Predicting Treatment Response with Sensory Phenotyping in Post-Traumatic Neuropathic Pain.

OBJECTIVE: Currently available treatments for neuropathic pain are only modestly efficacious when assessed in randomized clinical trials and work for only some patients in the clinic. Induced-pain or gain-of-function phenotypes have been shown to predict response to analgesics (vs placebos) in patients with neuropathic pain. However, the predictive value of these phenotypes has never been studied in post-traumatic neuropathic pain. METHODS: Mixed-effects models for repeated measures were used to evaluate the efficacy of pregabalin vs placebo in subgroups with induced-pain phenotypes (i.e., hyperalgesia or allodynia) in data from a recent, multinational randomized clinical trial (N = 539) that identified phenotypic subgroups through the use of a structured clinical exam. RESULTS: The difference in mean pain score between the active and placebo groups (i.e., delta) after 15 weeks of treatment for the subgroup with hyperalgesia was -0.76 (P = 0.001), compared with 0.19 (P = 0.47) for the subgroup that did not have hyperalgesia. The treatment-by-phenotype interaction, which tests whether subgroups have statistically different treatment responses, was significant (P = 0.0067). The delta for the subgroup with allodynia was -0.31 (P = 0.22), compared with -0.30 (P = 0.22) for the subgroup that did not have allodynia (treatment-by-phenotype interaction P = 0.98). CONCLUSIONS: These data suggest that hyperalgesia, but not allodynia, predicts response to pregabalin in patients with chronic post-traumatic neuropathic pain. This study extends the growing data supporting the utility of induced-pain phenotypes to predict response to analgesics in post-traumatic neuropathic pain. Sensory phenotyping in large, multisite trials through the use of a structured clinical exam has the potential to accelerate the development of new analgesics and improve the generalizability of clinical trial results.

Generating differentially targeted amyloid-beta specific intrabodies as a passive vaccination strategy for Alzheimer's disease.

Amyloid-beta (A beta) has been identified as a key component in Alzheimer's disease (AD). Significant in vitro and human pathological data suggest that intraneuronal accumulation of A beta peptides plays an early role in the neurodegenerative cascade. We hypothesized that targeting an antibody-based therapeutic to specifically abrogate intracellular A beta accumulation could prevent or slow disease onset. A beta 42-specific intracellular antibodies (intrabodies) with and without an intracellular trafficking signal were engineered from a previously characterized single-chain variable fragment (scFv) antibody. The intrabodies, one with an endoplasmic reticulum (ER) targeting signal and one devoid of a targeting sequence, were assessed in cells harboring a doxycycline (Dox)-regulated mutant human amyloid precursor protein Swedish mutant (hAPP(swe)) transcription unit for their abilities to prevent A beta peptide egress. Adeno-associated virus (AAV) vectors expressing the engineered intrabodies were administered to young adult 3xTg-AD mice, a model that develops amyloid and Tau pathologies, prior to the initial appearance of intraneuronal A beta. Chronic expression of the ER-targeted intrabody (IB) led to partial clearance of A beta 42 deposits and interestingly, in reduced staining for a pathologic phospho-Tau epitope (Thr231). This approach may provide insights into the functional relevance of intraneuronal A beta accumulation in early AD and potentially lead to the development of new therapeutics.

Triple-transgenic Alzheimer's disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology.

Alzheimer's disease (AD) is a progressively debilitating brain disorder pathologically defined by extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and synaptic disintegrity. AD has not been widely considered a disease of white matter, but more recent evidence suggests the existence of abnormalities in myelination patterns and myelin attrition in AD-afflicted human brains. Herein, we demonstrate that triple-transgenic AD (3xTg-AD) mice, which harbor the human amyloid precursor protein Swedish mutant transgene, presenilin knock-in mutation, and tau P301L mutant transgene, exhibit significant region-specific alterations in myelination patterns and in oligodendrocyte marker expression profiles at time points preceding the appearance of amyloid and tau pathology. These immunohistochemical signatures are coincident with age-related alterations in axonal and myelin sheath ultrastructure as visualized by comparative electron microscopic examination of 3xTg-AD and nontransgenic mouse brain tissue. Overall, these findings indicate that 3xTg-AD mice represent a viable model in which to examine mechanisms underlying AD-related myelination and neural transmission defects that occur early during presymptomatic stages of the disease process.

Reduced Pathology and Improved Behavioral Performance in Alzheimer's Disease Mice Vaccinated With HSV Amplicons Expressing Amyloid-ß and Interleukin-4.

Immunotherapeutics designed to dissolve existing amyloid plaques or to interrupt amyloid-ß (Aß) accumulation may be feasible for treatment and/or prevention of Alzheimer's disease (AD). "Shaping" the immune responses elicited against Aß is requisite toward generating an efficacious and safe outcome; this can be achieved by minimizing the possibility of deleterious inflammatory reactions in the brain as observed in clinical testing of Aß peptide/adjuvant-based modalities. Herpes simplex virus (HSV)-based amplicons can coexpress multiple antigens and/or immunomodulatory genes due to their large genetic size capacity, thereby facilitating antigen-specific immune response shaping. We have constructed an amplicon (HSVIEAßCMVIL-4) that co-delivers Aß1-42with interleukin-4 (IL-4), a cytokine that promotes the generation of Th2-like T-cell responses, which are favored in the setting of AD immunotherapy. Triple-transgenic AD (3xTg-AD) mice, which progressively develop both amyloid and neurofibrillary tangle pathology, were vaccinated thrice with HSVIEAßCMVIL-4, or a set of control amplicon vectors. Increased Th2-related, Aß-specific antibodies, improved learning and functioning of memory, and prevention of AD-related amyloid and tau pathological progression were observed significantly more in the HSVIEAßCMVIL-4 vaccinated mice as compared to the other experimental groups. Our study underscores the potential of Aß immunotherapy for AD and highlights the potency of amplicons in facilitating the immune response modulation to a disease-relevant antigen.

Reduced pathology and improved behavioral performance in Alzheimer's disease mice vaccinated with HSV amplicons expressing amyloid-beta and interleukin-4.

Immunotherapeutics designed to dissolve existing amyloid plaques or to interrupt amyloid-beta (Abeta) accumulation may be feasible for treatment and/or prevention of Alzheimer's disease (AD). "Shaping" the immune responses elicited against Abeta is requisite toward generating an efficacious and safe outcome; this can be achieved by minimizing the possibility of deleterious inflammatory reactions in the brain as observed in clinical testing of Abeta peptide/adjuvant-based modalities. Herpes simplex virus (HSV)-based amplicons can coexpress multiple antigens and/or immunomodulatory genes due to their large genetic size capacity, thereby facilitating antigen-specific immune response shaping. We have constructed an amplicon (HSV(IE)Abeta(CMV)IL-4) that co-delivers Abeta(1-42) with interleukin-4 (IL-4), a cytokine that promotes the generation of Th2-like T-cell responses, which are favored in the setting of AD immunotherapy. Triple-transgenic AD (3xTg-AD) mice, which progressively develop both amyloid and neurofibrillary tangle pathology, were vaccinated thrice with HSV(IE)Abeta(CMV)IL-4, or a set of control amplicon vectors. Increased Th2-related, Abeta-specific antibodies, improved learning and functioning of memory, and prevention of AD-related amyloid and tau pathological progression were observed significantly more in the HSV(IE)Abeta(CMV)IL-4 vaccinated mice as compared to the other experimental groups. Our study underscores the potential of Abeta immunotherapy for AD and highlights the potency of amplicons in facilitating the immune response modulation to a disease-relevant antigen.

Extended-release gabapentin for failed back surgery syndrome: results from a randomized double-blind cross-over study.

Persistent pain after lumbar surgery (failed back surgery syndrome [FBSS]) remains a leading indication for chronic analgesia. However, no analgesics have proven efficacious for this condition. Although trials have evaluated gabapentinoids for chronic low back pain, none of these trials focused solely on FBSS. This randomized, double-blind cross-over trial evaluated the efficacy of gabapentin (1800 mg/day) for FBSS. Eligible patients had a diagnosis of FBBS, an average daily pain score of at least 4 of 10, a neuropathic pain component (indicated by the PainDetect), and reported at least half of their pain radiating in their lower extremity. Participants were randomized to 2, 7-week study periods separated by a 10-day washout. The primary outcome measure was a 0 to 10 numeric rating scale (NRS) of average pain. Secondary measures included the McGill Pain Questionnaire and Patient Global Impression of Change. The treatment effect was analyzed using a mixed effect analysis of covariance with fixed effects for treatment, period, and baseline 7-day mean NRS pain score and a random effect for the participant. The outcome of the model was the mean 7-day NRS score for the last 7 days of each treatment period. Thirty-two participants were randomized and included in the primary analysis; 25 completed both study periods. No difference was detected between treatments on any outcome measure, including the primary (least square mean difference in NRS: -0.01 confidence interval: [-0.22 to 0.20]). Given the escalating rate of complex lumbar surgery, future research to develop novel therapies for this prevalent syndrome is needed.

Evaluation of outcome measures for neurogenic claudication: A patient-centered approach.

OBJECTIVES: To determine whether patients with neurogenic claudication associated with lumbar spinal stenosis would prefer a treatment that makes it possible for them to walk farther or walk with less pain; to examine associations between this treatment preference and patient-reported and in-clinic treadmill testing measures of walking ability and walking-associated pain. METHODS: In this cross-sectional study, 269 patients with neurogenic claudication were asked to report their pain intensity when walking, complete the Swiss Spinal Stenosis Questionnaire, rank their outcome preferences for treatment, and undergo standardized treadmill testing, including measures of final pain rating and time to first pain of moderate intensity (Tfirst). Descriptive statistics were used to characterize patient preferences for treatment outcome. Associations between self-report questionnaires and standardized treadmill testing outcomes were evaluated using Spearman correlations. RESULTS: Seventy-nine percent of patients expressed a preference for treatment that allowed them to walk with less pain. Preference for reduced pain was associated with higher pain during daily walking, along with a shorter Tfirst and higher final pain severity on treadmill testing. In contrast, patient preference for treatment outcome was not associated with self-reported measures of daily walking capacity or walking distance on the treadmill. CONCLUSIONS: A majority of patients with neurogenic claudication prioritized walking with reduced pain over walking farther. Reduction in pain while walking may therefore constitute a sufficient patient-focused treatment outcome for the majority of these patients. These results have implications for clinical trial design and assessment of treatment efficacy in neurogenic claudication.

Double-blind, randomized, controlled, crossover trial of pregabalin for neurogenic claudication.

OBJECTIVES: To test the effects of pregabalin on the induction of neurogenic claudication. METHODS: This study was a randomized, double-blind, active placebo-controlled, 2-period, crossover trial. Twenty-nine subjects were randomized to receive pregabalin followed by active placebo (i.e., diphenhydramine) or active placebo followed by pregabalin. Each treatment period lasted 10 days, including a 2-step titration. Periods were separated by a 10-day washout period, including a 3-day taper phase after the first period. The primary outcome variable was the time to first moderate pain symptom (Numeric Rating Scale score ≥4) during a 15-minute treadmill test (Tfirst). Secondary outcome measures included pain intensity at rest, pain intensity at the end of the treadmill test, distance walked, and validated self-report measures of pain and functional limitation including the Roland-Morris Disability Questionnaire, modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. RESULTS: No significant difference was found between pregabalin and active placebo for the time to first moderate pain symptom (difference in median Tfirst = -1.08 [95% confidence interval -2.25 to 0.08], p = 0.61). In addition, none of the secondary outcome measures of pain or functional limitation were significantly improved by pregabalin compared with active placebo. CONCLUSIONS: Pregabalin was not more effective than active placebo in reducing painful symptoms or functional limitations in patients with neurogenic claudication associated with lumbar spinal stenosis. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with neurogenic claudication, compared with diphenhydramine, pregabalin does not increase the time to moderate pain during a treadmill test.

A Randomized, Double-blind, Placebo-Controlled Crossover Trial of Oxymorphone Hydrochloride and Propoxyphene/Acetaminophen Combination for the Treatment of Neurogenic Claudication Associated With Lumbar Spinal Stenosis.

STUDY DESIGN: Randomized, double-blind, placebo-controlled, single-dose crossover study. OBJECTIVE: To test the analgesic efficacy of oxymorphone hydrochloride (OH) and propoxyphene/acetaminophen (PA) for patients with neurogenic claudication associated with lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA: Although opioids are often prescribed for neurogenic claudication, no randomized controlled studies support their efficacy for this condition. Patients with neurogenic claudication are generally excluded from clinical trials or included with patients who have nonspecific chronic low back pain, yielding a heterogeneous study population with very different pathophysiologies and clinical presentations. METHODS: Participants received a single dose of each of the 3 treatments in random order. Treatments were separated by at least 3-day washout periods. The primary outcome variable was the time to first treadmill walking-induced moderate pain (≥4 out of 10 on a Numeric Rating Scale) (Tfirst) assessed 90 minutes after treatment administration. Secondary outcome measures included patient global assessment of low back pain, Roland-Morris Disability Questionnaire, Modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. RESULTS: The study was prematurely terminated because of the removal of PA from the US market. Twenty-four patients were randomized; 21 completed all 3 treatment periods. There were no significant differences among the treatment groups with respect to the median Tfirst (OH-placebo: median [98.3% confidence limits]=-0.25 min [-6.54, 5.00]; PA-placebo: 0.02 min [-7.65, 4.90]; OH-PA: -0.27 min [-5.56, 6.66]). CONCLUSION: This trial failed to demonstrate a benefit of OH or PA in patients experiencing neurogenic claudication. Considering the potential negative side effects of chronic opioid use, additional research is necessary to evaluate the efficacy of sustained opioid treatment specifically for neurogenic claudication. LEVEL OF EVIDENCE: 2.