains. The main peripheral pain conditions respond similarly well to tricyclic antidepressants, gabapentin, and pregabalin, but some conditions, such as HIV-associated polyneuropathy, are more refractory. There are too few studies on central pain, combination therapy, and head-to-head comparison. For future trials, we recommend to assess quality of life and pain symptoms or signs with standardized tools.
Article
The antinociceptive activity of dexketoprofen was studied in mice using the acetic acid writhing test (acute tonic pain), the tail flick test (acute phasic pain) and the formalin assay (inflammatory pain). Isobolographic analysis was used to study the antinociceptive interactions between morphine and paracetamol co-administered with dexketoprofen. In the writhing test, the intraperitoneal administration of dexketoprofen or ketoprofen resulted in parallel dose-response curves with equal efficacy, but higher relative potency for dexketoprofen. In the tail flick test, the curves were parallel with similar efficacy and potency. The administration of morphine or paracetamol in both tests resulted in dose-response curves not parallel with that of dexketoprofen, which showed a potency between morphine and paracetamol. In the formalin assay, the antinociceptive activity of morphine during phase I was 122, 295 and 1695 times higher than dexketoprofen, ketoprofen and paracetamol, respectively. Isobolographic analysis demonstrated that the combination of sub-analgesic doses of dexketoprofen with morphine or with paracetamol was strongly synergic in all three tests. Synergistic drug combinations should improve effective pharmacological treatment of pain, minimizing drug specific adverse effects. These findings are undoubtedly worthy of additional controlled clinical trials in severe pain syndromes.