Pain-relieving Drugs Research Articles

Computational design of β-fluorinated morphine derivatives for pH-specific binding

Opioids such as morphine are important pain-relieving drugs but also carry a risk of harmful side effects including addiction. Morphine is active in both healthy and inflamed tissue, however, decreasing the pKa of the biochemically-active amine group can promote selective binding in the more acidic conditions of inflamed tissue and reduce harmful side effects associated with opioids. Herein, we explore the impact of fluorination on the pKa of fluoromorphine derivatives to identify which will bind selectively in inflamed tissue. Theoretical pKa values are determined at the M06-2X(SMD)/aug-cc-pVDZ level of theory by calculating the ΔGaq values for the amine deprotonation reactions.

Prevalence and Characteristics of Chronic Pain in Buprenorphine and Methadone-Maintained Patients.

Chronic pain and substance use disorders frequently co-occur. Indeed, chronic pain is highly prevalent, affecting 23–68% of patients receiving opioid agonist treatments (OAT) worldwide. The majority of available estimates come from American studies, but data are still lacking in Europe. We aim to provide European estimates of the prevalence of chronic pain in patients receiving OAT using French data, since France is the first European country in terms of number of patients with OAT. The secondary objectives were to characterize the features and management of chronic pain, as well identify associated risk factors. We conducted a multicenter, cross-sectional study, recruiting patients treated either with buprenorphine or methadone in 19 French addiction centers, from May to July 2016. All participants had to complete a semi-directed questionnaire that collected sociodemographic and medical data, pain characteristics, and licit or illicit drug consumption. In total, 509 patients were included. The prevalence of chronic pain was estimated at 33.2% (95% CI: 29.1–37.3). Compared to non-chronic pain patients, chronic pain patients were older (38.4 vs. 36.1 years, p = 0.006), were more unemployed (66 vs. 52%, p = 0.003), had more psychiatric comorbidities (50 vs. 39%, p = 0.02), and split their OAT for pain management more frequently (24 vs. 7%, p = 0.009). Pain intensity was moderate or severe in 75% of chronic pain patients. Among patients with chronic pain, 15.4% were not prescribed, and did not self-medicate with, any analgesic drugs, 52.1% were prescribed analgesics (non-opioid analgesics, 76.3%; codeine, tramadol, opium, 27.2%; and morphine, fentanyl, oxycodone, 11.8%), and 32.5% exclusively self-medicated with analgesics. Moreover, 20.1% of patients with chronic pain also used illicit drugs for pain relief. On multivariate analysis, variables that remained significantly associated with chronic pain were age [OR = 1.03 (95% CI: 1.00–1.05], p = 0.02], anxiety [OR = 1.52 (1.15–2.02), p = 0.003], and depression [OR = 1.25 (1.00–1.55), p = 0.05]. Chronic pain is a highly prevalent condition in patients receiving OAT, and its appropriate management remains uncertain, since insufficient relief and frequent additional self-medications with analgesics or illicit drugs were reported by these patients. Increased awareness among caregivers is urgently needed regarding a systematic and careful assessment, along with an adequate management of chronic pain in patients receiving OAT.

Selective and sensitive colorimetric detection of p-aminophenol in human urine and paracetamol drugs based on seed-mediated growth of silver nanoparticles

p -aminophenol ( p AP), which is a well-known nephrotoxicant, has been widely used in diverse industries as a versatile intermediate material for the synthesis of chemical products. The concentration of p AP in urine is one of the markers for exposure assessment of carcinogenic aniline compounds, and p AP is also the main impurity in paracetamol-based pain-relieving drugs. Herein, we developed a colorimetric sensor for selective and sensitive assay of p AP in human urine and paracetamol drugs. Silver nanoparticles were used as a colorimetric indicator that changes color upon its growth because of the reducing power of p AP. The developed p AP sensor provides a dynamic linear range of 0–85 μ M with a low limit of detection of 0.32 μ M through an ultraviolet (UV)–visible (Vis) spectrometer. A clear color change was observed at 15 μ M, making the proposed colorimetric sensor suitable for a point-of-care diagnosis by naked eyes. Our p AP assay is highly accurate for the standard addition method for both urine and paracetamol samples, with a recovery rate above 94%, proving the feasibility of using the sensor in daily applications. • We developed a selective and sensitive colorimetric sensor for p-aminophenol ( p AP). • The colorimetric p AP sensor has a dynamic linear range 0–85 μ M & LOD of 0.32 μ M. • Convenient visual inspection is available at 15 μ M concentration of p AP. • The developed sensor can efficiently detect p AP in human urine and paracetamol drug.

Kahweol, a natural diterpene from coffee, induces peripheral antinociception by endocannabinoid system activation.

Kahweol is a compound derived from coffee with reported antinociceptive effects. Based on the few reports that exist in the literature regarding the mechanisms involved in kahweol-induced peripheral antinociceptive action, this study proposed to investigate the contribution of the endocannabinoid system to the peripheral antinociception induced in rats by kahweol. Hyperalgesia was induced by intraplantar injection of prostaglandin E2(PGE2) and was measured with the paw pressure test. Kahweol and the drugs to test the cannabinoid system were administered locally into the right hind paw. The endocannabinoids were purified by open-bed chromatography on silica and measured by LC-MS. Kahweol (80 µg/paw) induced peripheral antinociception against PGE2-induced hyperalgesia. This effect was reversed by the intraplantar injection of the CB1 cannabinoid receptor antagonist AM251 (20, 40, and 80 μg/paw), but not by the CB2 cannabinoid receptor antagonist AM630 (100 μg/paw). Treatment with the endocannabinoid reuptake inhibitor VDM11 (2.5 μg/paw) intensified the peripheral antinociceptive effect induced by low-dose kahweol (40 μg/paw). The monoacylglycerol lipase (MAGL) inhibitor, JZL184 (4 μg/paw), and the dual MAGL/fatty acid amide hydrolase (FAAH) inhibitor, MAFP (0.5 μg/paw), potentiated the peripheral antinociceptive effect of low-dose kahweol. Furthermore, kahweol increased the levels of the endocannabinoid anandamide, but not of the other endocannabinoid 2-arachidonoylglycerol nor of anandamide-related N-acylethanolamines, in the plantar surface of the rat paw. Our results suggested that kahweol induced peripheral antinociception via anandamide release and activation of CB1 cannabinoid receptors and this compound could be used to develop new drugs for pain relief.

The molecular neurobiology and neuropathology of opioid use disorder.

The number of people diagnosed with opioid use disorder has skyrocketed as a consequence of the opioid epidemic and the increased prescribing of opioid drugs for chronic pain relief. Opioid use disorder is characterized by loss of control of drug taking, continued drug use in the presence of adverse consequences, and repeated relapses to drug taking even after long periods of abstinence. Patients who suffer from opioid use disorder often present with cognitive deficits that are potentially secondary to structural brain abnormalities that vary according to the chemical composition of the abused opioid. This review details the neurobiological effects of oxycodone, morphine, heroin, methadone, and fentanyl on brain neurocircuitries by presenting the acute and chronic effects of these drugs on the human brain. In addition, we review results of neuroimaging in opioid use disorder patients and/or histological studies from brains of patients who had expired after acute intoxication following long-term use of these drugs. Moreover, we include relevant discussions of the neurobiological mechanisms involved in promoting abnormalities in the brains of opioid-exposed patients. Finally, we discuss how novel strategies could be used to provide pharmacological treatment against opioid use disorder.

Targeting nerve growth factor, a new option for treatment of osteoarthritis: a network meta-analysis of comparative efficacy and safety with traditional drugs.

Objective: Osteoarthritis (OA) is the most common joint disease and leading cause of pain and disability in the elderly population. Most guidelines recommend the use of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids for the non-operative treatment of OA. Monoclonal nerve growth factor (NGF) antibodies are new drugs with the potential to provide pain relief and functional improvement in OA. We compared the efficacy (pain reduction and functional improvement), and safety of monoclonal NGF antibodies with NSAIDs and opioids in the treatment of OA with a Bayesian network meta-analysis.Results: 38 articles, comprising 41 trials and 20489 patients with OA were included. Overall from the network meta-analysis, anti-NGFs were the most effective drugs for pain relief (Standardized Mean Difference or SMD compared with placebo 4.25, 95% CI 2.87 to 5.63, Surface Under the Cumulative RAnking curve or SUCRA=93.7%) and for functional improvement (SMD 4.90, 95% CI 3.46 to 6.33, SUCRA=98.3%). Although anti-NGFs were associated with higher risk of peripheral sensation abnormality (paresthesia and pruritus), they were not associated with higher risk of other AEs (headaches and nausea) or with higher withdrawal rates related to AEs.Conclusions: Monoclonal NGF antibodies provide significantly greater pain relief and functional improvement in OA compared to NSAIDs and opioids. Monoclonal NGF antibodies are not associated with severe AEs. More studies are needed to confirm these findings.Methods: PubMed, CNKI, Web of Science, Scopus, Embase and Cochrane Library databases were searched for relevant studies (OA treated with anti-NGFs, opioids, selective COX-2 inhibitors or NSAIDs) published between January 1999 to January 2020. Bayesian network and conventional meta-analyses were conducted. Pain relief, functional improvement and AEs were assessed.

Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity.

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both invitro and invivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio.

Preoperative Preparation Of Elderly Patients With Concomitant Hypertension In The Practice Of Ophthalmic Surgery

Background: The relevance of the problem of arterial hypertension (AH) is determined by its high frequency in the population, the influence on the state of health, working capacity and longevity of the population. Persons of old and old age, as a rule, have a significant amount of risk factors for cardiovascular diseases, very often there are lesions of target organs and associated clinical conditions, therefore, the majority of painful AHs of these age-related categories belong to high and very high-risk groups. Purpose of the research: To optimize the existing methods of managing elderly and senile patients with hypertension during cataract extraction, including preoperative assessment of patients' condition and preparation, intraoperative protection. Materials and methods: Clinical observations cover 150 patients aged 60 to 89 years (74.7 ± 0.5), who were required for surgical treatment for age-related cataracts in the department of ophthalmology at the Sam clinic. Depending on the method of anesthesiology, all patients were divided into 2 groups. Results: All patients with hypertension on the background of an antihypertensive therapy have clinically achieved the target numbers for arterial pressure. . Arterial hypertension before surgery in patients of the II group testified to a pressurized reaction of the cardiovascular system (CCC) in response to psycho-emotional irritation and a short-term associated with it. After the operative period, indicators of the functional state of the CVS improved, however, tachycardia of the heart rate of 85.4 ± 1.4 use of antihypertensive and pain-relieving drugs. In patients of the I-group, the SAD stabilized at 87.7 ± 3.7 mm Hg, heart rate 66.2 ± 3.4 beats. in minutes at the I-stage already after premedication. Conclusion. The results of the study suggest that conducting adequate antihypertensive therapy in combination with drugs that reduce mental and emotional stress in the preoperative period, exclusion of eye contact, psychoemotional stress through sedation and neuroleptanalgesia in waiting rooms allows to stabilized the clinical state of patients, clearly correlating with an improvement in hemodynamic parameters.

A step closer in the management of uncontrolled neuropathic pain: gabapentin-nortriptyline combination

<p class="abstract">Neuropathic pain is extremely distressing as it significantly hampers the performance of daily activities and impedes overall quality of life. A large number of illnesses are linked with neuropathic pain like radiculopathy, sciatica, diabetes, herpes infection, spinal injury, stroke, etc. Treating neuropathic pain is challenging as response to the treatment is at times uncertain and associated with undesirable side effects. Uncontrolled neuropathic pain is observed in large group of patients receiving current treatment regimen. Almost half of the neuropathic pain patients need more than two drugs for pain relief. Various clinical trials have demonstrated better efficacy of combination therapy in reducing pain than monotherapy. Utilizing drug combination with different mechanism of action or acting on two different sites has demonstrated superior analgesic effect in painful neuropathic condition. The first tier agents recommended by various guidelines are calcium channel alpha-2-delta ligands and tricyclic antidepressants that act on different pain pathways. A clinical trial has shown enhanced pain relief with no increase in side effects with the administration of gabapentin and nortriptyline combination in patients suffering from neuropathic pain. Moreover, symptoms associated with neuropathic pain like sleep disturbances, altered mood, decreased walking ability, depression and quality of life were also significantly improved. Hence, combination therapy of gabapentin and nortriptyline offers a pivotal modality in the management of uncontrolled neuropathic pain.</p>

Irritable bowel syndrome and biliary tract pathology. Clinical analysis

Irritable bowel syndrome (IBS) – a recurrent functional disorder of the gastrointestinal tract (GIT), the main symptom of which is abdominal pain necessarily associated with a change in intestinal function. IBS is a functional intestinal disorder in which recurrent abdominal pain is associated with a defecation act and a change in the frequency or shape of the stool. The diagnosis of IBS remains exclusively clinical. The difficulty in studying IBS, especially from the perspective of its epidemiology, is that there is still no universal and specific biological marker. Very often patients complain about symptoms typical for several functional disorders, in particular, biliary tract pathology and IBS. The article discusses the multi-component causes and mechanisms of IBS formation, which are also present in other functional gastrointestinal tract diseases. Patients with IBS often have functional disorders of the biliary tract (FDBT) that are not associated with organic pathology. There are no reliable differences in the frequency and nature of FDBT in patients with IBS, depending on its current variant - with constipation or diarrhea prevalence. As a result, the treatment of patients with IBS remains a challenge, and the recurrence of the disease depends on the state of psycho-emotional health, the presence of overlap syndrome in most cases. The article presents the main international criteria for diagnostics of IBS. The main approaches to the treatment of IBS are considered. Good results in the treatment of IBS are observed when using drugs that affect the complex of pathophysiological mechanisms of the disease. This is confirmed in the article by a clinical case study. The prescription of the Sparex drug for pain relief in a patient with IBS and FDBT is justified by the fact that it not only eliminates pain, but also improves the rheological properties of bile, typical for overlap “IBS-FDBT” syndrome.

Use of pain relieving drugs in community-dwelling older people with and without type 2 diabetes

AimsTo analyze the use of pain medication among community-dwelling people aged 65 years or older with and without type 2 diabetes in primary care. MethodsA total of 187 patients with and 176 patients without diabetes were randomly selected from a primary care sample of 389 patients with diabetes and 604 age- and gender-matched controls. Pain status was defined as no pain, nociceptive pain or neuropathic pain. Pain medication (paracetamol, NSAID, opioids, neuropathic pain medication) use was based on electronic patient records and checked by a physician during a health examination. ResultsSome pain was present in 90 (51%) patients without and in 106 (57%) patients with diabetes (p = 0.55). Of the patients without diabetes, 109 (62%) and with diabetes 123 (66%) used some pain medication (p = 0.45). The respective proportions for the regular use were 13% and 11% and for the as needed use 56% and 61%. Diabetes was not associated with any of the pain medications used. The use of pain-relieving drugs was most common for neuropathic pain. ConclusionsThe present study indicated that community-dwelling people with and without diabetes used pain medication similarly. Pain medication was used mostly as needed instead of being regular.

Is there an alternative to diclofenac i/m injections for rapid relief of severe pain? Results of randomized controlled and partially blind forsage study

Diclofenac Potassium sachets (DPS) is a new faster-absorption and rapid onset of pain relief drug dosage form of Diclofenac with high analgesic potential.Objective. To assess efficacy and safety of Diclofenac sachets and intramuscular injections in relieving acute pain in patients with rheumatic diseases (RDs).Materials and methods: The study group included 30 RD patients, 53.3% females and 46.7% males, mean age 41.8 ± 10.7 years, with severe acute pain (≥7 cm VAS pain rating, VAS 0-10 cm). After signing informed consent patients were randomized into DPS 50 mg t.i.d. and Diclofenac 75 mg i/m b.i.d. The first administration of Diclofenac was blind, i.e., patients from both groups were also administered placebo – either placebo injection in Group 1 randomized to sachet or placebo sachet in Group 2. The study lasted for 3 days. Level of analgesia was assessed in 15, 30, 60, 120, 180 minutes after the first administration, then three times a day during two following days and in the morning on day 4. Serum levels of CRP, IL-6 and P substance biomarkers were also monitored.Results. Pain relief in Group 1 was documented already in 15 min after administration – from 8.1±0.8 to 5.7±1.7 cm VAS (р=0.012), with continuing increase of analgesic effect thereafter. Group 2 demonstrated significant pain relief in 1 hour after Diclofenac administration – from 7.6±0.7 to 4.5±1.9 cm VAS (р=0.04). Based on obtained data analgesic effect was more powerful in Group 1 vs Group 2 in 15 and 30 minutes after drug administration (р=0.019; р=0.037). Starting from the 3rd hour post-administration there was no statistically significant difference in pain intensity between the two groups. Final assessment in the morning on day 4 showed significant pain reduction by 4.5±2.6 cm VAS in Group 1 vs baseline, and by 3.6±1.4 cm VAS in Group 2 (p=0.545). Functional improvement in both groups reached 3.7±1.9 and 3.3±1.3 cm VAS, respectively (p=0.837). The results were rated as “good” and “excellent” by 77.0% in Group 1, and 61.5% – in Group 2 (р=0.302). No correlation between decreasing pain intensity and fluctuating CRP, IL-6, and substance P concentrations was established. Three patients from Group 1 reported new-onset dyspepsia, resulting in discontinuation of treatment in 2 of them. Similarly, 2 discontinuations occurred in 2 patients with new-onset dyspepsia in Group 2, plus one additional withdrawal due to gastric ulcer and elevated blood pressure.Conclusion. DPS is not inferior to i/m Diclofenac injections in terms of analgesic potential and rapid onset of pain relief. Oral intake is associated with fewer adverse reactions compared to i/m injections.

ESCAPE pain trial - The effects of Curcumin in pain relief in women diagnosed with primary dysmenorrhea: A triple blinded, placebo-controlled, phase II, randomized clinical trial protocol.

Introduction: Primary dysmenorrhea affects many women, being a major cause of absenteeism and reduced productivity at work and at school. Although non-steroidal anti-inflammatory drugs (NSAIDs) are a good treatment option, up to 18% of women show no response or present allergic reactions and adverse events. Curcumin has antispasmodic, antinociceptive, and both specific and nonspecific anti-inflammatory effects, with good tolerability and safety. To date, no previous trial involving curcumin and dysmenorrhea pain has been performed. Therefore, our main goal is to assess the efficacy of curcumin for pain relief among women with primary dysmenorrhea, along with determining curcumin’s adverse effects and tolerability profile.Methods: A phase II, single-center, randomized, triple-blinded, placebo-controlled, parallel-group, superiority trial to evaluate the effect of curcumin (500 mg/12h) in pain reduction in women (18 to 35-year-old) with primary dysmenorrhea. A first cycle will be used for a passive, observational run-in phase. A sample of 108 participants (54 per group) is necessary to detect a 30% difference in pain sensitivity between groups assessed by visual analogue scale (VAS). Secondary outcomes include side effects, Cox Menstrual Symptom Scale (CMSS), and use of rescue drugs for pain relief. Discussion: Clinical evidence has shown analgesic and anti-inflammatory effects of curcumin and in view of dysmenorrhea’s physiopathology being related to those mechanisms targeted by curcumin, we hypothesize its use could represent an innovative and effective therapy to reduce the severity of this disease and its symptoms. Keywords: primary dysmenorrhea, Curcumin, pain relief, Visual Analogue Scale, Cox Menstrual Symptom Scale.

Therapeutic Manipulation of Macrophages Using Nanotechnological Approaches for the Treatment of Osteoarthritis.

Osteoarthritis (OA) is the most common joint pathology causing severe pain and disability. Macrophages play a central role in the pathogenesis of OA. In the joint microenvironment, macrophages with an M1-like pro-inflammatory phenotype induce chronic inflammation and joint destruction, and they have been correlated with the development and progression of the disease, while the M2-like anti-inflammatory macrophages support the recovery of the disease, promoting tissue repair and the resolution of inflammation. Nowadays, the treatment of OA in the clinic relies on systemic and/or intra-articular administration of anti-inflammatory and pain relief drugs, as well as surgical interventions for the severe cases (i.e., meniscectomy). The disadvantages of the pharmacological therapy are related to the chronic nature of the disease, requiring prolonged treatments, and to the particular location of the pathology in joint tissues, which are separated anatomical compartments with difficult access for the drugs. To overcome these challenges, nanotechnological approaches have been investigated to improve the delivery of drugs toward macrophages into the diseased joint. This strategy may offer advantages by reducing off-target toxicities and improving long-term therapeutic efficacy. In this review, we describe the nanomaterial-based approaches designed so far to directly or indirectly manipulate macrophages for the treatment of osteoarthritis.

Deepening the Mechanisms of Visceral Pain Persistence: An Evaluation of the Gut-Spinal Cord Relationship.

The management of visceral pain is a major clinical problem in patients affected by gastrointestinal disorders. The poor knowledge about pain chronicization mechanisms prompted us to study the functional and morphological alterations of the gut and nervous system in the animal model of persistent visceral pain caused by 2,4-dinitrobenzenesulfonic acid (DNBS). This agent, injected intrarectally, induced a colonic inflammation peaking on day 3 and remitting progressively from day 7. In concomitance with bowel inflammation, the animals developed visceral hypersensitivity, which persisted after colitis remission for up to three months. On day 14, the administration of pain-relieving drugs (injected intraperitoneally and intrathecally) revealed a mixed nociceptive, inflammatory and neuropathic pain originating from both the peripheral and central nervous system. At this time point, the colonic histological analysis highlighted a partial restitution of the tunica mucosa, transmural collagen deposition, infiltration of mast cells and eosinophils, and upregulation of substance P (SP)-positive nerve fibers, which were surrounded by eosinophils and MHC-II-positive macrophages. A significant activation of microglia and astrocytes was observed in the dorsal and ventral horns of spinal cord. These results suggest that the persistence of visceral pain induced by colitis results from maladaptive plasticity of the enteric, peripheral and central nervous systems.

Nanotechnology in Chronic Pain Relief.

Increasing awareness of chronic pain due to both injury and disease have encouraged drug companies and pharmaceutical researchers alike to design and fabricate better, more specific drugs for pain relief. However, overuse of clinically available pain medication has caused a multitude of negative repercussions, including drug tolerance, addiction, and other severe side effects, which can prolong suffering and reduce pain mediation. Applications of nanotechnology to the field of drug delivery has sought to enhance the treatment efficiency, lower side effects, and mitigate the formation of tolerance. The use of nanomaterials has several advantages for chronic pain relief, such as controlled release, prolonged circulation time, and limited side effects. With the development of nanotechnology, strategies for chronic pain relief have also bourgeoned utilizing a variety of nanomaterials and targeting surface modifications. In addition to using these materials as carriers for drug delivery, nanomaterials can also be designed to have inherent properties that relieve chronic pain. This minireview covers the current status of designed nanomaterials for pain relief and provides a discussion of future considerations for nanotechnology designed for relieving chronic pain.

European headache federation consensus on the definition of resistant and refractory migraine

IntroductionDespite advances in the management of headache disorders, some patients with migraine do not experience adequate pain relief with acute and preventive treatments. It is the aim of the present document to provide a definition of those migraines which are difficult-to-treat, to create awareness of existence of this group of patients, to help Healthcare Authorities in understanding the implications, and to create a basis to develop a better pathophysiological understanding and to support further therapeutic advances.Main bodyDefinitions were established with a consensus process using the Delphi method.Patients with migraine with or without aura or with chronic migraine can be defined as having resistant migraine and refractory migraine according to previous preventative failures. Resistant migraine is defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating headache days per month for at least 3 consecutive months without improvement; definition can be based on review of medical charts. Refractory migraine is defined by having failed all of the available preventatives and suffer from at least 8 debilitating headache days per month for at least 6 consecutive months. Drug failure may include lack of efficacy or lack of tolerability. Debilitating headache is defined as headache causing serious impairment to conduct activities of daily living despite the use of pain-relief drugs with established efficacy at the recommended dose and taken early during the attack; failure of at least two different triptans is required.ConclusionsWe hope, that the updated EHF definition will be able to solve the conflicts that have limited the use of definitions which have been put forward in the past. Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved. This new definition has also the aim to increase the understanding of the impact of the migraine as a disease with all of its social, legal and healthcare implications. It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat.

Salivary microRNAs are potential biomarkers for the accurate and precise identification of inflammatory response after tail docking and castration in piglets.

The present study aimed to investigate whether acute pain associated with castration and tail docking of male piglets may modulate the expression of salivary microRNAs (miRNAs) and to explore their potential use as biomarkers. Thirty-six healthy 4-d-old piglets (Hermitage × Duroc) were randomly assigned to three groups: the first group (12 piglets) has been pretreated with anesthetic and anti-inflammatory drugs (ANA) and then castrated and tail docked; the second one (12 piglets) has been castrated and tail docked without any drugs (CONV); the third one (12 piglets) has been only handled (SHAM). Saliva was collected 10 min before (control group) and 30 to 45 min after the procedures. Salivary cortisol has been quantified. The expression concentrations of seven miRNAs, namely miR-19b, miR-27b-3p, miR-215, miR-22-3p, miR-155-5p, hsa-miR-365-5p, and hsa-miR-204, were measured and assessed as potential biomarkers of pain by quantitative Polimerase Chain Reaction using TaqMan probes. The area under the receiver operating curve (AUC) was used to evaluate the diagnostic performance of miRNAs. The concentration of salivary cortisol increased after treatment in CONV and ANA, while no significant variation was observed in the SHAM group. The comparative analysis demonstrated that the concentrations of salivary miR-19b (P = 0.001), miR-27b (P = 0.042), and miR-365 (P < 0.0001) were significantly greater in CONV as compared with pretreatment. The AUC of pretreatment vs. CONV and CONV vs. ANA were excellent for miR-19b and miR-365 and fair for miR-27b. Combining two miRNAs, namely miR-19b and miR-365, in a panel increased the efficiency of distinguishing between pre- and post-treatment groups. No differences have been identified between SHAM and ANA groups. mRNA potential targets of differentially expressed-miRNA were investigated, and genes related to pain and inflammation were identified: miR-19b potentially modulates TGF-beta and focal adhesion pathways, miR-365 regulates cytokines expression (i.e., IL-1, Tumor Necross Factor-alpha, and IL-8 cytokine), and miR-27b regulates macrophage inflammatory protein pathways (i.e., MIP1-beta). In conclusion, we demonstrated that the abundance of miR-19b, miR-27b, and miR-365 increases in the saliva of piglets castrated and tail docked without the administration of pain-relieving drugs. Further studies are needed to assess their potential during routine husbandry procedures and to extend their assessment in other stressful events, such as weaning or chronic pain.

Evaluation of analgesic activity of the methanol extract from the galls of Quercus infectoria alone and as an adjuvant in wistar rats

Background: Non-steroidal anti-inflammatory drugs and opioids are the most preferred drugs for pain relief. Considering the gastrointestinal toxicity, dependence and other side effects, search for better analgesic drug continues. Quercus infectoria (QI) is from the family Fagaceae. The galls of QI are comprised of tannin (36 to 60%), gallic acid, ellagic acid, and syringic acid. They possess antioxidant, anti-inflammatory, antimicrobial, and anti-diabetic properties. In India, galls of QI have been used for the treatment of toothache, diarrhoea, sore throat and inflammatory diseases as a home remedy. This study was conducted to evaluate the analgesic activity of methanolic extract of galls of QI on wistar rats using tail-flick and Eddy’s hot-plate methods. The objective of the study was to evaluate the analgesic activity of methanolic extract of galls of QI alone and as an adjuvant with tramadol on Wistar rats.Methods: Total of 24 wistar rats were included in the study and divided into 4 groups. They received drugs intra-peritoneally as follows. In group 1, normal saline, in group 2, tramadol, in group 3, methanolic extract of galls of QI and in group 4, tramadol with methanolic extract of galls of QI was available.Results: Methanolic extract of galls of QI produced significant maximal possible analgesia (&lt;0.001) at 30 and 60 minutes in tail-flick method whereas it failed to produce analgesia in hot-plate method during all time intervals.Conclusions: Methanolic extract of galls of QI showed analgesic activity in tail-flick method indicating that its possible mechanism of action is spinally mediated.

Association between receiving different elements of care and satisfaction with care in patients with knee osteoarthritis treated by their general practitioner

Purpose: The recommended first line treatment for patients with knee osteoarthritis (OA) includes patient education, exercise therapy, and weight reduction (if overweight). If pain relief and functional improvement are not satisfactory, pain-relieving drugs and referrals for imaging and orthopaedic surgical evaluation can be considered. Studies indicate that the first line treatments are often not applied even though they are evidence based. Concern for patient satisfaction with first line treatments could be a reason for general practitioners (GPs) to prefer second line treatments.