The Effect of Gabapentin Enacarbil on Pain Associated with Moderate-to-Severe Primary Restless Legs Syndrome in Adults: Pooled Analyses from Three Randomized Controlled Trials.

BACKGROUND: Adults with moderate-to-severe primary restless legs syndrome (RLS) often experience painful dysesthesias, which may lead to impaired quality of life. OBJECTIVES: The aim of this study was to assess the effects of gabapentin enacarbil (GEn) on pain associated with moderate-to-severe primary RLS in adults. METHODS: Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials (NCT00298623, NCT00365352, NCT01332305) for adults receiving GEn or placebo once daily. Change in average daily RLS pain score and a combined International Restless Legs Scale (IRLS)-pain response were examined. RESULTS: The modified intention-to-treat population included 671 adults (placebo, n = 244; GEn 600 mg, n = 161; GEn 1200 mg, n = 266). Both GEn doses significantly improved average daily RLS pain score at week 12 (p < 0.001 for GEn 600 mg vs. placebo and GEn 1200 mg vs. placebo). The combined IRLS-pain response subanalysis included 366 patients with a baseline IRLS total score ≥15 and pain score ≥4 (placebo, n = 133; GEn 600 mg, n = 86; GEn 1200 mg, n = 147). Most patients were both IRLS and pain responders (placebo, 40 %; GEn 600 mg, 70 %; GEn 1200 mg, 67 %). Spearman rank correlations between IRLS total and pain score (change from baseline to week 12) were moderate or strong. The most frequent treatment-emergent adverse events were somnolence (placebo, 5 %; GEn 600 mg, 20 %; GEn 1200 mg, 23 %) and dizziness (placebo, 4 %; GEn 600 mg, 13 %; GEn 1200 mg, 22 %). CONCLUSIONS: This post hoc pooled analysis suggests that GEn (600 and 1200 mg) once daily significantly improved pain associated with moderate-to-severe primary RLS in adults; however, the analysis was not powered to detect statistical differences between the two GEn doses. Numerically, more GEn-treated patients had a combined IRLS-pain response than placebo-treated patients.

Long-term safety of gastroretentive gabapentin in postherpetic neuralgia patients.

OBJECTIVE: This study evaluated the long-term safety and tolerability of a gastroretentive formulation of gabapentin (G-GR) and its effect on weight gain in postherpetic neuralgia (PHN) patients participating in a 14-week, open-label extension to a 10-week double-blind study. METHODS: Patients with PHN ≥ 3 months, who had completed participation in a phase 3 randomized, double-blind, placebo-controlled study of the safety and efficacy of G-GR in PHN, who wished to continue treatment with G-GR, and who the investigator thought would benefit from study participation received G-GR 1800 mg as an asymmetrically divided dose (600 mg AM/1200 mg PM) for an additional 14 weeks. Analyses were performed on safety data from patients who received G-GR for 10 weeks in the randomized controlled study and who then received an additional 14 weeks of G-GR, asymmetrically dosed in the current study. Safety assessments included the incidence and severity of adverse events (AEs), the occurrence of serious AEs, changes in physical and neurological examination findings, clinical laboratory assessments, and changes in weight. RESULTS: Eighty patients treated with G-GR in the randomized, controlled study participated in this 14-week extension study. The incidence of AEs commonly observed with gabapentin (dizziness, somnolence) was low and the frequency, intensity, and severity of AEs did not change with long-term treatment. The mean weight change from baseline in the randomized controlled study to the end of the extension study was +0.76 kg. Weight increase was reported as an AE for 2 (2.5%) patients. CONCLUSIONS: Long-term treatment (up to 24 wk) with G-GR of 1800 mg was well tolerated and associated with little weight gain (< 1 kg) in patients with PHN. No new safety issues emerged with G-GR long-term treatment.

Once-daily gastroretentive gabapentin for postherpetic neuralgia: integrated efficacy, time to onset of pain relief and safety analyses of data from two phase 3, multicenter, randomized, double-blind, placebo-controlled studies.

CONTEXT: Treatment options for postherpetic neuralgia (PHN), a complication of herpes zoster, are commonly unsatisfactory and associated with adverse events. OBJECTIVES: To evaluate the efficacy, onset of pain relief, and safety of gastroretentive gabapentin (G-GR) in patients with PHN. METHODS: In two placebo-controlled studies, 357 patients with PHN were randomized to 1800mg G-GR and 364 patients were randomized to placebo taken with the evening meal. Patients underwent a two week titration, eight weeks of stable dosing, and one week of tapering. Efficacy assessments included change in average daily pain (ADP) score from baseline to Week 10, time to onset of pain relief, the proportion of patients feeling improved using the Patient Global Impression of Change, and the proportion of responders (≥30% pain reduction). RESULTS: At Week 10, patients randomized to G-GR reported greater reductions in ADP score compared with placebo (-37.0% vs. -29.1; P=0.0025). More G-GR patients felt improved compared with placebo (44% vs. 33%; P=0.003) and responded to treatment (54% vs. 41%; P=0.001). As early as Day 2, greater pain reductions were observed for the G-GR group compared with the placebo group (-6.6% vs. -1.6%; P=0.0017). The median time to a one point or greater reduction in ADP score was four days for G-GR and six days for placebo (P<0.0001). The most frequently reported adverse events were dizziness (G-GR, 11%; placebo, 2%) and somnolence (G-GR, 5%; placebo, 3%). CONCLUSION: PHN pain reduction after G-GR treatment can be observed as early as the second day of dosing and continues for at least 10 weeks.

Tolerability and safety of gastroretentive once-daily gabapentin tablets for the treatment of postherpetic neuralgia.

OBJECTIVE: An immediate-release formulation of gabapentin is approved for treatment of postherpetic neuralgia (PHN). This formulation, however, requires multiple daily dosing, usually three times per day, and is associated with a high incidence of somnolence and dizziness. We assessed the tolerability and safety of a once-daily gastroretentive formulation of gabapentin (G-GR) in phase 3 clinical trials in patients with PHN. RESEARCH DESIGN AND METHODS: Data were pooled from two placebo-controlled studies involving 723 patients (G-GR 1800 mg, n = 359; placebo, n = 364). Patients (43% male, mean age 66 years) with PHN pain >4 (0-10 scale) for ≥3 months were enrolled. Summary statistics for the incidence of treatment-emergent adverse events (AEs) were performed. Laboratory parameters and vital signs were assessed. RESULTS: Treatment-emergent AEs were reported in 48% of patients (G-GR, 54%; placebo, 42%) and led to discontinuation in 8% of patients (G-GR, 10%; placebo, 7%). The most frequent (≥3% in any group) AEs were dizziness (G-GR, 11%; placebo, 2%), somnolence (G-GR, 5%; placebo, 3%), headache (G-GR, 4%; placebo, 4%), peripheral edema (G-GR, 4%; placebo, <1%), and diarrhea (G-GR, 3%; placebo, 3%). Serious AEs were reported in seven patients in the G-GR group (2%) and ten patients in the placebo group (3%). There were two deaths, both in the placebo group. No serious AEs were considered related to treatment. Mean values for laboratory parameters and vital signs at the end of each study were similar between groups. CONCLUSION: G-GR was safe and well tolerated for the treatment of PHN.

Once-daily gastroretentive gabapentin for the management of postherpetic neuralgia: an update for clinicians.

Gabapentin was originally developed as an add-on anticonvulsant drug, but has been widely used in the USA for the management of postherpetic neuralgia since its approval for this indication in 2002. Gabapentin has a short elimination half life and limited absorption due to a saturable L-amino acid transport system, which is expressed predominantly in the proximal small intestine. Hence, the original immediate-release gabapentin formulation (gabapentin TID) must usually be taken three times a day for optimal efficacy. Gabapentin TID is also associated with a high incidence of dizziness and somnolence and some patients are unable to tolerate the doses required for maximum pain relief. A once-daily, gastroretentive formulation of gabapentin was recently approved by the US Food and Drug Administration (FDA) for the management of postherpetic neuralgia. This formulation provides gradual release of gabapentin to the optimal site of absorption in the proximal small intestine and reduces the chance of saturating intestinal uptake, thus enabling once-daily dosing of gabapentin. This gradual release and absorption have been demonstrated in pharmacokinetic studies in healthy subjects. The efficacy of once-daily gastroretentive gabapentin for the management of postherpetic neuralgia has been demonstrated in placebo-controlled clinical studies. In addition, data from these studies suggest that the incidence of dizziness and somnolence may be reduced compared with similar studies using gabapentin TID. This article provides an overview of the pharmacokinetics, efficacy, and safety of once-daily gastroretentive gabapentin for the management of postherpetic neuralgia.

NGX-4010, a capsaicin 8% dermal patch, administered alone or in combination with systemic neuropathic pain medications, reduces pain in patients with postherpetic neuralgia.

OBJECTIVES: Analyses of integrated data from 4 controlled postherpetic neuralgia studies evaluated the effect of NGX-4010, a capsaicin 8% patch, administered alone or together with systemic neuropathic pain medications. METHODS: Patients recorded their "average pain for the past 24 hours" daily for 12 weeks using an 11-point Numeric Pain Rating Scale (NPRS). Efficacy assessment included the percentage NPRS score reduction from baseline during weeks 2 to 8 and 2 to 12, the proportion of patients responding during weeks 2 to 8 and 2 to 12 and the Patient Global Impression of Change (PGIC) at weeks 8 and 12. RESULTS: During the studies, 302 NGX-4010 and 250 control (capsaicin, 0.04% wt/wt) patients were using at least 1 systemic neuropathic pain medication; 295 NGX-4010 and 280 control patients were not. During weeks 2 to 8, NGX-4010 patients reported greater reductions in NPRS scores compared with control both in patients using systemic neuropathic pain medications (26.1% vs. 18.1%, P=0.0011) and in patients not using these medications (36.5% vs. 26.2%, P=0.0002). Patients not using systemic neuropathic pain medications reported a greater reduction in pain compared with patients using these medications in both, NGX-4010 and control groups, resulting in comparable treatment differences between NGX-4010 and control regardless of systemic neuropathic pain medication use. Similar results were seen during weeks 2 to 12, for the responder and PGIC analyses. Transient, capsaicin-related application site reactions were the most common adverse events and not affected by systemic neuropathic pain medication use. CONCLUSION: A single 60-minute NGX-4010 treatment reduces PHN for up to 12 weeks regardless of concomitant systemic neuropathic pain medication use.

Once-daily gastroretentive gabapentin for treatment of postherpetic neuralgia.

SUMMARY The immediate-release formulation of gabapentin (gabapentin three-times daily) is approved for treatment of postherpetic neuralgia (PHN). Although it has a low propensity for drug-drug interactions, it requires multiple daily dosing and is associated with a high frequency of dizziness and somnolence. A once-daily formulation of gabapentin was recently approved for the treatment of PHN. This formulation employs a gastroretentive technology to provide a prolonged release of gabapentin. Clinical studies have confirmed the efficacy of once-daily, gastroretentive gabapentin in the treatment of PHN. In addition, these studies have suggested that the rate of dizziness and somnolence may be reduced compared with similar studies using gabapentin three-times daily. This article reviews key aspects of the pharmacology, efficacy and safety of once-daily gabapentin in the treatment of PHN.

Management of chronic noncancer pain in depressed patients.

Many patients with chronic noncancer pain present with comorbid depression, which can greatly complicate the treatment of pain. Chronic pain and depression each increase the risk of licit and illicit substance abuse, including the abuse of opioids, and of suicide. Patients attempting suicide may overdose on opioids, which are commonly perceived as potentially harmful, or acetaminophen, an agent that is believed to be safe but is actually the leading cause of liver failure in the United States. Opioids, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs) have the potential to interact with antidepressants, and their adverse effects may be exacerbated by alcohol use, which is also common in patients with depression. Topical NSAIDs, capsaicin, and lidocaine provide effective analgesia for several pain conditions. These agents limit systemic drug exposure, reducing the risk of systemic adverse events without risk of accidental or deliberate overdose. However, use of topical agents is generally limited to localized pain syndromes and therefore does not substantially eliminate the need for systemic analgesics in those patients with diffuse persistent pain, central sensitization, and opioid-responsive pain. This review will discuss the challenges associated with treating chronic pain in depressed patients and will provide recommendations for optimizing treatment.

Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison.

OBJECTIVE: To determine whether duloxetine is noninferior to (as good as) pregabalin in the treatment of pain associated with diabetic peripheral neuropathy. PATIENTS AND METHODS: We performed a 12-week, open-label study of patients with diabetic peripheral neuropathic pain who had been treated with gabapentin (≥ 900 mg/d) and had an inadequate response (defined as a daily pain score of ≥ 4 on a numerical rating scale [0-10 points]). The first patient was enrolled on September 28, 2006, and the last patient visit occurred on August 26, 2009. Patients were randomized to duloxetine monotherapy (n=138), pregabalin monotherapy (n=134), or a combination of duloxetine and gabapentin (n=135). The primary objective was a noninferiority comparison between duloxetine and pregabalin on improvement in the weekly mean of the diary-based daily pain score (0- to 10-point scale) at end point. Noninferiority would be declared if the mean improvement for duloxetine was no worse than the mean improvement for pregabalin, within statistical variability, by a margin of -0.8 unit. RESULTS: The mean change in the pain rating at end point was -2.6 for duloxetine and -2.1 for pregabalin. The 97.5% lower confidence limit was a -0.05 difference in means, establishing noninferiority. As to adverse effects, nausea, insomnia, hyperhidrosis, and decreased appetite were more frequent with duloxetine than pregabalin; insomnia, more frequent with duloxetine than duloxetine plus gabapentin; peripheral edema, more frequent with pregabalin than with duloxetine; and nausea, hyperhidrosis, decreased appetite, and vomiting, more frequent with duloxetine plus gabapentin than with pregabalin. CONCLUSION: Duloxetine was noninferior to pregabalin for the treatment of pain in patients with diabetic peripheral neuropathy who had an inadequate pain response to gabapentin. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00385671.

A randomized, placebo-controlled phase 3 trial (Study SB-767905/013) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain.

UNLABELLED: The balance between the pain relief provided by opioid analgesics and the side effects caused by such agents is of particular significance to patients who take opioids for the long-term relief of non-cancer pain. The spectrum of signs and symptoms affecting the gastrointestinal (GI) tract associated with opioid use is known as opioid-induced bowel dysfunction. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist, approved in the US for the management of postoperative ileus in patients undergoing bowel resection (short-term, in-hospital use only). Alvimopan was under clinical development for long-term treatment of opioid-induced constipation (OIC) but this program has been discontinued. This double-blind, placebo-controlled trial, part of the former OIC development program, enrolled patients (N = 485) receiving opioids for non-cancer pain. Patients were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo, for 12 weeks. The primary efficacy endpoint was the proportion of patients who experienced ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period, and an average increase from baseline of ≥ 1 SBM per week. There were greater proportions of SBM responders in both alvimopan treatment groups (63% in both groups) compared with placebo (56%), although these differences were not statistically significant. Secondary efficacy analyses indicated that alvimopan was numerically superior to placebo in improving opioid-induced bowel dysfunction symptoms and patients' global assessment of opioid-induced bowel dysfunction, and reduced the requirement for rescue laxatives. Active treatment was well tolerated and alvimopan did not antagonize opioid analgesia. PERSPECTIVE: Although the primary endpoint was not met in this study, the magnitude of alvimopan-induced improvements versus baseline, together with previous study results, suggest that a PAM-OR antagonist has the potential to improve OIC.

A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia.

OBJECTIVES: To confirm the efficacy, tolerability, and safety of NGX-4010, an 8% capsaicin dermal patch (capsaicin 640 µg/cm(2) ), in patients with postherpetic neuralgia (PHN). PHN is a chronic pain disorder that can be difficult to treat and for which current treatment options are often limited by poor tolerability. DESIGN: A total of 418 patients were randomized to receive a single 60-minute application of NGX-4010 or a 0.04% capsaicin control patch (3.2 µg/cm(2) ) in a multicenter, double-blind, confirmatory, phase 3 study. PATIENTS: Patients were 18-90 years old with a diagnosis of PHN, pain for at least 6 months, and an average baseline Numeric Pain Rating Scale (NPRS) score of 3-9. OUTCOME MEASURES: The primary efficacy end point was the percentage change in NPRS score from baseline to weeks 2-8. RESULTS: NGX-4010 recipients had a significantly greater mean reduction from baseline in pain during weeks 2-8 compared with the control group (32.0% vs 24.4%; P=0.011). A ≥ 30% reduction in mean NPRS scores was achieved in 46% of NGX-4010 recipients compared with 34% of controls (P=0.02). Pain was significantly lower in NGX-4010 recipients than controls by week 2, and greater pain reduction was maintained throughout the remaining 12-week study period. Most treatment-emergent adverse events were application site specific (notably erythema and pain), transient, and generally mild to moderate in severity. CONCLUSIONS: In patients with PHN, a single 60-minute application of NGX-4010 produced significant reduction in pain that was maintained over a 12-week period.

The placebo response: relationship to outcomes in trials of postherpetic neuralgia.

Placebo responses in controlled studies of neuropathic pain, including postherpetic neuralgia, have increased in recent years and may obscure benefits of potential treatments. Investigations of the basis of the placebo effect have revealed some of the anatomical and physiological substrates for these responses. Placebo responses are accompanied by changes in activity in brain regions involved in analgesia, pain processing, reward and emotion, and they involve neurotransmitters with well established roles in pain modulation, including opioids and cholecystokinin. These findings may eventually provide useful suggestions for limiting placebo responses in clinical trials as identification of the cues that contribute to placebo responses could conceivably permit their avoidance in the design of clinical studies. Analyses of the characteristics of clinical trials in neuropathic pain have revealed some factors that might also help explain the increase in placebo responses. These factors include the longer duration of contemporary trials and recruitment practices of high-enrolling study centres. In trials of patients with postherpetic neuralgia, inclusion of patients with a short duration of post-zoster pain can result in a high rate of spontaneous remission that can contribute to an apparent 'placebo response'. Future placebo-controlled trials of treatments for postherpetic neuralgia may need to consider modifications of the design and conduct of these studies to maximize the chance of obtaining valid study results.

Gabapentin extended-release tablets for the treatment of patients with postherpetic neuralgia: a randomized, double-blind, placebo-controlled, multicentre study.

BACKGROUND: Postherpetic neuralgia (PHN) is a neuropathic pain syndrome that may develop subsequent to healing of herpes zoster rash. OBJECTIVES: This study aimed to determine the efficacy and safety of gabapentin extended-release (gabapentin ER) tablets for the treatment of patients with PHN and to determine whether optimal benefits might be achieved with once-daily (QD) or divided-dose (DD) administration. METHODS: This was a 10-week, randomized, double-blind, placebo-controlled, multicentre trial comparing gabapentin ER (total daily dose 1800 mg) either QD or as an asymmetrical DD with placebo in 407 patients with post-zoster pain for >or=3 months and a baseline average daily pain score (ADP)>or=4 on a 0-10 Likert numerical rating scale. The primary efficacy outcome was the ADP score mean change from baseline to week 10 using baseline observation carried forward (BOCF). Secondary efficacy outcomes included changes to week 10 in last observation carried forward (LOCF) ADP score, LOCF average daily sleep interference score, Short-Form McGill Pain Questionnaire score, Neuropathic Pain Scale score, and Brief Pain Inventory score. RESULTS: Of 407 randomized patients, 400 were included in the intent-to-treat population (gabapentin ER QD, n=134; gabapentin ER DD, n=135; placebo, n=131). Between-group differences in the least squares (LS) mean changes in BOCF ADP scores did not reach statistical significance (gabapentin ER QD -1.85 [p=0.110 vs placebo]; gabapentin ER DD -1.72 [p=0.255 vs placebo]; placebo -1.42). In the LOCF analysis, the LS mean ADP score for the gabapentin ER QD group, but not for the DD group, improved compared with placebo (gabapentin ER QD, -2.28; p=0.032 vs placebo). Improvements compared with placebo were also observed in the gabapentin ER QD group, but not for the DD group, for mean daily sleep interference scores (gabapentin ER QD, -2.49; placebo, -1.63; p<0.001). Most adverse events (AEs) were mild or moderate. Among gabapentin-treated patients, 12% and 11% withdrew due to AEs, most commonly for dizziness (2% and 3%), in the gabapentin ER QD and DD groups, respectively. Treatment-related AEs in the gabapentin ER-treated groups occurred in 31% of patients. The most common AEs in the gabapentin ER QD and DD groups included dizziness (10% and 15%), headache (4% and 7%), somnolence (3% and 7%) and peripheral oedema (5% and 5%), respectively. CONCLUSION: The primary efficacy endpoint for this study of gabapentin ER was not met, most likely due to the unexpectedly large placebo response. Outcomes on secondary endpoints suggest the potential efficacy of gabapentin ER QD. Gabapentin ER was well tolerated in this study. [Clinicaltrials.gov identifier NCT00335933].

Multimodal analgesia for chronic pain: rationale and future directions.

Chronic pain is a multifaceted disease requiring multimodal treatment. Clinicians routinely employ various combinations of pharmacologic, interventional, cognitive-behavioral, rehabilitative, and other nonmedical therapies despite the paucity of robust evidence in support of such an approach. Therapies are selected consistent with the biopsychosocial model of chronic pain, reflecting the subjective nature of the pain complaint, and the myriad stressors that shape it. Elucidating mechanisms that govern normal sensation in the periphery has provided insights into the biochemical, molecular, and neuroanatomic correlates of chronic pain, an understanding of which is leading increasingly to mechanism-specific multidrug therapies. Peripheral and central neuroplastic reorganization underlying the disease of chronic pain is influenced by patient-specific emotions, cognition, and memories, further impairing function and idiosyncratically defining the illness of chronic pain. Clinical perceptions of these and related subjective elements associated with the suffering of chronic pain drive psychosocial treatments, including, among other options, relaxation therapies, coping skills development, and cognitive-behavioral therapy. Treatment selection is thus guided by comprehensive assessment of the phenomenology and inferred pathophysiology of the pain syndrome; patient goals, preferences, and expectations; behavioral, cognitive, and physical function; and level of risk. Experiential, practice-based evidence may be necessary for improving patient care, but it is insufficient; certainly, well-designed studies are needed to support therapeutic decision making. This review will discuss the biochemical basis of pain, factors that govern its severity and chronicity, and foundational elements for current and emerging multimodal treatment strategies.

Quantitative sensory testing and mapping: a review of nonautomated quantitative methods for examination of the patient with neuropathic pain.

OBJECTIVES: Despite a growing interest in neuropathic pain, neurologists and pain specialists do not have a standard, validated, office examination for the evaluation of neuropathic pain signs to complement the neurologic, musculoskeletal, and general physical examinations. An office neuropathic pain examination focused on quantifying sensory features of neuropathic pain, ranging from deficits to allodynia and hyperalgesia, and evoked by a physiologically representative array of stimuli, will be an essential tool to monitor treatment effectiveness and for clinical investigation into the mechanisms and management of neuropathic pain. Such an examination should include mapping of areas of stimulus-evoked neuropathic pain and standardized, reproducible quantitative sensory testing (QST) of tactile, punctuate, pressure, and thermal modalities. METHODS: We review quantitative sensory testing methodology in general and specific tests for the evaluation of neuropathic pain phenomena. RESULTS: Numerous quantitative sensory testing techniques for dynamic mechanical, pressure, vibration, and thermal sensory testing and mapping have been described. We propose a comprehensive neuropathic pain evaluation protocol that is based upon these available techniques. CONCLUSIONS: A comprehensive neuropathic pain evaluation protocol is essential for further advancement of clinical research in neuropathic pain. A protocol that uses tools readily available in clinical practice, when established and validated, can be used widely and thus accelerate data collection for clinical research and increase clinical awareness of the features of neuropathic pain.

Quantitative sensory testing in measurement of neuropathic pain phenomena and other sensory abnormalities.

Neuropathic pain disorders are usually characterized by spontaneous ongoing or intermittent symptoms, stimulus-evoked positive sensory phenomena, and negative sensory phenomena. Spontaneous individual subject specific phenomena are identified in the neurologic history and are quantifiable by means of self-reported neuropathic pain symptoms tools such as scales, inventories, and questionnaires. Negative and positive sensory phenomena are assessed by the neurologic bedside examination and quantitative sensory testing (QST), which refers to psychophysical tests of sensory perception during the administration of stimuli with predetermined physical properties and following specific protocols. QST is able to capture and quantify stimulus-evoked negative and positive sensory phenomena, and as such should become standard if not a critical tool in neuropathic pain research and practice. Although the advent of anatomic and functional imaging modalities is revolutionizing our understanding of the mechanisms of neuropathic pain, only by anchoring such test results to individual subjects' own perceptions via QST can they provide meaningful information about neuropathic pain, which is based on perceptual experience. To yield useful results, QST requires a cooperative subject and carefully standardized methods, including standardization of the stimulus parameters as well as the testing environment, instructions, and evaluation methods. This manuscript provides a concise review of fundamental concepts necessary for understanding the role of QST in the process of eliciting information about sensory abnormalities associated with neuropathic pain and the place of that information in analysis of pain mechanisms. Together with the companion manuscript, this review provides definitions that should help further the use of QST as a diagnostic tool as well.

Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia: results of a double-blind, randomized, placebo-controlled clinical trial.

OBJECTIVE: To determine the efficacy and safety of a gastric-retentive, extended-release gabapentin (gabapentin ER) taken once or twice daily for treatment of postherpetic neuralgia. METHODS: Using an enrichment design, a randomized, double-blind, placebo-controlled study was conducted in 158 patients who had experienced pain for at least 3 months after healing of acute herpes zoster skin rash and who had a baseline average daily pain (ADP) score of > or =4 on a 0 to 10 Numerical Rating Scale. Patients received gabapentin ER either once daily (1800 mg PM) or twice daily (600 mg AM, 1200 mg PM) or placebo for 4 weeks. Efficacy measures included changes from baseline to end point in ADP score and average daily sleep interference score. RESULTS: Mean (SEM) changes for ADP score were -1.93 (0.28), -2.24 (0.29), and -1.29 (0.29) in the gabapentin ER once daily, twice daily, and placebo groups, respectively (P=0.089 and 0.014 for gabapentin ER once daily and twice daily, respectively, vs. placebo), with 25.5%, 28.8%, and 11.8% of patients, respectively, reporting > or =50% decrease from baseline in ADP score. Mean (SEM) changes in sleep interference scores were -1.94 (0.30), -2.28 (0.30), and -1.16 (0.30), respectively (P=0.048 and 0.006 for gabapentin ER once daily and twice daily, respectively, vs. placebo). Common adverse events in the gabapentin ER once daily, twice daily, and placebo groups, respectively, were dizziness (22.2%, 11.3%, and 9.8%) and somnolence (9.3%, 7.5%, and 7.8%). CONCLUSIONS: Gabapentin ER administered twice daily is effective and safe for the treatment of pain associated with postherpetic neuralgia.

Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain.

Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with >or=25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to >or=30 mg oral morphine/day were randomized to alvimopan 0.5mg twice daily (BID), 1mg once daily (QD), 1mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5mg BID (+1.71 mean SBMs/week), alvimopan 1mg QD (+1.64) and alvimopan 1mg BID (+2.52); P<0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.

Diabetic peripheral neuropathic pain: clinical and quality-of-life issues.

Diabetic peripheral neuropathy (DPN) is estimated to be present in 50% of people living with diabetes mellitus (DM). Comorbidities of DM, such as macrovascular and microvascular changes, also Interact with DPN and affect its course. In patients with DM, DPN Is the leading cause of foot ulcers, which in turn are a major cause of amputation in the United States. Although most patients with DPN do not have pain, approximately 11% of patients with DPN have chronic, painful symptoms that diminish quality of life, disrupt sleep, and can lead to depression. Despite the number of patients affected by DPN pain, little consensus exists about the pathophysiology, best diagnostic tools, and primary treatment choices. This article reviews the current knowledge about and presents recommendations for diagnostic assessment of DPN pain based on a review of the literature.

Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain.

Despite the number of patients affected by diabetic peripheral neuropathic pain (DPNP), little consensus exists about the pathophysiology, best diagnostic tools, and primary treatment choices. Theories about the causes of DPNP are inextricably linked with the causes of diabetic neuropathles, yet most patients with such neuropathies do not experience pain. The factors that differentiate patients with pain from those without remain unknown and are the subject of much research. When choosing treatment for patients with DPNP, physicians are confronted with a myriad of choices, none of which has been shown to be effective for all patients. This article reviews the evidence for these treatments and attempts to guide physicians in choosing those treatments based on evidence from well-designed clinical trials to support their use. Two agents, duloxetine and pregabalin, are formally approved by the Food and Drug Administration for the treatment of DPNP. In addition, several other agents, including the tricyclic class of antidepressants, have been effective in clinical trials. Ultimately, treatment choice must also Include consideration of adverse effects, individual patient factors such as comorbidities, and often cost.