Pregabalin Treatment Research Articles

Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome.

Introduction This observational study was designed to evaluate the efficacy of ultramicronized palmitoylethanolamide (um-PEA) (Normast®) administration, as add-on therapy for chronic pain, in the management of pain-resistant patients affected by failed back surgery syndrome. Methods A total of 35 patients were treated with tapentadol (TPD) and pregabalin (PGB). One month after the start of standard treatment, um-PEA was added for the next two months. Pain was evaluated by the Visual Analogue Scale (VAS) at the time of enrollment (T0) and after one (T1), two (T2), and three (T3) months. Results After the first month with TDP + PGB treatment only, VAS score decreased significantly from 5.7 ± 0.12 at the time of enrollment (T0) to 4.3 ± 0.11 (T1) (p < 0.0001); however, it failed to provide significant subjective improvement in pain symptoms. Addition of um-PEA led to a further and significant decrease in pain intensity, reaching VAS scores of 2.7 ± 0.09 (T2) and 1.7 ± 0.11 (T3, end of treatment) (p < 0.0001) without showing any side effects. Conclusions This observational study provides evidence, albeit preliminary, for the efficacy and safety of um-PEA (Normast) as part of a multimodal therapeutic regimen in the treatment of pain-resistant patients suffering from failed back surgery syndrome.

Facial pain and anxiety-like behavior are reduced by pregabalin in a model of facial carcinoma in rats

Pain and anxiety are common symptoms in head and neck cancer patients. The anticonvulsant pregabalin has therapeutic indication for the treatment of pain and anxiety, and may represent a useful drug for both conditions. Thus, the aim of this study was to investigate the relationship between pain and anxiety in rats with facial carcinoma, as the influence of pregabalin treatment in both aspects. Facial carcinoma was induced by subcutaneous inoculation of Walker-256 tumor cells in the vibrissa pad of Wistar rats. On day 6 after inoculation spontaneous facial grooming and conditioned place preference were assessed as non-evoked pain measurements and facial mechanical hyperalgesia were assessed 3 and 6 days after tumor cells inoculation. Moreover, anxiety-like behavior was evaluated on the elevated plus maze and light-dark transition tests at the same time points. The effect of pregabalin treatment (30 mg/kg, p.o.) was evaluated in all tests. Our results demonstrated that pregabalin treatment reduced the spontaneous facial grooming and induced conditioned place preference 6 days post tumor inoculation. Tumor-bearing rats developed mechanical hyperalgesia starting 3 days post tumor induction, which was also significant on day 6, but the anxiety-like behavior was detected only in tumor-bearing rats that developed mechanical hyperalgesia and only six days after tumor cells inoculation. Both, the mechanical hyperalgesia and the anxiety–like behavior related to the tumor were significantly reduced by pregabalin treatment on day 6. Pregabalin treatment resulted in antinociceptive and anxiolytic-like effects on facial tumor-bearing rats and may represent a promising therapeutic option for cancer patients.

Clinical, Electrophysiological, and Serological Evaluation of Patients with Cramp-Fasciculation Syndrome.

Cramp-fasciculation syndrome (CFS) is a rare peripheral nerve hyperexcitability syndrome. There are only a few reports on clinical and serological profile of a CFS cohort that was followed up by a single outpatient clinic. Clinical, electrophysiological, and serological features of 6 CFS patients (5 men, 1 woman; 27-65 years old) were investigated. All patients presented with cramps, fasciculations, muscle pain, and autonomic symptoms, and 2 also reported numbness and burning sensation in limbs, suggestive of neuropathic pain. Antibodies to uncharacterized voltage-gated potassium channel (VGKC)-complex proteins were found in 2 patients and to contactin-associated protein-like 2 (CASPR2) in 1 patient. None of the patients had a tumor. Most of the patients revealed prolonged after-discharges following tibial nerve stimulation. Nerve conduction studies and R-R interval variability tests were normal, whereas sympathetic skin responses were increased in amplitude in 3 seronegative patients. Five patients showed favorable response to carbamazepine or pregabalin treatment, whereas 1 VGKC-antibody-positive patient was resistant to carbamazepine and immunosuppressant treatment. Neuropathic pain and VGKC-complex antibodies may be encountered in CFS patients. Although autonomic symptoms are commonly found in CFS, routine autonomic system tests which are done in electrophysiology laboratories might yield normal results.

The effects of co-administration of pregabalin and vitamin E on neuropathic pain induced by partial sciatic nerve ligation in male rats.

This study was performed to evaluate the effect of pregabalin co-administration with vitamin E in Partial Sciatic Nerve Ligation (PSNL)-induced neuropathic pain in rats. Male Wistar rats were randomly allocated as control, sham, and PSNL groups (n=8). PSNL was induced by tight ligation of the sciatic nerve with a copper wire. On day 14th, the PSNL and sham operated rats received either pregabalin (1, 3, and 30mg/kg), vitamin E (100 and 200mg/kg), or their combination intraperitoneally. An antinociceptive effect was evaluated as latency times and Maximum possible Effect Percent (%MPE) using tail-flick test. Locomotor activity was evaluated by open-field test before PSNL surgery and then twice at the 14th days (before and after drug injection). Ligated nerves were removed on the 28th days after surgery for histological examinations. The time course of latency times and %MPE showed significant decrease in PSNL but not in sham and control groups. Pregabalin (3 and 30mg/kg) and vitamin E (100 and 200mg/kg) caused significant increases in latency time in PSNL (but not sham) group compared to control group. Vitamin E 200mg/kg increased significantly %MPE in PSNL group compared to sham group. In addition, the %MPE following combination treatment of pregabalin (30mg/kg) and vitamin E (100mg/kg) was significantly higher than both vitamin E and control group. Also combination of pregabalin with 100mg/kg of vitamin E reversed Wallerian degeneration of sciatic nerve and the inflammatory responses to almost similar to sham group. Pregabalin and vitamin E did not affect locomotor activity. Our results showed antinociceptive effects of both vitamin E and pregabalin alone or in combination in PSNL rats and also neuroprotective properties without affecting locomotor activity.

Perioperative pregabalin administration does not prevent chronic postoperative pain: systematic review with a meta-analysis of randomized trials.

The efficacy of perioperative pregabalin treatment for preventing chronic pain remains a matter of debate. We searched the MEDLINE, EMBASE, LILACS, Cochrane, and Clinical Trial Register databases, and other sources, for randomized controlled trials comparing the effects of pregabalin and placebo. The primary outcome was the incidence of chronic postsurgical pain (CPSP) at 3 months. The secondary endpoints were CPSP at 3, 6, and 12 months and the incidence of chronic postsurgical neuropathic pain at the same time points. A random-effect meta-analysis was performed on the combined data. Evidence quality was rated by the GRADE method. We included 18 studies (2485 patients) in the meta-analysis. Overall, 60% of the trials reporting the primary outcome at 3 months were unpublished; the unpublished trials corresponded to 1492/1884 (79%) of the patients included in these studies. No difference in CPSP incidence between pregabalin and placebo was found at any time point; the risk ratio was 0.87 (0.66, 1.14), I = 57% at 3 months. The evidence was considered to be of moderate quality. Subgroup analysis by publication status, daily dose, type of administration, and type of surgery did not highlight any differences between subgroups. Insufficient data concerning the incidence of chronic postsurgical neuropathic pain were available for any firm recommendation to be made. Pooled data from published and unpublished studies provide no support for the efficacy of pregabalin for preventing CPSP.

Effect of pregabalin administration upon reperfusion in a rat model of hyperglycemic stroke: Mechanistic insights associated with high-mobility group box 1.

Hyperglycemia, which reduces the efficacy of treatments and worsens clinical outcomes, is common in stroke. Ability of pregabalin to reduce neuroexcitotoxicity may provide protection against stroke, even under hyperglycemia. We investigated its protective effect against hyperglycemic stroke and its possible molecular mechanisms. Male Wistar rats administered dextrose to cause hyperglycemia, underwent middle cerebral artery occlusion for 1 h and subsequent reperfusion. Rats were treated with an intraperitoneal injection of 30 mg/kg pregabalin or an equal amount of normal saline at the onset of reperfusion (n = 16 per group). At 24 h after reperfusion, neurological deficit, infarct volume, and apoptotic cell count were assessed. Western blot analysis was performed to determine protein expression of high-mobility group box 1 (HMGB1), toll-like receptor-4 (TLR-4), phosphorylated nuclear factor-kappa B (p-NF-κB), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), phosphorylated inducible and endothelial nitric oxide synthase (p-iNOS, p-eNOS), Bcl-2, Bax, Cytochrome C, and caspase-3 in the brain. Pregabalin-treated rats showed significantly improved neurological function (31% decrease in score), reduced infarct size (by 33%), fewer apoptotic cells (by 63%), and lower expression levels of HMGB1, TLR4, p-NF-κB, IL-1β, and TNF- α, compared with control rats. Decreased p-iNOS and increased p-eNOS expressions were also observed. Expression of Bax, Cytochrome C, and cleaved caspase-3/caspase3 was significantly downregulated, while Bcl-2 expression was increased by pregabalin treatment. Pregabalin administration upon reperfusion decreased neuronal death and improved neurological function in hyperglycemic stroke rats. Cogent mechanisms would include attenuation of HMGB1/TLR-4-mediated inflammation and favorable modulation of the NOS.

A comparison of the effectiveness of amitriptilin and pregabalin treatment in fibromyalgia patients.

OBJECTIVE:The present study is a comparison of the effectiveness of amitriptyline and pregabalin on the symptoms of fibromyalgia patients.METHODS:A total of 71 female patients aged ≥18 years were included in this study. The patients were divided into 2 groups. Pregabalin (n=36) or amitriptyline (n=35) treatment was initiated at daily oral dose of 450 mg and 25 mg, respectively for the indicated number of patients. The patients were evaluated at the start of treatment and at the end of 12 weeks. The Fibromyalgia Impact Questionnaire, Fatigue Severity Scale, Modified Fatigue Impact Scale, Hospital Anxiety Depression Scale, Nottingham Health Profile, Mini Mental State Test, and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) were administered to all study participants. Pain at all tender points was measured using a pressure algometer.RESULTS:Significant improvement was observed in both groups after 12 weeks of treatment (p<0.05). Percent change in LANSS was greater in the pregabalin group compared with the amitriptyline group. Tender point pressure pain thresholds and total myalgic score improved significantly in both groups (p<0.05); however higher percentage change in these parameters was achieved in the amitriptyline group when compared with the pregabalin group (p<0.05).CONCLUSION:Both drugs improved pain, fatigue, sleep disorder, disability, psychological evaluation, and cognitive function; however, amitriptyline was more effective at reducing experimentally measured pain than neuropathic pain. According to these results, preference for pregabalin may be recommended in fibromyalgia patients whose primary complaint is neuropathic pain.

Pregabalin enhances myelin repair and attenuates glial activation in lysolecithin-induced demyelination model of rat optic chiasm

Multiple sclerosis (MS) is an autoimmune disease in which more than 70% of patients experience visual disturbance as the earliest symptoms. Lysolecithin (LPC)-induced focal demyelination model has been developed to evaluate the effects of different therapies on myelin repair improvement. In this study, the effects of pregabalin administration on myelin repair and glial activation were investigated. Local demyelination was induced by administration of LPC (1%, 2μL) into the rat optic chiasm. Rats underwent daily injection of pregabalin (30mg/kg, i.p) or vehicle. Visual-evoked potentials (VEPs) recordings were performed for evaluating the function of optic pathway on days 3, 7, 14 and 28 post lesions. Myelin specific staining and immunostaining against GFAP and Iba1 were also carried out for assessment of myelination and glial activation respectively. Electrophysiological data indicated that pregabalin administration could significantly reduce the P1-N1 latency and increase the amplitude of VEPs waves compared to saline group. Luxol fast blue staining and immunostaining against PLP, as mature myelin marker, showed that myelin repair was improved in animals received pregabalin treatment. In addition, pregabalin effectively reduced the expression of GFAP and Iba1 as activated glial markers in optic chiasm. The present study indicates that pregabalin administration enhances myelin repair and ameliorates glial activation of optic chiasm following local injection of LPC.

Issue Cover (January 2017)

Front cover: Confocal microphotography of a triple inmunolabeling of the dentate gyrus against makers of adult-born (Bromodeoxyuridine, blue), mature (NeuN, green), and immature (Doublecortin, red) dentate gyrus granule cells. In mice chronically treated with Pregabalin the maturation of adult-born dentate gyrus granule cells is accelerated. In the population of Bromodeoxyurudine positive cells, that effect is evidenced as an increase in the fraction of NeuN positive cells concomitant with a reduction in the fraction of Doublecortin positive cells. Read the full article ‘Chronic pregabalin treatment decreases excitability of dentate gyrus and accelerates maturation of adult-born granule cells’ by A. A. Lempel, L. Coll, A. F. Schinder, O. D. Uchitel and J. Piriz (J. Neurochem. 2017, vol. 140 (2), pp. 257–267) on doi: 10.1111/jnc.13740

Pregabalin prescription for terminally ill cancer patients receiving specialist palliative care in an acute hospital.

BackgroundPregabalin is recommended as an adjuvant analgesic for neuropathic cancer-related pain, and may be taken at all steps of the World Health Organization analgesic ladder. However, unlike opioids, pregabalin treatments are limited to an oral administration route. If patients have oral feeding difficulties, it is not possible to administer any drug as an adjuvant analgesic for neuropathic cancer-related pain. Therefore, the aim of the present study was to clarify the problems of pain control after pregabalin discontinuation in terminally ill cancer patients.MethodsOur subjects comprised cancer patients who died during their hospital stay and were referred between April 2013 and October 2015 to the palliative care team of the 899-bed Cancer Hospital at the Nippon Medical School Hospital in Japan. The medical records of each patient were retrospectively reviewed, and patient characteristics were recorded.ResultsWe obtained data on 183 patients during the study period. Thirty-eight (20.8 %) patients were treated with pregabalin. Thirty-three (86.8 %) out of 38 patients were prescribed pregabalin for neuropathic cancer-related pain. The incidence of bony metastases was significantly higher in patients administered pregabalin than in those not taking the drug (non-pregabalin group 32.4 % vs pregabalin group 57.9 %). Pregabalin was ultimately discontinued in all patients, with the main reason being oral feeding difficulties (81.6 %). After the discontinuation of pregabalin, the amount of opioid drugs administered was increased in 56.5 % of patients with oral feeding difficulties.ConclusionOur results demonstrated that the amount of opioid drugs administered was increased in more than 50 % of patients following the discontinuation of pregabalin, and was repeatedly increased for some patients. A new administration route is required for cancer patients unable to take oral medication.Trial registration UMIN000022507. May 28, 2016 retrospectively registered.

Effects of pregabalin on spinal d-serine content and NMDA receptor-mediated synaptic transmission in mice with neuropathic pain

Pregabalin (PGB) is a chemical derivative of the inhibitory neurotransmitter γ-aminobutyric acid, and is successfully used for the treatment of neuropathic pain. Substantial evidence suggests that d-serine, an endogenous co-agonist at the strychnine-insensitive glycine site of the NMDA receptor, counteracts the antinociceptive actions of PGB at the level of the spinal cord. In the present study, we examined the impact of PGB treatment on spinal d-serine content and NMDA receptor-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-ligated neuropathic mice. Mechanical allodynia was assessed using von Frey filaments. On post-surgical day 9 (after 5days of treatment with PGB [50mg/kg] or saline vehicle), the lumbar spinal cord was removed, homogenized, and ultrafiltrated. Supernatant samples were treated with Marfey's reagent and analyzed with liquid chromatography-mass spectrometry to measure d-serine content. In the electrophysiological experiments, tight-seal whole-cell recording was performed on neurons in the superficial dorsal horn of spinal cord slices. Partial sciatic nerve ligation increased spinal d-serine content, increased the NMDA/non-NMDA ratio of EPSC amplitudes, and slowed the decay phase of the NMDA component of EPSCs (NMDA-EPSCs). PGB treatment attenuated mechanical allodynia and reduced spinal d-serine content, decreased the NMDA/non-NMDA ratio, and shortened the decay time of NMDA-EPSCs. Furthermore, bath-applied d-serine attenuated the effects of PGB treatment. Although the precise mechanism for the effect of PGB on d-serine metabolism and abundance is unknown, the antinociceptive action of PGB likely involves the reduction of spinal d-serine content and subsequent attenuation of NMDA receptor-mediated synaptic transmission in the superficial dorsal horn.

Chronic pregabalin treatment decreases excitability of dentate gyrus and accelerates maturation of adult-born granule cells.

Pregabalin (PGB) is extensively prescribed to treat neurological and neuropsychiatrical conditions such as neuropathic pain, anxiety disorders, and epilepsy. Although PGB is known to bind selectively to the α2δ subunit of voltage-gated calcium channels, there is little understanding about how it exerts its therapeutic effects. In this article, we analyzed the effects of an invivo chronic treatment with PGB over the physiology of dentate gyrus granule cells (DGGCs) using exvivo electrophysiological and morphological analysis in adult mice. We found that PGB decreases neuronal excitability of DGGCs. In addition, PGB accelerates maturation of adult-born DGGCs, an effect that would modify dentate gyrus plasticity. Together, these findings suggest that PGB reduces activity in the dentate gyrus and modulates overall network plasticity, which might contribute to its therapeutic effects. Cover Image for this issue: doi: 10.1111/jnc.13783.

The influence of thiamin on the efficacy of pregabalin in rats with spinal nerve ligation (SNL)-induced neuropathic pain

Objective: The thiamin is often used in the treatment of neuropathy, and pregabalin is often used to treat neuropathic pain. Our study examined the influence of thiamin on the efficacy of pregabalin in a rat model of spinal nerve ligation (SNL)-induced neuropathic pain.Methods: Sprague-Dawley male rats were randomly divided into six groups. The neuropathic pain-relieving properties were measured by plantar test, cold plate test, and hot plate test after administration of pregabalin (i.v) and/or thiamin (i.p) in SNL rats 14 days after operation.Results: In the therapy period, pregabalin, or thiamin alone all produced antinociceptive effects in rats with neuropathic pain. And combination treatment of thiamin and pregabalin resulted in an enhanced pain relief compared to the administration of pregabalin or thiamin alone.Conclusion: Combination of thiamin and pregabalin produces an additive antinociceptive effect in neuropathic pain rats, this drug combination may offer a beneficial treatment option for neuropathic pain.

Association of Alterations in Gray Matter Volume With Reduced Evoked-Pain Connectivity Following Short-Term Administration of Pregabalin in Patients With Fibromyalgia.

Pregabalin (PGB) is an α2 δ calcium-channel subunit ligand that has previously been shown to reduce chronic pain in multiple conditions. Preclinical studies indicate that PGB may down-regulate brain glutamate release while also inhibiting astrocyte induction of glutamatergic synapse formation, and recent clinical findings support the notion that PGB modulates glutamatergic activity and functional brain connectivity in order to produce analgesia. The present study was undertaken to examine concurrent changes in brain gray matter volume (GMV) or evoked-pain connectivity in humans receiving PGB. Sixteen female fibromyalgia patients participated in a randomized double-blind 2-period crossover study of PGB versus placebo. Before and after each period, patients underwent high-resolution structural and evoked pressure-pain functional brain imaging. GMV was analyzed using voxel-based morphometry, and functional connectivity during evoked pressure-pain was assessed. PGB administration significantly reduced GMV within the posterior insula bilaterally, whereas there were no significant changes in insular GMV following placebo treatment. GMV reductions in the medial frontal gyrus were also observed when comparing PGB versus placebo treatment, and were associated with reduced clinical pain. These reductions in insular GMV were associated with concomitant reductions in connectivity to the default mode network, which was also associated with reduced clinical pain. Short-term PGB treatment altered brain structure and evoked-pain connectivity, and these decreases were associated with reduced clinical pain. We speculate that these fairly rapid changes in GMV may be related to brain neuroplasticity. It is unknown whether these effects are generalizable to other chronic pain states.

Real-life efficacy of pregabalin for the treatment of peripheral neuropathic pain in daily clinical practice in Denmark: the NEP-TUNE study.

ObjectiveThe aim of this study was to provide evidence regarding the real-life efficacy of pregabalin in the treatment of peripheral neuropathic pain (NeP) in Denmark.MethodsIn this prospective, observational, noninterventional study, pregabalin (Lyrica®) was prescribed following usual clinical practice. Compared with baseline, the primary study end points after 3 months of observation were changes in 1) the average level of pain during the past week, 2) the worst level of pain during the past week, and 3) the least level of pain during the past week. The Wilcoxon signed-rank test was used to perform paired analyses, and a multivariate regression analysis investigated factors driving change in pain.ResultsA total of 86 of the 128 patients included were regarded as efficacy evaluable (those completing 3 months of pregabalin treatment). Patients (59 years) were long-time sufferers of peripheral NeP, and 38% of them had comorbidities. The majority had previously been treated with tricyclic antidepressants or gabapentin. The average dose of pregabalin was 81.5 mg/d at baseline and 240 mg/d after 3 months. A clinically and statistically significant improvement of 2.2 points in the average level of pain intensity was found after 3 months. The higher the pain intensity at baseline, the higher was the reduction of the pain score. Positive results were also found for pain-related sleep interference, patients’ global impression of change, quality of life, and work and productivity impairment. Twenty-one patients reported 28 adverse events.ConclusionThis real-life study indicates that for some patients (two-thirds), addition of pregabalin for peripheral NeP helps to reduce their pain intensity significantly.

Effects of pregabalin on the nociceptive, emotional and cognitive manifestations of neuropathic pain in mice.

Preclinical drug discovery for the treatment of chronic pain is at present challenged by the difficulty to study behaviours comparable to the complex human pain experience in animals. Several reports have demonstrated a frequent association of chronic pain in humans with affective disorders, such as anxiety and depression, and impaired cognitive functions, including memory and decision making, and motivation for goal-directed behaviours. In this study, we validated different behavioural outcomes to measure the emotional and cognitive manifestations of neuropathic pain induced in mice by partial sciatic nerve ligation. In these mice, we evaluated at different time points the nociceptive responses, the anxiety- and depressive-like behaviours, the anhedonic state, object recognition memory and the operant responding maintained by food and the effects of the repeated administration of pregabalin on these manifestations. Our results demonstrated that the presence of allodynia and hyperalgesia in neuropathic pain mice was associated with increased anxiety- and depressive-like behaviours, reduced memory functions, development of an anhedonic state and impaired motivation to obtain food in the operant task. Chronic pregabalin treatment improved the nociceptive, anxiety-like and anhedonic responses, as well as the memory deficit, but did not modify the depressive-like alterations and the decreased motivation in these mice. These results indicate that some emotional manifestations of chronic pain do not necessarily resolve when pain is relieved and underline the relevance to evaluate multiple behavioural responses associated with chronic pain, including the affective-motivational and cognitive behaviours, to increase the predictive value of preclinical drug discovery. WHAT DOES THIS STUDY ADD?: In this study, we have validated different behavioural outcomes allowing a reliable measurement of the emotional and cognitive manifestations of neuropathic pain induced in mice by partial sciatic nerve ligation. These results underline the relevance to evaluate these multiple pain-related alterations to improve the predictive value of preclinical drug discovery.

Effect of pregabalin on contextual memory deficits and inflammatory state-related protein expression in streptozotocin-induced diabetic mice.

Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defects in insulin secretion or its action. Complications from long-term diabetes consist of numerous biochemical, molecular, and functional tissue alterations, including inflammation, oxidative stress, and neuropathic pain. There is also a link between diabetes mellitus and vascular dementia or Alzheimer’s disease. Hence, it is important to treat diabetic complications using drugs which do not aggravate symptoms induced by the disease itself. Pregabalin is widely used for the treatment of diabetic neuropathic pain, but little is known about its impact on cognition or inflammation-related proteins in diabetic patients. Thus, this study aimed to evaluate the effect of intraperitoneal (ip) pregabalin on contextual memory and the expression of inflammatory state-related proteins in the brains of diabetic, streptozotocin (STZ)-treated mice. STZ (200 mg/kg, ip) was used to induce diabetes mellitus. To assess the impact of pregabalin (10 mg/kg) on contextual memory, a passive avoidance task was applied. Locomotor and exploratory activities in pregabalin-treated diabetic mice were assessed by using activity cages. Using Western blot analysis, the expression of cyclooxygenase-2 (COX-2), cytosolic prostaglandin E synthase (cPGES), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-ĸB (NF-ĸB) p50 and p65, aryl hydrocarbon receptor (AhR), as well as glucose transporter type-4 (GLUT4) was assessed in mouse brains after pregabalin treatment. Pregabalin did not aggravate STZ-induced learning deficits in vivo or influence animals’ locomotor activity. We observed significantly lower expression of COX-2, cPGES, and NF-κB p50 subunit, and higher expression of AhR and Nrf2 in the brains of pregabalin-treated mice in comparison to STZ-treated controls, which suggested immunomodulatory and anti-inflammatory effects of pregabalin. Antioxidant properties of pregabalin in the brains of diabetic animals were also demonstrated. Pregabalin does not potentiate STZ-induced cognitive decline, and it has antioxidant, immunomodulatory, and anti-inflammatory properties in mice. These results confirm the validity of its use in diabetic patients.Graphical abstractEffect of pregabalin on fear-motivated memory and markers of brain tissue inflammation in diabetic mice

The efficacy of pregabalin in patients with moderate and severe pain due to diabetic peripheral neuropathy

Objective To compare the therapeutic response to pregabalin in patients with moderate or severe painful diabetic peripheral neuropathy (pDPN).Research design and methods Data were pooled from 11 placebo-controlled trials to evaluate the efficacy of pregabalin flexible or fixed dose (150, 300 or 600 mg/day) in pDPN patients with mean baseline pain scores of ≥4 to <7 (moderate) or ≥7 to ≤10 (severe). Last observation carried forward imputation was used.Study number/ClinicalTrials.gov identifier 1008-014/-, 1008-029/-, 1008-040/-, 1008-131/-, 1008-149/-, 1008-000-155/-, A0081030/NCT00156078, A0081060/NCT00159679, A0081071/NCT00143156, A0081081/NCT00301223, A0081163/NCT00553475.Main outcome measures Pregabalin-mediated change in pain, pain-related sleep interference (PRSI) and patient global impression of change (PGIC) were compared versus placebo and between moderate and severe pain cohorts. Adverse events (AEs) were reported.Results At baseline, 1816 patients had moderate pain (pregabalin, n = 1189) and 1119 patients had severe pain (pregabalin, n = 720). Pregabalin significantly reduced pain scores at endpoint compared with placebo when patients of all pain levels were combined (all doses; p < 0.05). In the moderate and severe pain cohorts, pregabalin treatment (300, 600 mg/day or flexible) significantly reduced mean pain scores at endpoint compared with placebo (p < 0.01). Pain reduction was greatest in patients with severe baseline pain compared with moderate baseline pain (pregabalin 300, 600 mg/day or flexible; p < 0.0001). Pregabalin improved PRSI and PGIC in the moderate and severe cohorts compared with placebo. The greatest improvement in PRSI also occurred in the severe cohort. Treatment-emergent AEs, most commonly dizziness, somnolence and peripheral edema, occurred more frequently in patients treated with pregabalin compared with placebo.Conclusions Pregabalin was effective in pDPN patients with both moderate and severe baseline pain. Patients with severe pain exhibited greater improvements in pain and PRSI than patients with moderate pain. Pain severity may, in part, predict therapeutic response to pregabalin.

Paraesthesia Caused by the Separated Endodontic Instrument: Case Report

In endodontics, separated endodontic instruments located in the mandibular canal may cause an injury of the inferior alveolar nerve (IAN) resulting in disabling sensory disturbances such as pain, paraesthesia, and dysaesthesia of the lower lip and chin area. In clinically paraesthesia usually manifests as numbness, tingling or any deviation from normal sensation. The suggested therapeutic sequence for endodontic related paraesthesia is the control of pain and inflammation and, whenever possible, the surgical elimination of the cause. A healthy 33-year-old woman was referred to the Department of Endodontics, Oral and Dental Healthy Hospital, Eskisehir suffering from pain and paraesthesia in the left lower lip and chin. Radiographic examination revealed the presence of a separated endodontic instrument beyond the apex of the mandibular left second molar and this instrument was inside the left mandibular canal. Damage to the IAN secondary to extrusion of a separated endodontic instrument was diagnosed. Extraction of the tooth was decided and after prednisone and pregabalin treatments both pain and paraesthesia on the left side of the lower lip and chin were gone.

Treatment Patterns Associated with ACR-Recommended Medications in the Management of Fibromyalgia in the United States.

Fibromyalgia (FM) affects up to 6% of U.S. adults, resulting in a significant burden on the health care system and poor quality of life for patients. Duloxetine, pregabalin, and milnacipran are approved for management of FM; however, consensus is lacking regarding optimal therapy. Patients with FM taking approved medications often do not experience meaningful symptom relief, and many experience intolerable adverse events. To assess treatment patterns associated with available and commonly used medications for the management of FM using U.S. health insurance claims. This retrospective analysis used the MarketScan claims database to identify adults with a first diagnosis of FM (ICD-9-CM code 729.1) between 2009 and 2011 with continuous health plan enrollment for 12 months pre- and post-index. Medications of interest were pregabalin, gabapentin, duloxetine, milnacipran, cyclobenzaprine, and tramadol. These are 6 of the 8 medications recommended by the American College of Rheumatology (ACR) for treating FM; the other 2 (amitriptyline and venlafaxine) were only included in some initial assessments. The Charlson Comorbidity Index (CCI) was used to assess overall comorbidity burden. Endpoints included proportion of patients treated within 1 year after first diagnosis; initial treatment pattern; adherence over the first-year follow-up period for the medications of interest; and discontinuation, switching, and combination therapy patterns among pain medications of interest at different time points. Proportion of days covered (PDC; defined as number of days in the period when the patient had drug supply divided by the number of days in the period) was used to define adherence, which was categorized as low (PDC < 50%), medium (PDC 50% to < 80%), or high (PDC ≥ 80%). The time to discontinuation (defined as the first drug supply gap ≥ 90 days) was estimated using Kaplan-Meier analysis. Overall, 240,144 patients met the inclusion criteria. Patients were predominantly women (68%), had preferred provider organization insurance coverage (68%), and had a CCI score < 1 at baseline (69%). Only 31% (n = 74,738) initiated a treatment with a prescription medication listed in the ACR guidelines, and many patients received less than the recommended dose. Most (n = 70,919) patients initially received monotherapy with one of the 8 prescription medications. Of those who started with ≥ 2 medications (n = 3,819), cyclobenzaprine plus tramadol was the most frequent combination. Adherence was suboptimal for all 6 medications of interest. Duloxetine had the highest mean PDC (59%); for all other agents, mean PDC was < 50%. With the exception of duloxetine, discontinuation rates at 6 months were > 50% for all agents. Alterations in therapy were common. Among patients who discontinued their initial treatment of duloxetine, pregabalin, or milnacipran, approximately one-third had switched treatments within 90 days after their first prescription. For those who maintained their initial treatment agent, approximately 50% of patients added a second pain medication within 1 year of treatment initiation. The evidence suggests that patients with FM often do not receive 1 of the prescription medications recommended by ACR guidelines, and those who do are commonly prescribed lower-than-recommended doses, potentially resulting in poor effectiveness and tolerability. Discontinuation, switching, and addition of new pain medications are common, which may indicate low levels of satisfaction with initial treatment. New therapies with improved effectiveness and better tolerability are urgently needed for patients with FM.