Topical clonidine for neuropathic pain in adults.

BACKGROUND: Clonidine is a presynaptic alpha-2-adrenergic receptor agonist that has been used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs has been gaining interest since the beginning of the century, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated for almost 20 years in clinical trials. This is an update of the original Cochrane Review published in Issue 8, 2015. OBJECTIVES: The objective of this review was to assess the analgesic efficacy and safety of TC compared with placebo or other drugs in adults aged 18 years or above with chronic neuropathic pain. SEARCH METHODS: For this update we searched the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid), and Embase (Ovid) databases, and reference lists of retrieved papers and trial registries. We also contacted experts in the field. The most recent search was performed on 27 October 2021. SELECTION CRITERIA: We included randomised, double-blind studies of at least two weeks' duration comparing TC versus placebo or other active treatment in adults with chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. Any discrepancies were resolved by discussion or by consulting a third review author if necessary. Where required, we contacted trial authors to request additional information. We presented pooled estimates for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with P values. We used Review Manager Web software to perform the meta-analyses. We used a fixed-effect model if we considered heterogeneity as not important; otherwise, we used a random-effects model.  The review primary outcomes were: participant-reported pain relief of 50% or greater; participant-reported pain relief of 30% or greater; much or very much improved on Patient Global Impression of Change scale (PGIC); and very much improved on PGIC. Secondary outcomes included withdrawals due to adverse events; participants experiencing at least one adverse event; and withdrawals due to lack of efficacy. All outcomes were measured at the longest follow-up period. We assessed the certainty of evidence using GRADE and created two summary of findings tables. MAIN RESULTS: We included four studies in the review (two new in this update), with a total of 743 participants with painful diabetic neuropathy (PDN). TC (0.1% or 0.2%) was applied in gel form to the painful area two to three times daily. The double-blind treatment phase of three studies lasted 8 weeks to 85 days and compared TC versus placebo. In the fourth study, the double-blind treatment phase lasted 12 weeks and compared TC versus topical capsaicin. We assessed the studies as at unclear or high risk of bias for most domains; all studies were at unclear risk of bias for allocation concealment and blinding of outcome assessment; one study was at high risk of bias for blinding of participants and personnel; two studies were at high risk of attrition bias; and three studies were at high risk of bias due to notable funding concerns. We judged the certainty of evidence (GRADE) to be moderate to very low, downgrading for study limitations, imprecision of results, and publication bias. TC compared to placebo There was no evidence of a difference in number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.78 to 1.86; 179 participants; 1 study; low certainty evidence). However, the number of participants with participant-reported pain relief of 30% or greater during longest follow-up period (8 to 12 weeks) was higher in the TC group compared with placebo (RR 1.35, 95% CI 1.03 to 1.77; 344 participants; 2 studies, very low certainty evidence). The number needed to treat for an additional beneficial outcome (NNTB) for this comparison was 8.33 (95% CI 4.3 to 50.0). Also, there was no evidence of a difference between groups for the outcomes much or very much improved on the PGIC during longest follow-up period (12 weeks) or very much improved on PGIC during the longest follow-up period (12 weeks) (RR 1.06, 95% CI 0.76 to 1.49 and RR 1.82, 95% CI 0.89 to 3.72, respectively; 179 participants; 1 study; low certainty evidence). We observed no evidence of a difference between groups in withdrawals due to adverse events and withdrawals due to lack of efficacy during the longest follow-up period (12 weeks) (RR 0.34, 95% CI 0.04 to 3.18 and RR 1.01, 95% CI 0.06 to 15.92, respectively; 179 participants; 1 study; low certainty evidence) and participants experiencing at least one adverse event during longest follow-up period (12 weeks) (RR 0.65, 95% CI 0.14 to 3.05; 344 participants; 2 studies; low certainty evidence).  TC compared to active comparator There was no evidence of a difference in the number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (RR 1.41, 95% CI 0.99 to 2.0; 139 participants; 1 study; low certainty evidence). Other outcomes were not reported. AUTHORS' CONCLUSIONS: This is an update of a review published in 2015, for which our conclusions remain unchanged. Topical clonidine may provide some benefit to adults with painful diabetic neuropathy; however, the evidence is very uncertain. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine whether it is possible to predict who or which groups of people will benefit from TC.

Paroxysmal extreme pain disorder in family with c.3892G > T (p.Val1298Phe) in the SCN9A gene mutation - case report.

BACKGROUND: To describe the clinical phenotype of paroxysmal extreme pain disorder, an autosomal dominant condition in four members in one family with the mutation NM_002977.3:c.3892G > T (p.Val1298Phe) in the SCN9A gene. Clinical examinations and details from members of one Polish family were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. CASE PRESENTATION: Twenty two individuals from this family with paroxysmal extreme pain disorder were identified. Seven of them presented clinical manifestation of paroxysmal extreme pain disorder, of which and in four were identified missens mutations in the SCN9A gene (NM_002977.3:c.3892G > T). The onset of the disorder took place in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate with extreme pain, skin flushing and harlequin colour change were observed in all. Attacks of excruciating deep burning pain often appear in the rectal, or jaw areas, but also diffuse in the body. Attacks are triggered by factors such as: defecation, eating, pressure and emotion. Carbamazepine and other antiepileptic drugs were only partly effective in almost all, but the response was incomplete. CONCLUSIONS: Paroxysmal extreme pain disorder is a hereditary sodium channelopathy with pain and an autonomic nervous system dysfunction. Paroxysmal extreme pain disorder is rare, so far only 500 cases of both women and men have been described in world literature.

Non-invasive transcutaneous Supraorbital Neurostimulation (tSNS) using Cefaly® device in prevention of primary headaches.

Headaches are one of the most common pain syndromes experienced by adult patients. International Classification of Headache Disorders identifies about 300 different entities. Primary headaches (migraine, tension-type headache, trigeminal autonomic cephalalgias, other primary headaches) has the common occurrence. Although effective treatment of these disorders is possible, it is inefficient or poorly tolerated in some patients. Neuromodulation methods, being element of multimodal treatment, provide an additional treatment option in pharmacotherapy-refractory patients. Both invasive and non-invasive stimulation methods are used. The non-invasive techniques is transcutaneous nerve stimulation using Cefaly® device. In this study, Cefaly® was used as prevention treatment in patients with pharmacotherapy-refractory headaches. This device is indicated for the prophylactic treatment of episodic primary headaches. A total of 91-patients (30 without and 61 with tSNS) were enrolled in the study, including 60-patients with migraine and 31-patients with other primary headaches. Ten courses of non-invasive peripheral (supraorbitral/supratrochlear) nerves stimulation were delivered to 57-patients; in the remaining 4 patients, the treatment was abandoned due to poor tolerance. Patients were observed for 30 days after stimulation treatment. Compared to the pre-treatment period, the reduction in the intensity of pain was observed in both the migraine group and patients with other types of headaches; this included the number of pain episodes being reduced by half, with simultaneous reduction in average pain intensity and duration of individual pain episodes. The subjective assessment of pain reduction was in the range of 40-47%. Based on our data we recommend tSNS as useful tool in the prophylaxis of primary headaches, including migraine.

Topical clonidine for neuropathic pain.

BACKGROUND: Clonidine is a presynaptic alpha-2-adrenergic receptor agonist used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs is currently gaining interest, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated recently in clinical trials. OBJECTIVES: The objectives of this review were to assess the analgesic efficacy of TC for chronic neuropathic pain in adults and to assess the frequency of adverse events associated with clinical use of TC for chronic neuropathic pain. SEARCH METHODS: We searched the Cochrane Register of Studies (CRS) Online (Cochrane Central Register of Controlled Trials (CENTRAL)), MEDLINE and EMBASE databases, reference lists of retrieved papers and trial registries, and we contacted experts in the field. We performed the most recent search on 17 September 2014. SELECTION CRITERIA: We included randomised, double-blind studies of at least two weeks' duration comparing TC versus placebo or other active treatment in patients with chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors extracted data from the studies and assessed bias. We planned three tiers of evidence analysis. The first tier was designed to analyse data meeting current best standards, by which studies reported the outcome of at least 50% pain intensity reduction over baseline (or its equivalent) without use of the last observation carried forward or other imputation method for dropouts, reported an intention-to-treat (ITT) analysis, lasted eight weeks or longer, had a parallel-group design and included at least 200 participants (preferably at least 400) in the comparison. The second tier was designed to use data from at least 200 participants but in cases in which one of the above conditions was not met. The third tier of evidence was assumed in other situations. MAIN RESULTS: We included two studies in the review, with a total of 344 participants. Studies lasted 8 weeks and 12 weeks and compared TC versus placebo. 0.1%. TC was applied in gel form to the painful area two to three times daily.Studies included in this review were subject to potential bias and were classified as of moderate or low quality. One drug manufacturer supported both studies.We found no top-tier evidence for TC in neuropathic pain. Second-tier evidence indicated slight improvement after the drug was used in study participants with painful diabetic neuropathy (PDN). A greater number of participants in the TC group had at least 30% reduction in pain compared with placebo (risk ratio (RR) 1.35, 95% confidence interval (CI) 1.03 to 1.77; number needed to treat for an additional beneficial outcome (NNTB) 8.33, 95% CI 4.3 to 50). Third-tier evidence indicated that TC was no better than placebo for achieving at least 50% reduction in pain intensity and on the Patient Global Impression of Change Scale. The two included studies could be subject to significant bias. We found no studies that reported other neuropathic pain conditions.The rate of adverse events did not differ between groups, with the exception of a higher incidence of mild skin reactions in the placebo group, which should have no clinical significance. AUTHORS' CONCLUSIONS: Limited evidence from a small number of studies of moderate to low quality suggests that TC may provide some benefit in peripheral diabetic neuropathy. The drug may be useful in situations for which no better treatment options are available because of lack of efficacy, contraindications or adverse events. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine how patients who have a chance to respond to the drug should be selected for treatment.

Diagnosis and management of neuropathic pain: review of literature and recommendations of the Polish Association for the study of pain and the Polish Neurological Society - part one.

Neuropathic pain still present a major diagnostic and therapeutic challenge despite considerable progress in understanding of its mechanisms and publication of number of studies which assessed the efficacy and safety of drugs used in the symptomatic treatment. In practice, it is diagnosed less frequently than recognised in the epidemiological studies, and many patients do not achieve satisfactory outcomes of treatment. A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on neuropathic pain, with special focus on the published international recommendations, and formulated recommendations on neuropathic pain diagnosis and treatment, in accordance with the principles of evidence-based medicine. The paper presents also background information on the neuropathic pain definition, epidemiology, pathomechanism and method of assessment. The diagnosis of neuropathic pain may be established based on medical history and physical examination including special assessment of the somatosensory system. First-line drugs used in pharmacological management of neuropathic pain are: tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, gabapentin, pregabalin, opioids and lidocaine patches.

Diagnosis and management of neuropathic pain: review of literature and recommendations of the Polish Association for the Study of Pain and the Polish Neurological Society - Part Two.

Neuropathic pain may be caused by a variety of lesions or diseases of both the peripheral and central nervous system. The most common and best known syndromes of peripheral neuropathic pain are painful diabetic neuropathy, trigeminal and post-herpetic neuralgia, persistent post-operative and post-traumatic pain, complex regional pain syndrome, cancer-related neuropathic pain, HIV-related neuropathic pain and pain after amputation. The less common central pain comprises primarily central post-stroke pain, pain after spinal cord injury, central pain in Parkinson disease or in other neurodegenerative diseases, pain in syringomyelia and in multiple sclerosis. A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on various types of neuropathic pain, with special focus on the available international guidelines, and has formulated recommendations on their diagnosis and treatment, in accordance with the principles of evidence-based medicine (EBM). High quality studies on the efficacy of various medicines and medical procedures in many neuropathic pain syndromes are scarce, which makes the recommendations less robust.

NADA Ear Acupuncture and Medical Acupuncture for Pain- and Health-Related Quality of Life among Older Patients with Chronic Nonspecific Low Back Pain: A Prospective Clinical Trial.

BACKGROUND: The purpose of this study was to investigate the efficacy and safety of the NADA (National Acupuncture Detoxification Association)-standardized ear acupuncture protocol in comparison to medical acupuncture (MA) in the treatment of chronic nonspecific low back pain (LBP) in older adults. METHODS: This was a prospective, clinical, single center, open label, comparative study. A total of 60 older patients with chronic nonspecific LBP were enrolled in the study. The patients were divided into two groups. The MA group received treatment with medical acupuncture (MA), while the NADA group received NADA ear acupuncture once a day for 20 min, for a total of 10 sessions. The co-primary outcome measures were the reduction in pain intensity evaluated by the Numeric Rating Scale (NRS) compared to baseline and improvement in patients' quality of life (QOL) assessed in the SF-36 questionnaire before and after treatment; this was compared between the two groups. RESULTS: After two weeks of treatment, a significant reduction compared to baseline was observed in the NRS scores following treatment with medical acupuncture as well as after the utilization of NADA ear acupuncture protocol: NRS score for average pain experienced by the patients over the previous week (NRSa) MA: p = 0.002; NADA: p < 0.001, maximum NRS score in the past week (NRSm) MA: p < 0.001; NADA: p < 0.001, and NRS score at the time of examination (NRSe) MA: p = 0.001; NADA: p < 0.001. Reduction of the NRSa score compared to baseline was significantly greater in the NADA group (p = 0.034). Significant improvements in the QOL of patients according to the SF-36 questionnaire compared to baseline were observed in the MA group in the following domains: PF (p = 0.003), RP (p = 0.002), SF (p = 0.041), RE (p = 0.005), MH (p = 0.043), HT (p = 0.013), PCS (p = 0.004), and MCS (p = 0.025); and in the NADA group, in the following domains: PF (p = 0.004), RP (p = 0.048), BP (p = 0.001), VT (p = 0.035), RE (p = 0.006), MH (p < 0.001), HT (p = 0.003), PCS (p < 0.001), and MCS (p < 0.001). There were minor complications observed in 35% of patients (total of 20 participants); 31% (9 patients) in the MA group and 39% (11 patients) in the NADA group. These were minor and quickly resolved, including insertion point pain, minor bleeding after needle removal, and one instance of fainting. No patients in either group reported worsening of LBP. These complications occurred in 4.14% of MA sessions (12 times/290 sessions) and in 6.07% of NADA acupuncture sessions (16 times/280 sessions). CONCLUSION: The outcomes of this study suggest that both MA and NADA ear acupuncture could be a valuable and personalized component of a comprehensive approach to managing chronic nonspecific LBP in older patients. Incorporation of MA and NADA ear acupuncture into the clinical management of chronic nonspecific LBP in elderly patients has the potential to reduce pain intensity and improve the overall quality of life of affected individuals. However, further studies are needed to confirm our findings.

Cross-cultural adaptation and validation of the Polish version of the core outcome measures index for low back pain.

PURPOSE: The core outcome measures index (COMI) is a short, multidimensional outcome scale validated for the use by patients with spinal disorders. It is a recommended instrument in the Spine Society of Europe Spine Tango Registry. The purpose of this study was to produce a cross-culturally adapted and validated Polish COMI. METHODS: The cross-cultural adaptation was carried out using the established guidelines. One-hundred and sixty-nine patients with chronic low back pain were enrolled, 89 took part in the reproducibility part of the study. Data quality, construct validity and reproducibility were assessed. RESULTS: The quality of data was very good with very few missing answers and modest floor effect. Reliability expressed as intraclass correlation coefficient (ICC) was 0.90 (95 % CI 0.85-0.93) for the overall COMI score and for most of the individual core items. The minimum detectable change (MDC95%) was 1.79. CONCLUSIONS: The Polish version of COMI showed a favorable reproducibility similar to that of previously tested language versions. The COMI scores correlated sufficiently with existing measures. This version of the COMI is a valuable instrument for the use by Polish-speaking patients with spinal disorders.

Phenytoin Decreases Pain-like Behaviors and Improves Opioid Analgesia in a Rat Model of Neuropathic Pain.

Neuropathic pain remains a clinical challenge due to its complex and not yet fully understood pathomechanism, which result in limited analgesic effectiveness of the management offered, particularly for patients with acute, refractory neuropathic pain states. In addition to the introduction of several modern therapeutic approaches, such as neuromodulation or novel anti-neuropathic drugs, significant efforts have been made in the repurposing of well-known substances such as phenytoin. Although its main mechanism of action occurs at sodium channels in excitable and non-excitable cells and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level and how it influences morphine-induced analgesia have not been clarified, both being crucial from a clinical perspective. We demonstrated that single and repeated systemic administrations of phenytoin decreased tactile and thermal hypersensitivity in an animal model of neuropathic pain. Importantly, we observed an increase in the antinociceptive effect on thermal stimuli with repeated administrations of phenytoin. This is the first study to report that phenytoin improves morphine-induced antinociceptive effects and influences microglia/macrophage activity at the spinal cord and dorsal root ganglion levels in a neuropathic pain model. Our findings support the hypothesis that phenytoin may represent an effective strategy for neuropathic pain management in clinical practice, particularly when combination with opioids is needed.

Beneficial effect of amantadine on postoperative pain reduction and consumption of morphine in patients subjected to elective spine surgery.

OBJECTIVE: To analyze the effect of coadministration of morphine and amantadine on postoperative pain reduction and morphine consumption in patients after elective spine surgery. METHODS: In double-blinded study, 60 patients (ASA physical status I-II) were randomized into two groups. Group A was given oral amantadine 50 or 100 mg 1 hour before surgery and 8, 20, 32 hours after operation. Group P received placebo at identical times. Pain was assessed using numerical rating scale before first administration of morphine and in 2, 3, 4, 6, 24, and 48 hours after operation. The amounts of morphine consumed were recorded up to 48 hours after surgery. Blood samples were taken twice in 2 hours after surgery and plasma levels of morphine and its main metabolites were measured. RESULTS: As compared with placebo, amantadine significantly reduced intra-operative Fentanyl use and sensation of postoperative pain. Up to 48 hours after operation, the cumulative consumption of morphine was 25% lower in the amantadine group. Moreover, intensity of nausea and vomiting tended to be lower in A group. Starting from 12th hour after surgery, the level of postoperative sedation was lower in patients who received amantadine, as compared with placebo group. No significant differences in plasma levels of morphine ant its metabolites were observed between A and P groups. CONCLUSIONS: Pre- and postoperative administration of amantadine significantly reduced fentanyl use during operation, as well as reduced the postoperative pain and decreased morphine consumption in young patients undergoing orthopedic surgery.

Effects of vagus nerve stimulation in visceral pain model.

Visceral pain is an important therapeutic problem. A number of studies have established that abdominal vagal afferents modulate somatic pain behavior. Although it is not clear if vagal afferents transmit nociceptive information, a change in their activity can increase or decrease nociceptive transmission in visceral pain. Aims of the present study were to determine whether the subdiaphragmatic vagus nerves play a role in the endogenous pain inhibitory mechanisms in visceral pain model and whether it involves opioidergic pathways. Data obtained in our studies show that vagus nerve plays the direct role in conveying the nociceptive information in the peritonitis model of visceral pain. We have shown, that vagal afferents exhibit an increase in excitability and subdiaphragmatic vagotomy decrease nociceptive behavior in visceral pain in rats. We have also tested two different stimulation parameters of chronic subdiaphragmatic vagal nerve stimulation: VNS1 (high-intensity) and VNS2 (low-intensity) in visceral pain model in rats. Both stimulation parameters increased pain threshold but VNS1 was more effective than VNS2. Naloxone inhibited the antinociceptive effects of VNS, reversing partially increase in the pain threshold in rats and increases number of writhes in visceral pain model. Therefore, our data indicate that this analgesic effect of the VNS is mediated, at least in part, by descending opioidergic pathways. The present study has confirmed the importance of vagal afferents for nociception in general and proven that this role is not limited to somatic pain but also extends to visceral pain.

Pentoxifylline modifies central and peripheral vagal mechanism in acute and chronic pain models.

The inflammatory process gives the way to hyperalgesia that is documented by the animal experimental studies. Pentoxifylline (PTX) has strong antyinflamatory effects, decreases TNF-alpha and other proinflammatory cytokines production. Therefore, the aim of present investigation was to evaluate the effectiveness of PTX in nociception processes, especially in aspects of vagal activity, in experimental pain models: visceral pain (VP), neuropathy (CCI) and neurogenic inflammation (NI). In VP and CCI models we observed significant increase in the pain threshold after blocking proinflammatory cytokines whereas in NI there was no such effect. In our studies we also observed the increase of vagal afferents activity in VP and CCI, on the contrary to NI model. In summary, our study demonstrates that preemptive inhibition of proinflammatory cytokine synthesis by treatment with PTX is useful in antagonizing hyperalgesia in inflammatory pain. Pentoxifylline reduces central and peripheral sensitization processes depend on the vagal component in both acute and chronic pain models but in a different manner and mechanisms. Our results establish the participation of inflammatory and vagal component in nociception. The modulation of the vagal system offers the new possibilities of the pain treatment in patients resistant to the classical analgesic therapy.

Peripheral Mechanisms of Neuropathic Pain-the Role of Neuronal and Non-Neuronal Interactions and Their Implications for Topical Treatment of Neuropathic Pain.

Neuropathic pain in humans arises as a consequence of injury or disease of somatosensory nervous system at peripheral or central level. Peripheral neuropathic pain is more common than central neuropathic pain, and is supposed to result from peripheral mechanisms, following nerve injury. The animal models of neuropathic pain show extensive functional and structural changes occurring in neuronal and non-neuronal cells in response to peripheral nerve injury. These pathological changes following damage lead to peripheral sensitization development, and subsequently to central sensitization initiation with spinal and supraspinal mechanism involved. The aim of this narrative review paper is to discuss the mechanisms engaged in peripheral neuropathic pain generation and maintenance, with special focus on the role of glial, immune, and epithelial cells in peripheral nociception. Based on the preclinical and clinical studies, interactions between neuronal and non-neuronal cells have been described, pointing out at the molecular/cellular underlying mechanisms of neuropathic pain, which might be potentially targeted by topical treatments in clinical practice. The modulation of the complex neuro-immuno-cutaneous interactions in the periphery represents a strategy for the development of new topical analgesics and their utilization in clinical settings.

Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain-Narrative Review.

Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.

Blockade of CCR4 Diminishes Hypersensitivity and Enhances Opioid Analgesia - Evidence from a Mouse Model of Diabetic Neuropathy.

Chemokine signaling has been implicated in the pathogenesis of diabetic neuropathy; however, the role of chemokine CC motif receptor 4 (CCR4) remains unknown. The goal was to examine the function of CCR4 in hypersensitivity development and opioid effectiveness in diabetic neuropathy. Streptozotocin (STZ; 200 mg/kg, intraperitoneally administered)-induced mouse model of diabetic neuropathy were used. An analysis of the mRNA/protein expression of CCR4 and its ligands was performed by qRT-PCR, microarray and/or Western blot methods. C021 (CCR4 antagonist), morphine and buprenorphine were injected intrathecally or intraperitoneally, and pain-related behavior was evaluated by the von Frey, cold plate and rotarod tests. We observed that on day 7 after STZ administration, the blood glucose level was increased, and as a consequence, hypersensitivity to tactile and thermal stimuli developed. In addition, we observed an increase in the mRNA level of CCL2 but not CCL17/CCL22. The microarray technique showed that the CCL2 protein level was also upregulated. In naive mice, the pronociceptive effect of intrathecally injected CCL2 was blocked by C021, suggesting that this chemokine acts through CCR4. Importantly, our results provide the first evidence that in a mouse model of diabetic neuropathy, single intrathecal and intraperitoneal injections of C021 diminished neuropathic pain-related behavior in a dose-dependent manner and improved motor functions. Moreover, both single intrathecal and intraperitoneal injections of C021 enhanced morphine and buprenorphine effectiveness. These results reveal that pharmacological modulation of CCR4 may be a good potential therapeutic target for the treatment of diabetic neuropathy and may enhance the effectiveness of opioids.

CCR4 Antagonist (C021) Administration Diminishes Hypersensitivity and Enhances the Analgesic Potency of Morphine and Buprenorphine in a Mouse Model of Neuropathic Pain.

Neuropathic pain is a chronic condition that remains a major clinical problem owing to high resistance to available therapy. Recent studies have indicated that chemokine signaling pathways are crucial in the development of painful neuropathy; however, the involvement of CC chemokine receptor 4 (CCR4) has not been fully elucidated thus far. Therefore, the aim of our research was to investigate the role of CCR4 in the development of tactile and thermal hypersensitivity, the effectiveness of morphine/buprenorphine, and opioid-induced tolerance in mice exposed to chronic constriction injury (CCI) of the sciatic nerve. The results of our research demonstrated that a single intrathecal or intraperitoneal administration of C021, a CCR4 antagonist, dose dependently diminished neuropathic pain-related behaviors in CCI-exposed mice. After sciatic nerve injury, the spinal expression of CCL17 and CCL22 remained unchanged in contrast to that of CCL2, which was significantly upregulated until day 14 after CCI. Importantly, our results provide evidence that in naive mice, CCL2 may evoke pain-related behaviors through CCR4 because its pronociceptive effects are diminished by C021. In CCI-exposed mice, the pharmacological blockade of CCR4 enhanced the analgesic properties of morphine/buprenorphine and delayed the development of morphine-induced tolerance, which was associated with the silencing of IBA-1 activation in cells and decrease in CCL2 production. The obtained data suggest that the pharmacological blockade of CCR4 may be a new potential therapeutic target for neuropathic pain polytherapy.

CCR4 antagonist (C021) influences the level of nociceptive factors and enhances the analgesic potency of morphine in a rat model of neuropathic pain.

Neuropathic pain is a chronic condition which significantly reduces the quality of life and serious clinical issue that is in general resistant to available therapies. Therefore looking for new analgesics is still critical issue. Recent, studies have indicated that chemokine signaling pathways are crucial for the development of neuropathy; however, the role of CC chemokine receptor 4 (CCR4) in this process has not yet been studied. Therefore, the aim of our research was to investigate the influence of C021 (a CCR4 antagonist) and CCR4 CC chemokine ligands 17 and 22 (CCL17 and CCL22) on the development of hypersensitivity and the effectiveness of morphine induced analgesia in naive animals and/or animals exposed to chronic constriction injury (CCI) of the sciatic nerve. Firstly, we demonstrated that the intrathecal administration of CCL17 and CCL22 induced pain-related behavior in naive mice. Secondly, we revealed that the intrathecal injection of C021 significantly reduced CCI-induced hypersensitivity after nerve injury. In parallel, C021 reduced microglia/macrophages activation and the level of some pronociceptive interleukins (IL-1beta; IL-18) in the spinal cord 8 days after CCI. Moreover, C021 not only attenuated mechanical and thermal hypersensitivity but also enhanced the analgesic properties of morphine. Our research indicates that CCR4 ligands might be important factors in the early stages of neuropathy, when we observe intense microglia/macrophages activation. Moreover, pharmacological blockade of CCR4 may serve as a potential new target for better understanding the mechanisms of neuropathic pain development.

Postoperative pain relief in general surgery - recommendations of the Association of Polish Surgeons, Polish Society of Anaesthesiology and Intensive Therapy, Polish Association for the Study of Pain and Polish Association of Regional Anaesthesia and Pain Treatment.

It is estimated that there are over 310 million surgeries performed in the world every year. Appropriate analgesic management in the perioperative period constitutes a fundamental right of every patient, significantly reducing the number of postoperative complications and the time and costs of hospitalization, particularly in the high-risk group of patients (ASA III-V) subject to extensive surgical procedures and hospitalized in intensive care units. Despite such significant arguments speaking for the conduct of effective analgesia in the perioperative period, nearly 79% of patients operated in hospitalization settings and 71% of patients operated in outpatient settings (so-called first day surgery) experienced postoperative pain of moderate, strong or extreme intensity. Hence, effective relief of postoperative pain should constitute one of the priorities of integrated, modern perioperative management, the components of which apart from adequate analgesia involve early nutrition through the alimentary canal, early patient activation and active physiotherapy. In the currently published "Guidelines", a team of authors has updated the previous "Recommendations" primarily in terms of methods for optimizing postoperative pain relief and new techniques and drugs introduced for postoperative pain therapy in recent years. The algorithms of postoperative pain management in different treatment categories were also updated.

The analysis of CD34 antigen immunoreactivity level in invasive ductal breast cancer with respect to the presence of lymph node metastases.

BACKGROUND: Angiogenesis is a basic process that enables neoplasms to thrive. Microvessel density (MVD) evaluation is an accepted parameter for assessing the angiogenesis process within a tumor. The aim of the present study has been to assess the number of microcapillaries in both invasive ductal breast cancer with the presence of metastases in regional lymph nodes and in invasive ductal breast cancer without such metastases. METHODS: The CD34 antigen immunoreactivity level was assessed by immunohistochemistry in both types of invasive ductal breast cancer. Tissue samples were obtained from 40 patients and were divided into two groups according to whether or not there were lymph node metastases. RESULTS: The patients with lymph node metastases exhibited statistically significantly higher numbers of stained microcapillaries than the patients who did not have lymph node metastases. CONCLUSION: Thus the number of stained microcapillaries as evaluated by using the CD34 immunoreactivity level seems to be a useful predictor for the development of local lymph node metastases in female invasive ductal breast cancer.

[Persistent post-operative pain]. / Przetrwaly ból pooperacyjny--patomechanizm i leczenie.

Persistent post-operative pain is defined as a pain in the location of the surgery that persist for many months or even years beyond the usual course of an acute injury and is different of that suffered preoperatively. Persistent pain can be due to long lasting nociception caused by processes such as information, chronic infection or tumor. The most important causes are neuropathic pain states due to nerve compression, entrapment or other damage. Chronic pain, that is very often resistant to treatment, occurs after failed back surgery. Traumatic nerve injury during surgery results in persistent pain known as a post-surgical neuralgia. The most susceptible nerves are: intercostobrachial nerve, intervertebral nerves, ilio-hypogastric nerve, ilio-inguinal nerve, genito-femoral nerve and femoral and sciatic nerve. It means that after some, also elective, surgeries, e.g. mastectomy, thoracotomy, herniotomy, limb amputations, chelecystomy, hysterectomy and nephrectomy, persistent postoperative pain is more common than after other operations. Persistent pain can occur even in 60% patients after limb amputation, in 30% after breast tumor excicion or mastectomy, in 40% after thoracotomy and in 10-30% after hernia repair, but severe pain (NRS>5) lasting even for many years is observed in 5-10% after limb and breast amputation, thoracotomy and Post-CABG operations and in 2-4% patients after hernia repair. Modern approaches including satisfactory perioperative analgesia, nerve sparing, minimally invasive techniques, and the use of a surgical approach that minimizes tissue trauma are crucial. Following inguinal hernia repair, chronic pain is less common than after laparoscopic and mesh repairs. The prompt diagnosis of acute neuropathic pain after operation is very important and management is based on extrapolation of data from the chronic neuropathic pain setting.