Topiramate in painful diabetic polyneuropathy: findings from three double-blind placebo-controlled trials

OBJECTIVES: To evaluate the efficacy and tolerability of topiramate in patients with painful diabetic polyneuropathy. MATERIALS AND METHODS: Patients with moderate to extreme pain (0-4 Categorical Pain Scale score > or = 2) were randomized to placebo or topiramate (100, 200, or 400 mg/day) in three similar double-blind trials. The primary efficacy analysis was pain reduction from final visit to baseline in the 100-mm Visual Analog Scale (VAS) for the intent-to-treat populations. RESULTS: After 18-22 weeks of double-blind treatment, pain reductions were numerically greater with topiramate in two studies but differences between topiramate and placebo in VAS scores or in the secondary efficacy endpoints did not reach statistical significance in any of the three studies. Across all studies, 24% of topiramate-treated patients and 8% of placebo-treated patients discontinued due to adverse events; groups did not differ in the occurrence of serious adverse events. CONCLUSION: These studies did not find topiramate to be significantly more effective than placebo in reducing pain scores in patients with painful diabetic polyneuropathy. Several design features may have precluded the studies from having sufficient sensitivity to differentiate effective and ineffective treatments. The study design and results are instructive for other investigators designing future clinical studies in neuropathic pain.     

Lacosamide

Lacosamide is a new chemical entity being investigated as an adjunctive treatment for epilepsy, as well as monotherapy for diabetic neuropathic pain. Lacosamide appears to have a dual mode of action: selective enhancement of sodium channel inactivation and modulation of collapsin response mediator protein-2. Rapidly and completely absorbed after oral administration, lacosamide has an elimination half-life of approximately 13 hours and a low potential for drug interactions. Additionally, lacosamide exhibits linear, dose-proportional pharmacokinetics with low intra- and interpatient variability. Randomized controlled trials of adjunctive lacosamide (200, 400, and 600 mg/day) have demonstrated statistically significant reduction in median seizure frequency compared with placebo. In addition, 50% responder rates for lacosamide (400 and 600 mg/day) were statistically superior to placebo. The most frequently reported adverse events (≥10% of lacosamide-treated patients) included dizziness, headache, and nausea. A double-blind, double-dummy randomized trial of intravenous lacosamide (30- and 60-minute infusion) as replacement for oral lacosamide showed that the safety and tolerability profiles were comparable for intravenous and oral lacosamide. The efficacy and safety results from completed clinical trials, as well as the favorable pharmacokinetic profile, suggest that lacosamide may represent a significant advance in antiepileptic drug therapy.     

A randomized, controlled trial of high-dose dextromethorphan in facial neuralgias

BACKGROUND: NMDA glutamate receptor antagonists such as ketamine and dextromethorphan reduce pain in certain neuropathic pain conditions. However, there have been no controlled trials of NMDA antagonists in facial neuralgias. METHODS: A randomized, double-blind, crossover trial compared 6 weeks of oral dextromethorphan with active placebo (low-dose lorazepam) in 19 patients, stratified into three groups: 11 with facial pain and possible trigeminal neuropathy, five with anesthesia dolorosa, and three with idiopathic trigeminal neuralgia. Dosage was titrated in each patient to the highest level reached without disrupting normal activities. RESULTS: Patients completing the trial included 10 with possible trigeminal neuropathy, four with anesthesia dolorosa, and two with trigeminal neuralgia. In patients with possible trigeminal neuropathy and anesthesia dolorosa, dextromethorphan decreased pain by a mean of only 2 to 4%, and these estimates were not significant. Both patients with trigeminal neuralgia had more pain during dextromethorphan treatment than during placebo treatment. Of three patients who demonstrated an analgesic response to dextromethorphan during the main trial, only one repeatedly responded in four subsequent confirmatory drug-placebo crossovers. CONCLUSIONS: Dextromethorphan shows little or no analgesic efficacy in pain due to possible trigeminal neuropathy and anesthesia dolorosa. Additional trials are necessary to conclusively evaluate the efficacy of NMDA-receptor antagonists in trigeminal neuralgia.     

Efficacy of Peripheral Nerve Field Stimulation for the Management of Chronic Low Back Pain and Persistent Spinal Pain Syndrome: A Narrative Review

ObjectivesVarious approaches have been developed with a view to treating the back pain component in patients with chronic low back pain (CLBP) and persistent spinal pain syndrome (PSPS). Emerging evidence shows that peripheral nerve field stimulation (PNFS) may be an efficacious therapeutic modality against axial low back pain. Hence, the aim of the review was to evaluate the analgesic efficacy and safety of PNFS, when used alone or as an adjunct to spinal cord stimulation (SCS), for managing CLBP and PSPS.Materials and MethodsA comprehensive search for clinical studies on PNFS and PNFS + SCS used for the management of CLBP and/or PSPS was performed using PubMed, EMBASE, MEDLINE via Proquest, and Web of Science.ResultsA total of 15 studies were included, of which four were randomized controlled trials (RCTs), nine were observational studies, and two were case series. For patients receiving PNFS, a significant decrease in back pain intensity and analgesic consumption, together with a significant improvement in physical functioning, was observed upon implant of the permanent system. Meanwhile, the addition of PNFS to SCS in refractory cases was associated with a significant reduction in back and leg pain, respectively.ConclusionsThis review suggests that PNFS, when used alone or in combination with SCS, appears to be effective in managing back pain. However, high-quality evidence that supports the long-term analgesic efficacy and safety is still lacking. Hence, RCTs with a larger patient population and of a longer follow-up duration are warranted.     

Emerging trends in the management of neuropathic pain

Despite significant improvements in our ability to treat neuropathic pain, we are far from the situation of being able to guarantee pain relief. The next few years promise to see the introduction of novel pharmacologic entities that show potential in the field of neuropathic pain treatment. Allied to this will be the realization that some drugs originally released for nonpain indications in fact have an analgesic effect in neuropathic pain. Our treatment armamentarium will be further enhanced by the release of currently available agents with proven efficacy but in new formulations. However, not every product of our improved knowledge will manifest as a new drug treatment for neuropathic pain. Despite evidence of efficacy, some drugs will fail to reach commercialization due to the lack of investment in their clinical development.     

Lacosamide for the treatment of diabetic neuropathic pain

Lacosamide is a novel chemical entity with anticonvulsant and analgesic properties that is being developed to treat epilepsy and neuropathic pain conditions. Lacosamide has shown efficacy in many animal models of chronic pain and in several short- and long-term Phase II/III clinical trials in humans with diabetic neuropathic pain. The mechanism of action of lacosamide differs from other drugs used to treat neuropathic pain in that it selectively enhances sodium channel slow inactivation without affecting fast inactivation, and may modulate collapsin-response mediator protein 2. The pharmacokinetic properties of lacosamide include a fast rate of absorption, little or no interaction with cytochrome P450 isoenzymes, limited effect of age and gender on plasma levels and low potential for drug-drug interactions.     

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.     

Combination pharmacotherapy for neuropathic pain: current evidence and future directions

Current drugs reduce neuropathic pain and improve mood and quality of life. However, as single agents they are limited by incomplete efficacy and dose-limiting adverse effects. Recent experimental and clinical data support the potential of combination pharmacotherapy for neuropathic pain. Therapeutic benefits may include greater efficacy, lower doses and fewer adverse effects. Due to potential adverse, as well as beneficial, drug interactions, safety and efficacy of specific combinations must be empirically evaluated. Techniques such as isobolographic analysis, response-surface modeling and other model-free tests have been used in order to characterize analgesic interactions as antagonistic, additive or synergistic. Whether synergistic or not, a clinically useful combination could simply have additive or even subadditive analgesia, provided that there is less additivity for side effects. Despite widespread clinical use, there are surprisingly few published observations on combination therapy for neuropathic pain. This review discusses future directions and proposes research strategies aimed at bridging current knowledge gaps, including safety, compliance and cost-effectiveness; discovering optimal drug combinations and dose ratios; comparing concurrent with sequential combination therapy; and combining more than two drugs. Continued close integration of basic and clinical sciences is crucial in further harnessing the potential of combination pharmacotherapy in neuropathic pain.     

Effects of levetiracetam on chronic pain in multiple sclerosis: results of a pilot, randomized, placebo-controlled study

Background and purpose:  Central neuropathic pain (CNP) is a prevalent and distressing symptom in patients with multiple sclerosis (MS). The anticonvulsant levetiracetam (LEV) has been shown to be efficacious in some types of CNP, but its efficacy in MS-related CNP has not been confirmed.
Methods:  To investigate the tolerability and potential effects of LEV against CNP in MS subjects, we performed a single-center, prospective, randomized, single-blind, placebo-controlled study in twenty patients with MS and CNP. Outcomes before and during the 3-month study were assessed using validated measures of pain, depression, disability and quality of life.
Results:  The medication was well tolerated and analysis revealed a significant difference between the LEV and placebo arm in all study outcomes related to pain (mean pain intensity score, mean pain difference, percentage of patients with a clinically significant pain reduction). Furthermore, the individual quality of life rating improved in treated patients, showing a significant correlation with pain reduction.
Conclusions:  These findings suggest that further studies with larger samples of patients be carried out in order to confirm the efficacy of LEV in MS-related CNP population.     

Review of olanzapine in the management of bipolar disorders

Olanzapine is an atypical antipsychotic currently with indications for the treatment of schizophrenia, acute mania and the prevention of relapse in bipolar disorder. A growing body of clinical evidence supports these indications. Acute mania trials have demonstrated superior efficacy of olanzapine to placebo, equal or superior efficacy to valproate and superior efficacy in combination therapy with lithium or valproate compared to mood stabilizer monotherapy. Olanzapine demonstrated a modest effect in the treatment of bipolar depression with a substantially enhanced effect in combination with fluoxetine. Maintenance trials showed olanzapine to be more efficacious than placebo in the prevention of manic and depressive relapses and non-inferior to lithium or valproate. Combination of olanzapine with lithium or valproate was also found to be more efficacious than lithium or valproate monotherapy in the prevention of manic relapse in patients with a partial response to monotherapy with lithium or valproate. These trials suggest that olanzapine is a viable option and an invaluable addition to the pharmacological armamentarium in the treatment of bipolar I disorder. However, this can often be mitigated by safety and tolerability concerns with this agent including weight gain and metabolic syndrome that warrants clinician vigilance and discernment that is imperative in today’s clinical practice.     

Oxcarbazepine is effective and safe in the treatment of neuropathic pain: pooled analysis of seven clinical studies

Abstract The results of 7 open-label clinical studies on oxcarbazepine (OXC) in different neuropathic pain conditions, sharing the same protocols, were pooled together in order to evaluate whether the results obtained in the individual trials were confirmed in the pooled analysis of this larger sample, providing more evidence for efficacy and tolerability of OXC in these conditions. Eligible patients (>18 years old) with a diagnosis of neuropathic pain were enrolled in seven open-label trials, consisting of a oneweek prospective Screening Phase followed by an eight-week Treatment Phase. Treatment with OXC was initiated at 150 mg/day, and the daily dose was increased by 150 mg/day on a 2–3 day basis to the maximum tolerated dose over four weeks, up to 1800 mg/day. The primary outcome measure was the change in the actual pain rating assessed on the visual analogue scale (VAS) between the end of the Screening Phase and the end of the Treatment Phase. One hundred and thirty-six patients were enrolled in the trials. The mean VAS score dropped from 77.13 at the end of the Screening Phase to 38.41 at the end of the trial for a mean reduction of 50.2%. The percentage of responders (mean VAS score reduction ≥50%) was 49.2%. OXC was well tolerated, with the most common adverse events consisting of vertigo, tremor, somnolence, hypotension and nausea. The results of this analysis suggest that OXC administered as monotherapy is an efficacious and safe option for the symptomatic treatment of pain associated with neuropathies.     

Almotriptan: a review of 10 years' clinical experience

Almotriptan, a serotonin 5-HT 1B/1D agonist, was developed for the acute treatment of migraine with or without aura and has been available for 10 years. This article evaluates the wealth of experience that has been obtained with almotriptan, including large randomized clinical trials (RCTs) and post-marketing studies that more closely reflect everyday clinical practice. Initial RCTs required patients to take almotriptan when migraine pain was of moderate or severe intensity, and found that 12.5 mg provided optimal outcomes for both pain relief and tolerability. Almotriptan effectively improved 2-h pain-relief, reduced migraine-associated symptoms and demonstrated low recurrence rates. These findings were also shown in patient subgroups, such as adolescents and menstrual migraineurs. A secondary finding in these trials was that patients who took almotriptan early, when the pain was still mild, achieved better outcomes. This prompted the initiation of studies designed to assess the effect of almotriptan in early intervention. Open-label trials reported improvements in pain-free end points (2 h, 24 h), and subsequent RCTs confirmed these findings. Pharmacovigilance data from more than 100 million tablets dispensed worldwide have confirmed that almotriptan is associated with a low occurrence of adverse effects, which, in clinical trials, has been shown to be similar to that observed with placebo. The clinical evidence obtained and comparisons made over a decade of use have demonstrated that almotriptan is one of the more effective and fast-acting triptans available, with a placebo-like tolerability profile. This suggests that almotriptan is an excellent choice for patients requiring specific acute migraine treatment.     

Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia.

We studied the analgesic efficacy of an intravenous infusion of lidocaine and morphine in 19 adults with well-established postherpetic neuralgia in a three-session, randomized, double-blind, placebo-controlled trial. Compared with saline placebo, both lidocaine and morphine reduced pain intensity. Reductions in pain did not correlate with side effects produced by the infusions. For morphine, there was a significant correlation between reductions in pain intensity and blood level achieved. In the majority of subjects who reported definite pain relief, allodynia also disappeared. The results show that neuropathic pain can respond to opioids and to systemically administered local anesthetic drugs.     

EFNS guidelines on neurostimulation therapy for neuropathic pain

Pharmacological relief of neuropathic pain is often insufficient. Electrical neurostimulation is efficacious in chronic neuropathic pain and other neurological diseases. European Federation of Neurological Societies (EFNS) launched a Task Force to evaluate the evidence for these techniques and to produce relevant recommendations. We searched the literature from 1968 to 2006, looking for neurostimulation in neuropathic pain conditions, and classified the trials according to the EFNS scheme of evidence for therapeutic interventions. Spinal cord stimulation (SCS) is efficacious in failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS) type I (level B recommendation). High-frequency transcutaneous electrical nerve stimulation (TENS) may be better than placebo (level C) although worse than electro-acupuncture (level B). One kind of repetitive transcranial magnetic stimulation (rTMS) has transient efficacy in central and peripheral neuropathic pains (level B). Motor cortex stimulation (MCS) is efficacious in central post-stroke and facial pain (level C). Deep brain stimulation (DBS) should only be performed in experienced centres. Evidence for implanted peripheral stimulations is inadequate. TENS and r-TMS are non-invasive and suitable as preliminary or add-on therapies. Further controlled trials are warranted for SCS in conditions other than failed back surgery syndrome and CRPS and for MCS and DBS in general. These chronically implanted techniques provide satisfactory pain relief in many patients, including those resistant to medication or other means.     

Divalproex sodium in nursing home residents with possible or probable Alzheimer Disease complicated by agitation: a randomized, controlled trial.

OBJECTIVE: Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer's Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia. METHODS: This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N = 75) or placebo (N = 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability. RESULTS: Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/placebo differences. CONCLUSIONS: This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit.     

Ziconotide: a review of its pharmacology and use in the treatment of pain

Ziconotide is a powerful analgesic drug that has a unique mechanism of action involving potent and selective block of N-type calcium channels, which control neurotransmission at many synapses. The analgesic efficacy of ziconotide likely results from its ability to interrupt pain signaling at the level of the spinal cord. Ziconotide is a peptidic drug and has been approved for the treatment of severe chronic pain in patients only when administered by the intrathecal route. Importantly, prolonged administration of ziconotide does not lead to the development of addiction or tolerance. The current review discusses the various studies that have addressed the in vitro biochemical and electrophysiological actions of ziconotide as well as the numerous pre-clinical studies that were conducted to elucidate its antinociceptive mechanism of action in animals. In addition, this review considers the pivotal Phase 3 (and other) clinical trials that were conducted in support of ziconotide’s approval for the treatment of severe chronic pain and tries to offer some insights regarding the future discovery and development of newer analgesic drugs that would act by a similar mechanism to ziconotide but which might offer improved safety, tolerability and ease of use.     

Therapeutic advances in pharmaceutical treatment of neuropathic pain

Neuropathic pain is difficult to treat. Recommended first-line treatments include tricyclic antidepressants and alpha2delta agonists pregabalin and gabapentin for multiple neuropathic conditions, the antidepressants duloxetine and venlafaxine in diabetic painful neuropathies and lidocaine patches for postherapetic neuralgia. Therapeutic prospects include focal therapy with sustained analgesic efficacy (capsaicin patches, botulinum toxin), treatments acting on new targets (i.e., cytokine inhibitors, metabotropic glutamate inhibitors, TRPV1 antagonists). The methodology of clinical trials also tends to take better into account the symptomatic profiles of patients, which should contribute to better prediction or responders to treatment.     

Pain relief and tolerability balance of immediate release tapentadol or oxycodone treatment for patients with moderate to severe osteoarthritis or low back pain

Purpose. Opioid treatment effectiveness may be best compared using definitions of treatment response, which combine measures assessing pain reduction and the occurrence of adverse events (AEs). This analysis of data from two phase III clinical trials was conducted to examine the pain relief and tolerability (PRT) balance of immediate release (IR) tapentadol and oxycodone in patients with moderate to severe osteoarthritis (OA) or low back pain. Methods. This was a post hoc analysis of two multicenter, randomized, double-blind studies (10-day and 90-day) that evaluated the efficacy and safety of tapentadol IR in patients with moderate-severe OA pain. PRT was defined as adequate pain reduction (30% or 50% pain intensity improvement from baseline) and no gastrointestinal AE or other type of treatment-emergent AE. The percentage of patients and mean number of days per patient meeting the PRT criteria were summarized. Results. In the 10-day trial, the percentages of patients meeting PRT criteria (30% reduction) for both tapentadol groups were consistently above that for oxycodone 10?mg, although only significantly different for the 50?mg formulation. The mean number of days per patient meeting the PRT criteria was 3.7, 3.2, and 2.3 days for tapentadol 50?mg, 75?mg and oxycodone 10?mg, respectively. No significant difference between the groups was observed using the 50% pain reduction criterion. For the 90-day trial, using multiple definitions, tapentadol IR showed a significantly higher proportion of days meeting PRT criteria. Conclusion. Pain reduction and tolerability are both important attributes of an effective analgesic treatment. Based on data from two trials, tapentadol IR produced an improved PRT balance compared with oxycodone IR.     

An Overview of the Efficacy and Tolerability of New Antiepileptic Drugs

Summary: To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo-controlled, randomized controlled trials (RCTs) of the AEDs as add-on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a ≥50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between-drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.