Abstract: Diabetes mellitus is a world-wide epidemic with many long-term complications, with neuropathy being the most common. In particular, diabetic peripheral neuropathic pain (DPNP), can be one of the most distressing complications associated with diabetes, leading to decreases in physical and mental quality of life. Despite the availability of many efficient medications, DPNP remains a challenge to treat, and the optimal sequencing of pharmacotherapy remains unknown. Currently, there are only three medications approved by the US Food and Drug Administration specifically for the management of DPNP. Duloxetine (DUL), a selective serotonin-norepinephrine reuptake inhibitor, is one of these. With the goal of optimizing pharmacotherapy use in DPNP population, a review of current literature was conducted, and the clinical utility of DUL described. Along with early clinical trials, recently published observational studies and pharmacoeconomic models may be useful in guiding decision making by clinicians and managed care organizations. In real-world practice settings, DUL is associated with decreased or similar opioid utilization, increased medication adherence, and similar health care costs compared with current standard of care. DUL has consistently been found to be a cost-effective option over short time-horizons. Cur- rently, the long-term cost-effectiveness of DUL is unknown. Evidence derived from randomized clinical trials, real-world observations, and economic models support the use of DUL as a first-line treatment option from the perspective of the patient, clinician, and managed care payer. Keywords: clinical trials, pharmacoeconomic studies, opioid-utilization, health care utilization, pregabalin, tricyclic antidepressants, gabapentin
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Abstract: Peripheral neuropathic pain (PNP) and complex regional pain syndrome (CRPS) can be effectively treated with peripheral nerve stimulation. In this clinical trial report, effec- tiveness of novel, miniature, wirelessly controlled microstimulator of tibial nerve in PNP and CRPS was evaluated. In this pilot study the average preoperative visual analog scale (VAS) score in six patients was 7.5, with 1, 3 and 6 months: 2.6 (p=0.03), 1.6 (p=0.03), and 1.3 (p=0.02), respectively. The mean average score in the six patients a week preceding the baseline visit was 7.96, preceding the 1, 3 and 6 month visits: 3.32 (p=0.043), 3.65 (p=0.045), and 2.49 (p=0.002), respectively. The average short-form McGill pain score before surgery was 23.8, and after 1, 3 and 6 months it was 11.0 (p=0.45), 6.3 (p=0.043), and 4.5 (p=0.01), respectively. Applied therapy caused a reduction of pain immediately after its application and clinical improvement was sustained on a similar level in all patients for six months. No complications of the treatment were observed. Intermittent tibial nerve stimulation by using a novel, miniature, wirelessly con- trolled device can be effective and feasible in PNP and CRPS. It is a safe, minimally invasive, and convenient neuromodulative method.
Consecutive patients of both sexes who met the selection cri- teria were enrolled between March 2011 and September 2012. The inclusion criteria were age ≥ 18 years, being diagnosed with a peripheral neuropathic pain syndrome, unsatisfactory control of pain with existing medication (numeric rating scale [NRS] score ≥ 6), at least 6 months of pain duration, prescription of 5% lidocaine-medicated plaster on the day of the basal visit, and having signed the informed consent. The exclusion criteria were allergy or hypersensitivity toward amide-type anesthetics or ethers, pregnancy, or breastfeeding.
Abstract: Peripheral Neuropathic Pain (PNP) as well as the Complex Regional Pain Syndrome (CRPS), also known as “ Re ﬂ ex Sympathetic Dystrophy ” , or “ Sudeck Dystrophy ” , all of them have a poor prognosis. The numerous therapeutic offers are rarely accompanied by convincing success over a long duration of time. Even worse is the prognosis of a ﬁ xed dystonia which may develop in the extremities of PNP or CRPS patients. In literature a few cases are reported in which the often unbearable pain of those patients with or without a disabling dystonia disappeared immediately after the injection of local anesthetics (LAs) into the scars of a preceding trauma. This review evaluates publications concerning the neuropathological characteristics of ﬁ xed dystonia in PNP/ CRPS patients and the electrophysiological processes of scar neuromas. The results of these evaluations support the understanding of the therapeutic successes and their immediate results reported above by the injection of LAs into triggering scars. Therapeutic options are discussed. Keywords: peripheral neuropathic pain, complex regional pain syndrome, ﬁ xed dystonia, scar neuroma, local anesthetics, subthreshold membrane potential oscillations
include the fact that it is difficult to compare outcomes, especially when related to pain, if different primary endpoints are used. In addition, sample sizes of the included trials were small, the treatment period was less then 6 months in all the studies, and some of the trials used a crossover design with- out a washout period. In the studies with a crossover design there may have been selection bias because only data from the first period was used to calculate efficacy. Furthermore, some medications had multiple studies included in the analysis, some of which had contradictory results, and other medications may have only had 1 study included. It is clear that further, long-term and head-to-head studies are needed to examine the efficacy of commonly used pharmacological treatments for diabetic peripheral neuropathic pain.
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We assessed for tolerability and efficacy of pharmacotherapy as the primary outcome measure. Definition of a successful pharmacotherapeutic intervention was dependent upon ade- quate pain relief in the absence of medication discontinuation. For the determination of successful pain relief, we used a threshold of $30% pain relief at 3 or 6 months based on the baseline pain VAS score for pain severity recorded pre-intervention. The VAS was determined by measuring an unmarked 100 mm line between anchors of no pain on the left (0) and worst possible pain on the right (10) – this was bisected by the patient upon being asked to reflect the patient’s average NeP severity over the past 7 days. A successful outcome also required that the patient remain on the prescribed medication for the duration of 6 months of follow-up without medication discontinuation due to intolerable adverse effects or inefficacy as perceived by the patient with respect to pain relief. Failure was recorded as discontinuation of pharmacotherapy provided due to inef- ficacy, intolerance, or inability to achieve $30% pain relief after 3 or 6 months.
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Analyses of the tolerability data from the NGX-4010 clinical study program demonstrate that patch application-related pain increases were transient and generally began to resolve following removal of NGX-4010. Interestingly, despite the fact that the patch application-related pain increase during and shortly after patch application was higher in patients with PHN, the average pain score in the PHN cohort returned to baseline on the day of treatment, whereas in the PDN and HIV-DSP cohorts pain scores declined more gradually. These results appear to indicate a slower rate of pain decrease after the treatment procedure in patients with HIV-DSP or PDN than in those with PHN. These differences may be due to the difference in skin thickness between the trunk (PHN) and the feet (HIV-DSP or PDN). This study also found that repeated applications of NGX-4010 did not affect patch application- related pain and tolerability.
Finally, a number of limitations of this research can be cited. NP representation in pain clinics may be overesti- mated with regard to its prevalence in the general popula- tion or other clinical settings. Furthermore, the diagnosis of anxiety and/or depression or sleep disturbances was not tested by a specific medical examination or by a neuropsy- chological evaluation, which could lead to the frequency of these disorders being underestimated. On the other hand, the fact that the information in the paper was collected in 2010 could be a limitation; however, we believe that the lack of data on the prevalence of PNP, especially CNP obtained at a national level in the pain clinics in Spain,
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activation and altered nociceptive transmission within the spinal cord are associated with the pathogenesis of mechanical allodynia, changes in cortical circuits also accompany peripheral nerve injury and may represent additional therapeutic targets. Dendritic spine plasticity in the S1 cortex appears within days following nerve injury; however, the underlying cellular mechanisms of this plasticity and whether it has a causal relationship to allodynia remain unsolved. Furthermore, it is not known whether glial activation occurs within the S1 cortex following injury or whether it contributes to this S1 synaptic plasticity. Using in vivo 2-photon imaging with genetic and pharmacological manipulations of murine models, we have shown that sciatic nerve ligation induces a re-emergence of immature metabotropic glutamate receptor 5 (mGluR5) signaling in S1 astroglia, which elicits spontaneous somatic Ca 2+ transients, synaptogenic thrombospondin 1 (TSP-1) release, and synapse
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The clinical relevance of the open-label studies that used a duloxetine dose of 120 mg/day is questionable since the approved DPNP treatment dose for duloxetine is 60 mg once daily and no compelling data suggest increased efficacy for treating DPNP at duloxetine doses higher than 60 mg/day. However, the data derived from group means provide the basis for this assumption, and our experience with individual patients indicates that some DPNP patients may have addi- tional clinical benefit with duloxetine doses above 60 mg/day. While we do not recommend routine use of duloxetine doses above 60 mg/day, higher doses may be beneficial to some patients. If clinicians chose to use higher than indicated duloxetine doses, we recommend possible adverse events be reviewed with patients and that close monitoring for adverse events be performed at regular intervals. It is also important to note that all the efficacy studies were conducted in associa- tion with Eli Lilly, the manufacturer of duloxetine. The similar study design used in all trials, likely due to the Lilly association, is beneficial since it makes direct comparisons between studies possible. However, this sponsorship could also be a liability since the affiliation may have influenced the interpretation of study data and thereby biased trial results. A recent Cochrane Review determined that 6 DPNP patients would need to be treated with 60 mg/day of dulox- etine for one patient to have a 50% reduction in pain after 12 weeks of therapy. 53 It is interesting that this number needed
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The results of the DN4 were similar in patients with "pure" neuropathic pain or mixed pain syndromes, (i.e. the combination of neuropathic and non neuropathic pain in the same patient). Thus, the present data suggest that the neuropathic component of the "mixed pain" syn- drome has clinical characteristics similar to those of "pure" neuropathic pain. Interestingly, this is consistent with the results recently reported by Freynhagen et al , showing that radiculopathies associated with mixed pain syndromes have clinical characteristics similar to those of definite neuropathic pain syndromes. In addition, the sta- tistical estimators of validity of the test remained mostly unchanged after removing both the subgroups of patients with mixed pain and with central pain, leaving pure peripheral neuropathic pain only. This suggests that the error level of the questionnaire will remain largely unchanged. More generally, our data tend to support the interest of NP screening tools in the clinical setting. These tools should be of particular interest for both Primary Care Physicians (PCPs) and other non pain specialists to identify NP, diagnose its cause, and adapt the analgesic treatment. Thus, screening tools like DN4 should help PCPs to take a more pro-active role in appropriate treat- ment selection, thus avoiding early therapeutic failure and patient suffering.
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to multimodal analgesia aims to encourage healing and control pain. However, notwithstanding effective treatment of varicella zoster virus, PHN can still arise. The resulting pain remains very difficult to manage and has a major impact on patients’ quality of life, functional status, and mental health. The oral analgesic medications currently available to treat PHN (tricyclic antidepressants [TCAs], pregabalin, gabapentin, and opioids) have the risk of serious systemic side effects. This has sparked a great deal of interest in topi- cally applied agents. Topical therapy has the main benefits of delivering targeted therapy over the painful area and curbing the overall pill burden, which in turn encourages patient adherence.
Background: The assessment of a neuropathic pain component (NePC) to establish the neurological criteria required to comply with the clinical description is based on history taking, clinical examination, and quantitative sensory testing (QST) and includes bedside examination (BSE). The objective of this study was to assess the potential association between the clinically diagnosed presence or absence of an NePC, BSE, and the Nijmegen–Aalborg screening QST (NASQ) paradigm in patients with chronic (≥3 months) low back and leg pain or with neck shoulder arm pain or in patients with chronic pain due to suspected peripheral nerve damage.
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MH, JCC, AS, BP, PH, AHA, and MD are employees of Pfizer, Inc, which funded the current study. KK-C and RL are employees of Kantar Health, which received funding from Pfizer, Inc for conducting and reporting on the current study, and for manuscript development. IK was employed by Kantar Health at the time this study was conducted. MD was a Kantar employee during study conduct and is a current employee of Pfizer and was involved in manuscript development as a Pfizer employee. BRS, JDM, and JTF were investigators for this study. They were not financially com- pensated for their collaborative efforts or publication-related activities, but JTF and JDM have previously served as study design consultants for Pfizer and have received investigator- initiated grant funding for studies of pain unrelated to this study. JDM has served as a consultant to: Editas Medicine, Flexion Therapeutics, Quark, Quartet, Collegium, Purdue, Biogen, Novartis, Aptinyx, Nektar, Plasmasurgical, Allergan, Grunenthal , Eli Lilly, Depomed, Jansen, Teva, Kempharm, Abbott, Plasmasurgical, Chromocell, Convergence, Inspirion, Pfizer, Sanofi, Diacchi Sankyo, and Trevena. JDM has also received a research grant from Pfizer. The authors report no other conflicts of interest in this work.
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The permanent neuronal hyperactivity observed in the PHSC in peripheral neuropathy cases may be due to the preservation and persistence of the connection between the sensory ganglia and the CNS neurons, a condition that allows neuronal activation by ganglionic ectopic po- tentials . It suggests that in BPA there is a lack of inhib- ition because of the impairment of rostrocaudal neuronal inhibition in the CNS, caused by avulsion but not by other peripheral neuropathies . Molecular studies (immuno- histochemistry and in situ hybridization) further support this idea. It has been shown that early genes such as c-Jun and growth-related proteins such as GAP-43 are up- regulated when axotomy takes place distal to the dorsal root ganglia. On the other hand, when a lesion occurs proximally, such as in the case of BPA, the reverse oc- curs, and no up regulation of these genes is triggered. This further supports the importance of central damage with a poor regenerative response compared to distal in- juries in the development of autotomy [61,62]. These data lend support for the presence of the phenotypical patterns seen after central lesions of afferent sensory neurons and not just the functional changes expected to occur centrally due to peripheral deafferentation. As ex- plained, these phenotypical patterns involve less collateral sprouting and poorer regenerative response compared to those observed in lesions distal to the DRG .
are possible thanks to the presence of the fascial tissues and their inseparable interconnection, which allows the sliding of the muscular framework and the sliding of nerves and vessels between/around contractile fields and joints, the same way all the organs can slide and move among each other, influenced by the position of the body (Figure 1). An alteration of the bodily movements would have a negative influence on neural, peripheral, and central processes, which would induce modi- fications in the motor patterns. 52 An alteration of the function
efficacy of the lidocaine plaster in different neuropathic pain conditions has led to the hypothesis of a common localized symptomatology that might provide common predictors of treatment success. The availability of positive- and negative-outcome predictors for a certain treatment might shorten the “trial and error” period in finding a successful treatment for a patient, thus providing pain relief and better quality of life faster. Previous meetings of pain specialists in 2007, 2008, and 2009 focused on potential outcome pre- dictors for the indications diabetic polyneuropathy (DPN), complex regional pain syndrome (CRPS), chronic low back pain with neuropathic components, and chronic neuropathic pain after surgical and nonsurgical trauma. Based on case reports and clinical experience of the participants, presence of localized pain, allodynia, hyperalgesia, and superficial pain were considered positive predictors for treatment suc- cess with the lidocaine plaster, whereas the predictive value of pain quality differed depending on the indication and was considered uncertain. Treatment success was generally considered unlikely in the presence of chronic widespread pain, deep pain, or numbness. 24 The probability of treatment
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relief of neuropathic pain, with improvement often occurring with the first treatment. Repeated treatments may, however, be necessary for long-term relief. Where acupuncture is not available, acupressure—in which energy points are pressed or massaged—may be another possibility for treating neuropathy.
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There were statistically significant differences in the change in the average daily pain score between pregabalin 300 mg and mirogabalin 15 and 30 mg. However, subjects in the pregabalin arm received 300 mg in divided doses and it remains unknown whether higher single doses would have affected efficacy. Second, the placebo response rate was higher than expected in this study as Freeman et al previously showed a placebo
The demonstrated results are mainly attributed to the suppression of sensitive afferent action potentials from peripheral nociceptors in the skin to neurons in the spinal cord and the simultaneous suppression of efferent sympathetic activity from these neurons back to the peripheral nocicep- tors in the skin. These processes were demonstrated under laboratory conditions with animals in vitro and in vivo only. To our knowledge, there are no studies so far to show the efficiency of LAs in very low concentration and quantity in the treatment of peripheral pain in patients. It is not surpris- ing therefore that many questions remain open. For instance, the long duration of the suppression of membrane potential oscillations, which last much longer than an axon conduction block due to LAs 5,22,37,44,50–52 ; the rapid action of nonblocking