Clinical use of pregabalin in the management of central neuropathic pain

Central neuropathic pain (central pain) is treated with antidepressants, various anticonvulsants, opioids, and cannabinoids, but in many cases treatment is insufficient and associated with a range of side-effects. This review addresses a new treatment for neuropathic pain, the anticonvulsant pregabalin. We review the pharmacology, mode of action, pharmacokinetics, and safety of pregabalin as well as two randomized efficacy studies in central pain and a brief overview of efficacy in peripheral neuropathic pain. Pregabalin appears to have efficacy in treating central pain comparable to that in peripheral neuropathic pain as well as efficacy of other recommended drugs for central pain. Pregabalin also improves disturbed sleep and anxiety. Pregabalin is well tolerated; the most common side-effects are somnolence, dizziness, ataxia, and weight gain. Pregabalin is suitable for patients on multiple drugs although there may be additive CNS-related side-effects. Thus, pregabalin has a primary role in central pain patients.     

Pregabalin: a new antiepileptic drug for refractory epilepsy.

Pregabalin is a recently licensed and marketed antiepileptic drug for use as adjunctive treatment of partial epilepsy. It acts at presynaptic calcium channels, modulating neurotransmitter release in the CNS, properties it shares with gabapentin. Its clinical development over the past decade has included its use in the treatment of neuropathic pain, and generalized anxiety disorder, in addition to epilepsy. Three multi-centre randomised, double-blind, placebo-controlled trials enrolling patients with refractory partial epilepsy have demonstrated an antiepileptic effect of pregabalin against placebo, as adjunctive therapy, with 31-51% of patients showing a 50% reduction in seizure frequency. Adverse effects were dose related, the commonest being somnolence, dizziness, and ataxia. Weight gain was seen in 14% of patients on the highest dose of 600 mg/day. Around 9000 people have been exposed to pregabalin in its development for all indications. No idiosyncratic reactions have been described to date. Pregabalin may be a useful addition in the treatment of refractory partial epilepsy. As with all new AEDs long-term follow up and post marketing surveillance is required.     

Pregabalin for the treatment of painful neuropathy

Pregabalin is an alpha(2)-delta ligand that binds to and modulates voltage-gated calcium channels, exerting its intended effect to reduce neuropathic pain. Pregabalin is the second of only two medications that are US FDA approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy; it is also the third medication for the treatment of postherpetic neuralgia. Currently, there are three pivotal clinical studies documenting the efficacy and safety of pregabalin for the treatment of painful diabetic neuropathy, and three clinical studies regarding the use of pregabalin for pain associated with postherpetic neuralgia. This article will review each of these studies, as well as provide a clinical review for the use of pregabalin in the treatment of neuropathic pain.     

Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam

BACKGROUND: Pregabalin inhibits release of excess excitatory neurotransmitters, presumably by binding to the alpha2-delta subunit protein of widely distributed voltage-dependent calcium channels in the brain and spinal cord. OBJECTIVE: To assess the anxiolytic efficacy of pregabalin in patients with generalized anxiety disorder. DESIGN: Double-blind, placebo-controlled, active-comparator trial. Patients were randomized to 4 weeks of treatment with pregabalin, 300 mg/d (n = 91), 450 mg/d (n = 90), or 600 mg/d (n = 89); alprazolam, 1.5 mg/d (n = 93); or placebo (n = 91). SETTING: Psychiatry research and clinic settings. PATIENTS: Outpatients meeting the DSM-IV criteria for generalized anxiety disorder, with a baseline Hamilton Anxiety Rating Scale (HAM-A) total score of 20 or greater. MAIN OUTCOME MEASURES: Change from baseline to end point in total HAM-A score in the pregabalin and alprazolam groups compared with the placebo group. The end point response criterion was 50% or greater reduction in the HAM-A total score. RESULTS: Pregabalin and alprazolam produced a significantly greater reduction in mean +/- SE HAM-A total score at last-observation-carried-forward end point compared with placebo (-8.4 +/- 0.8): pregabalin, 300 mg (-12.2 +/- 0.8, P<.001), 450 mg (-11.0 +/- 0.8, P = .02), and 600 mg (-11.8 +/- 0.8, P = .002), and alprazolam (-10.9 +/- 0.8, P = .02). By week 1 and at last-observation-carried-forward end point, the 3 pregabalin groups and the alprazolam group had significantly (P<.01) improved HAM-A psychic anxiety symptoms compared with the placebo group. Compared with the placebo group, HAM-A somatic anxiety symptoms were also significantly (P<.02) improved by the 300- and 600-mg pregabalin groups, but not by the 450-mg pregabalin (week 1, P = .06; week 4, P = .32) and the alprazolam groups (week 1, P = .21; week 4, P = .15). Of the 5 treatment groups, the 300-mg pregabalin group was the only medication group that differed statistically in global improvement at treatment end point not only from the placebo group but also from the alprazolam group. CONCLUSION: Pregabalin was significantly more efficacious than placebo for the treatment of psychic and somatic symptoms of generalized anxiety disorder and was well tolerated by most study patients.     

Multicenter,randomized, double‐blind,active comparator and placebo‐controlled trial of a corticotropin‐releasing factor receptor‐1 antagonist in generalized anxiety disorder

Background: Antagonism of corticotropin‐releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF‐1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double‐blind, placebo‐controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half‐powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2‐2016) with the HAM‐A psychic subscale score for the entire cohort at baseline (FDR‐adjusted P=.015). Conclusions: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

New treatment options in the management of fibromyalgia: role of pregabalin

Fibromyalgia (FM) is a common, chronic pain disorder with unknown etiology, characterized by widespread musculoskeletal pain and tenderness, and accompanied by several other symptoms such as sleep disturbance, fatigue, and mood disorders. Pregabalin is the first drug approved for the treatment of FM. Pregabalin has analgesic, anticonvulsant, and anxiolytic activity and has earlier demonstrated efficacy in the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and as adjuvant therapy for adult patients with partial onset seizures. Pregabalin, a lipophilic gamma-aminobutyric acid (GABA) analog, is α₂δ-1 ligand that binds to, and modulates, voltage-gated calcium channels. This modulation is characterized by a reduction of the excessive neurotransmitter release that is observed in certain neurological and psychotic disorders. Several randomized, double-blind, placebo-controlled studies have demonstrated that pregabalin has been effective in pain management, improving sleep quality and fatigue, as well as in several domains of health related quality of life. Because of mild to moderate adverse effects it can be considered a well-tolerated therapy for FM.     

Pregabalin in partial seizures: a pragmatic 21‐week,open‐label study (PREPS)

Background and purpose: Pregabalin has demonstrated efficacy in controlled trials as adjunctive treatment in patients with refractory seizures. Methods: This open‐label, 21‐week study in adults with at least two partial seizures in the last 2 months, who were inadequately controlled with one to three antiepileptic drugs, evaluated pregabalin 150–600 mg/day (dosed twice daily). The study comprised a prospective or retrospective 8‐week baseline phase, and 9‐week dose optimization and 12‐week maintenance periods. The primary assessment was the mean percentage change in 28‐day seizure frequency between baseline and end‐point (last 12 weeks of treatment, last observation carried forward, modified intention‐to‐treat population). Results: Four hundred and seventy‐six patients from Europe were included in this study (51% men; mean age/epilepsy duration 40.1/24.1 years). The median baseline seizure frequency was 5.5/28 days. Amongst the patient population, 78% completed the 21‐week treatment period; 7% discontinued for lack of efficacy and 12% because of adverse events (AEs). The mean last pregabalin dose was 359 mg/day. The mean (95% CI) reduction in seizure frequency was 36% (31%; 41%). The median reduction was 33%, and 39% of patients had a ≥50% reduction in seizure frequency. There were 19% and 8% of patients free of seizures during their last 4 and 12 weeks of treatment, respectively. The three most common AEs were dizziness (17%), somnolence (13%) and weight increase (13%). Conclusions: This open‐label study of pregabalin demonstrated efficacy that was consistent with that observed in previous controlled epilepsy trials. Pregabalin was well tolerated. The AE profile was also consistent with that reported in previous trials.     

Dose-response relationship of pregabalin in patients with generalized anxiety disorder. A pooled analysis of four placebo-controlled trials

BACKGROUND: Pregabalin has been evaluated in randomised clinical trials in patients with generalised anxiety disorder (GAD) in a fixed-dose design and with the Hamilton Anxiety Scale (HAM-A) as outcome measure. Four of the available six placebo-controlled trials were found acceptable for a pooled analysis of dose-response relationship. METHOD: Both the full HAM-A (14) and the six-item subscale covering the core items of GAD (HAM-A (6)) were analysed. The unbiased effect size statistic was used to evaluate the advantage of pregabalin over placebo. An effect size of 0.40 or higher was used to indicate a clinically significant effect. RESULTS: Four placebo-controlled trials running over four weeks and covering the dose range from 150 mg to 600 mg pregabalin were sufficiently homogeneous to be pooled for the analysis. Both HAM-A (6) and HAM-A (14) showed that for the dose of 150 mg pregabalin daily the effect size was clearly below 0.40. For the dose range of 200-450 mg daily, the effect sizes exceeded 0.40, with a plateau-like curve. The maximum dose of 600 mg daily did not increase effect size. On the HAM-A (14) as well as the item of sleep, effect size was generally higher, but followed the same pattern as the HAM-A (6). DISCUSSION: The dose of 150 mg pregabalin over the four weeks of the trials was found insufficient for the treatment of GAD. In the dose range of 200-450 mg daily, a clinically significant effect was obtained, although with a plateau-like curve which was not increased for the maximum dose of 600 mg daily.     

Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized,double-blind,placebo-controlled phase 3 trial

The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤?8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries—the longest, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150–600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, ??0.22 points (95% confidence interval, 0.54–0.10); p?=?0.1823]. However, comparisons for key secondary outcome measures yielded p values?<?0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population.ClinicalTrials.gov NCT01701362.     

Long‐term add‐on pregabalin treatment in patients with partial‐onset epilepsy: Pooled analysis of open‐label clinical trials

Purpose: To evaluate the safety, tolerability, and efficacy of long‐term pregabalin as add‐on therapy for patients with poorly controlled partial seizures. Methods: Analysis of data from six long‐term clinical trials involving 2,061 patients receiving open‐label pregabalin 75–600 mg/day adjunctive therapy for partial onset epilepsy refractory to multiple antiepileptic drugs. Results: Total pregabalin exposure was 3,877 person‐years. The mean duration of pregabalin treatment was 534 days (range 0.3–8 years) and 59% completed 1 year. One‐third of patients discontinued for lack of efficacy. The most common dose was ≥300 mg/day; over half took ≥450 mg/day. There was a mean reduction in the 28‐day seizure rate of 25–40%, and more than 40% of all patients had a ≥50% reduction in seizures from baseline during the last 3 months of treatment. Twelve percent of all patients had a 6‐month period continuously free of seizures. In the last year, 6% were seizure‐free for the entire year. Pregabalin was generally well‐tolerated and the safety profile favorable in patients treated for up to several years, with an adverse event (AE) profile similar to short‐term placebo‐controlled trials. Common AEs included CNS symptoms (dizziness, somnolence, headache, and asthenia), accidental injury, and weight gain. CNS AEs tended to be mild and transient. Rates of sudden unexpected death in epilepsy (SUDEP), mortality, cancer, and status epilepticus were within the expected range for this population. Conclusions: Adjunctive pregabalin was effective, generally well tolerated, and safe in the long‐term treatment of partial seizures, and provided clinically meaningful seizure reduction and freedom without evidence of tolerance over 2 years of follow‐up.     

Effects of pain treatment on sleep in nursing home patients with dementia and depression: A multicenter placebo‐controlled randomized clinical trial

Objective

To investigate the effects of pain treatment on sleep in nursing home (NH) patients with dementia and depression.

Methods

A multicenter, 2‐armed, double‐blinded, placebo‐controlled, randomized clinical trial conducted between August 2014 and September 2016. One hundred six long‐term patients from 47 NHs in Norway with dementia and depression according to the Mini‐Mental State Examination and the Cornell Scale for Depression in Dementia were included. Patients received stepwise pain treatment in which those who did not use analgesics were randomized to receive either paracetamol (3 g/day) or placebo tablets; those who already used pain treatment were allocated to buprenorphine transdermal system (max. 10 μg/h/7 days) or placebo transdermal patches. Sleep was assessed continuously for 14 days by actigraphy, 1 week of baseline measurement, and 1 week of ongoing treatment. The following sleep parameters were evaluated: total sleep time, sleep efficiency (SE), sleep onset latency (SOL), wake after sleep onset, early morning awakening (EMA), and number of wake bouts.

Results

In the intervention group (paracetamol/buprenorphine), SE (70%‐72%), SOL (32‐24 min), and EMA (50‐40 min) improved compared with the control group (SE, 70%‐67%; SOL, 47‐60 min; EMA, 31‐35 min). Treatment effects were significant (P < .01, P < .05, and P < .05, respectively).

Conclusion

Compared with placebo, pain treatment improved sleep as measured with actigraphy. This implies that sleep, pain, and depression in NH patients should be critically evaluated and that pain treatment should be considered to be a potentially beneficial treatment.     

Rotigotine effects on early morning motor function and sleep in Parkinson's disease: A double‐blind,randomized, placebo‐controlled study (RECOVER)

In a multinational, double‐blind, placebo‐controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early‐morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early‐morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS‐2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by ?7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by ?3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS‐2 total score had decreased by ?5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by ?1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: ?3.55 [95% confidence interval (CI) ?5.37, ?1.73]; P = 0.0002) and PDSS‐2 (treatment difference: ?4.26 [95% CI ?6.08, ?2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty‐four‐hour transdermal delivery of rotigotine to PD patients with early‐morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances. © 2010 Movement Disorder Society     

Investigating the possible pain attenuating mechanisms of pregabalin in chronic constriction injury-induced neuropathic pain in rats

Abstract

Aim of the study: The current study was aimed to investigate the neuropathic pain attenuating mechanism of pregabalin using chronic constriction injury (CCI) model in rats.

Material and Methods: The sciatic nerve was ligated by placing four loose ligatures around it to induce neuropathic pain. The pain development in terms of cold allodynia, mechanical hyperalgesia, and heat hyperalgesia was assessed on the 7th and 14th day after surgery, using acetone drop, pinprick, and hot plate tests. On the 14th day after the injury, pain parameters were assessed 30?minutes after administration of pregabalin (30?mg/kg) and sodium nitroprusside (5?mg/kg) in CCI-subjected rats.

Results: CCI led to induction of neuropathic pain, which was more prominent on 14th day in comparison to 7th day. A single administration of pregabalin and sodium nitroprusside on 14th day, markedly reduced pain parameters and increased serum nitrite levels. Pretreatment with L-NAME abolished neuropathic pain attenuating effects of pregabalin suggesting that pregabalin may increase the levels of nitric oxide to mitigate neuropathic pain. Pretreatment with naloxone significantly abrogated pain attenuating effects of pregabalin and sodium nitroprusside in CCI-subjected rats suggesting that pregabalin and nitric oxide-mediated analgesic action are mediated through release of endogenous opioids. Moreover, naloxone failed to modulate pregabalin-induced increase in nitric oxide levels suggesting that the opioid system does not control the nitric oxide levels, and opioids may be downstream modulators of nitric oxide.

Conclusion: Pregabalin may increase the release of nitric oxide, which may increase the release of endogenous opioids to attenuate neuropathic pain in CCI subjected rats.     

A randomized,double-blind, 6-week,dose-ranging study of pregabalin in patients with restless legs syndrome

ObjectiveThis study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS).MethodsThis six-arm, double-blind, placebo-controlled, dose–response study randomized patients (N = 137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose–response was characterized using an exponential decay model, which estimates the maximal effect (E_max) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety.ResultsThe separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED₅₀) and 90% (ED₉₀) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related.ConclusionsIn this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.     

Spinal Cord Stimulation for Post‐Herniorrhaphy Pain

Objective. Post‐herniorrhaphy pain syndrome can be difficult to treat. The exact mechanism of pain is not always apparent. Multiple therapeutic modalities have been suggested for the treatment of this syndrome. Method. This includes both conservative (medical management), surgical (scar revision, excision of neuroma), and/or interventional approaches (local blocks to the entrapped nerves or sympathetic ganglion). Results. Two cases of intractable post–herniorrhaphy pain syndrome which failed to respond to conservative therapy are reviewed. Both cases had a successful trial therapy with spinal cord stimulation for their pain. Both then had permanent implantable systems inserted with favorable outcomes. Conclusion. Post‐herniorrhaphy pain can have the same features of both nociceptive and neuropathic pain syndromes. In cases which have failed conservative therapy we believe that a trial of spinal cord stimulation is warranted as in other cases of neuropathic pain syndromes.     

Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine

OBJECTIVE: Pregabalin has demonstrated robust, rapid efficacy in reducing symptoms of generalized anxiety disorder (GAD) in 4 placebo-controlled clinical trials. The current study compared the efficacy and safety of pregabalin and venlafaxine in patients diagnosed with moderate to severe GAD. METHOD: The study was conducted from December 21, 1999, to July 31, 2001. Outpatients (N = 421) in primary care or psychiatry settings meeting DSM-IV criteria for GAD were randomly assigned to 6 weeks of double-blind treatment with pregabalin 400 or 600 mg/day, venlafaxine 75 mg/day, or placebo. The primary analysis was change in Hamilton Rating Scale for Anxiety (HAM-A) total score from baseline to last-observation-carried-forward (LOCF) endpoint. Secondary analyses included the change in HAM-A psychic (emotional) and somatic (physical) factor scores, significant improvement at week 1, and week 1 improvement sustained at every visit through endpoint. RESULTS: Pregabalin at both dosages (400 mg/day, p = .008; 600 mg/day, p = .03) and venlafaxine (p = .03) produced significantly-greater improvement in HAM-A total score at LOCF endpoint than did placebo. Only the pregabalin 400-mg/day treatment group experienced significant improvement in all a priori primary and secondary efficacy measures. Pregabalin in both dosage treatment groups (400 mg/day, p < .01; 600 mg/day, p < .001) significantly improved HAM-A total score at week 1, with significant improvement through LOCF endpoint. Statistically significant improvement began at week 2 for venlafaxine. Discontinuation rates due to associated adverse events were greatest in the venlafaxine treatment group: venlafaxine, 20.4%; pregabalin 400 mg/day, 6.2%; pregabalin 600 mg/day, 13.6%; placebo, 9.9%. CONCLUSION: Pregabalin was safe, well tolerated, and rapidly efficacious across the physical-somatic as well as the emotional symptoms of GAD in the majority of patients studied in primary care and psychiatric settings.     

Silicon-Containing GABA Derivatives,Silagaba Compounds, as Orally Effective Agents for Treating Neuropathic Pain without Central-Nervous-System-Related Side Effects

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Pregabalin Misuse and Abuse in Jordan: a Qualitative Study of User Experiences

Pregabalin is currently approved for the treatment of epilepsy, generalized anxiety disorder, neuropathic pain, and fibromyalgia. A qualitative study was undertaken in Jordan, where concerns have been raised about its unprescribed availability in community pharmacies and thereby its abuse. Semi-structured interviews were conducted with all patients with a history of pregabalin use in two Jordanian addiction treatment centers. All were male patients aged 21–30 years (n = 11). The majority was poly-drug abusers and had a previous history of substance abuse (tramadol, Captagon, synthetic cannabinoids, and marijuana). Six key themes emerged from a content textual analysis which centered on pregabalin and other drugs; the pregabalin effect; poly-pharming and pregabalin intoxication; trajectories, patterns, and routes of administration; dependence and withdrawal; and sourcing of pregabalin. The study underscores the need for continued pharmacovigilance to manage and address suspected abuse, along with community pharmacist and patient education regarding abuse liability and related harms.     

Increased miR‐195 aggravates neuropathic pain by inhibiting autophagy following peripheral nerve injury

Following peripheral nerve injury (PNI) microglia proliferates and adopts inflammation that contributes to development and maintenance of neuropathic pain. miRNAs and autophagy are two important factors in the regulation of inflammation. However, little is known about whether miRNAs regulate neuroinflammation and neuropathic pain by controlling autophagy. In the study, we demonstrated that miR‐195 levels were markedly increased in rats subjected to L5 spinal nerve ligation (SNL). Upregulated miR‐195 was also found in spinal microglia of rats with SNL. The overexpression of miR‐195 contributed to lipopolysaccharide‐induced expression of proinflammatory cytokines IL‐1β, TNF‐α, and iNOS in cultured microglia. Upregulated miR‐195 also resulted in increased mechanical and cold hypersensitivity after PNI, whereas miR‐195 inhibition reduced mechanical and cold sensitivity. We further demonstrated that PNI significantly inhibited microglial autophagy activation, whereas miR‐195 inhibitor treatment increased autophagy activation and suppressed neuroinflammation in vivo and in vitro. More important, autophagy inhibition impaired miR‐195 inhibitor‐induced downregulation of neuroinflammation and neuropathic pain. Additionally, ATG14 was identified as the functional target of miR‐195. Conclusions: These data demonstrated that miR‐195/autophagy signaling represents a novel pathway regulating neuroinflammation and neuropathic pain, thus offering a new target for therapy of neuropathic pain.     

The effects of pregabalin on sleep disturbance symptoms among individuals with fibromyalgia syndrome

ObjectivesSleep disturbances are common in patients with fibromyalgia (FM). The objective of this analysis was to evaluate the effects of pregabalin on sleep in patients with FM.MethodsAnalyses were based on two randomized, double-blind, placebo-controlled trials of pregabalin (300 mg, 450 mg, and 600 mg daily) in adult FM patients. Sleep outcomes included the Medical Outcomes Study (MOS) Sleep Scale and a daily diary assessment of sleep quality. Treatment effects were evaluated using analysis of covariance. Clinically important differences (CID) in the Sleep Quality Diary and MOS Sleep Disturbance scores were estimated using mixed-effects models of changes in scores as a function of patients’ global impressions of change. Mediation modeling was used to quantify the direct treatment effects on sleep in contrast to indirect influence of the treatment on sleep via pain.ResultsA total of 748 and 745 patients were randomized in the respective studies. Patients were predominantly Caucasian females, average age 48–50 years, on average had FM for 9–10 years, and experienced moderate to severe baseline pain. Pregabalin significantly improved the Sleep Quality Diary (P < 0.001), MOS Sleep Disturbance (P < 0.01), MOS Quantity of Sleep (P < 0.003), and MOS Sleep Problems Index scores (P < 0.02) relative to placebo. Treatment effects for the 450 mg and 600 mg groups exceeded the estimated CID thresholds of 0.83 and 7.9 for the Sleep Quality Diary and MOS Sleep Disturbance scores, respectively. Mediation models indicated that 43–80% of the benefits on sleep (versus placebo) were direct effects of pregabalin, with the remainder resulting from an indirect effect of treatment via pain relief.ConclusionsThese data demonstrate improvement in FM-related sleep dysfunction with pregabalin therapy. The majority of this benefit was a direct effect of pregabalin on the patients’ insomnia, while the remainder occurred through the drug’s analgesic activity.