Christine N. Sang

Diagnostic criteria for schwannomatosis

The neurofibromatoses are a diverse group of genetic conditions that share a predisposition to the development of tumors of the nerve sheath. Schwannomatosis is a recently recognized third major form of neurofibromatosis (NF) that causes multiple schwannomas without vestibular tumors diagnostic of NF2. Patients with schwannomatosis represent 2.4 to 5% of all patients requiring schwannoma resection and approximately one third of patients with schwannomatosis have anatomically localized disease with tumors limited to a single limb or segment of spine. Epidemiologic studies suggest that schwannomatosis is as common as NF2, but that familial occurrence is inexplicably rare. Patients with schwannomatosis overwhelmingly present with pain, and pain remains the primary clinical problem and indication for surgery. Diagnostic criteria for schwannomatosis are needed for both clinicians and researchers, but final diagnostic certainly will await the identification of the schwannomatosis locus itself.

Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials.

Background There are few repeated dose-controlled trials of N-methyl-d-aspartate glutamate receptor antagonists in patients with neuropathic pain. The authors sought to evaluate two low-affinity N-methyl-d-aspartate antagonists using a novel two-stage design. Methods The authors studied patients with painful diabetic neuropathy (DN) and postherpetic neuralgia (PHN) in two crossover trials: (1) efficacy trial (dextromethorphan vs. memantine vs. active placebo [lorazepam]) and (2) dose–response trial of the preferred active drug in responders from the first study (0%vs. 25%vs. 50%vs. 100% of each patients maximally tolerated dose). Pain intensity was measured on a 20-point scale. Results Nineteen of 23 DN patients and 17 of 21 PHN patients completed the efficacy trial. Median doses for DN and PHN were 400 and 400 mg/day dextromethorphan, 55 and 35 mg/day memantine, and 1.8 and 1.2 mg/day lorazepam. In the efficacy trial, among patients with DN, dextromethorphan reduced pain intensity by a mean of 33% from baseline, memantine reduced pain intensity by a mean of 17%, and lorazepam reduced pain intensity by a mean of 16%; the proportions of subjects achieving greater than moderate pain relief were 68% with dextromethorphan, 47% with memantine, and 37% with lorazepam. Mean reductions in pain intensity in patients with PHN were 6% with dextromethorphan, 2% with memantine, and 0% with lorazepam. No comparison with placebo reached statistical significance in the efficacy trial. In the 10 DN subjects who responded to dextromethorphan, there was a significant dose–response effect on pain intensity (P = 0.035), with the highest dose significantly better than that of lorazepam (P = 0.03). Conclusions Dextromethorphan is effective in a dose-related fashion in selected patients with DN. This was not true of PHN, suggesting a difference in pain mechanisms. Selective approaches to pain-relevant N-methyl-d-aspartate receptors are warranted.

LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine.

Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age ± SD = 40 ± 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.

NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials.

Recent clinical data suggest that chronic pain due to nerve or soft tissue injury may result in the sensitization of the central nervous system, mediated in part by the excitatory amino acids, glutamate and aspartate. Only a handful of N-methyl-D-aspartate antagonists are clinically available. These include ketamine, dextromethorphan, memantine, and amantadine, as well as three clinically used opioids (methadone, dextropropoxyphene, and ketobemidone). This review summarizes the single-dose efficacy of the first two compounds in the treatment of experimental and neuropathic pain. In all examples presented here, NMDA-receptor antagonists with affinity at the phencyclidine site have been shown to modulate pain and hyperalgesia but are limited by dose-limiting side effects. Thus, provided their therapeutic ratio is favorable, NMDA-receptor antagonists may be effective in the treatment of some types of chronic pain.

AMPA/Kainate Antagonist LY293558 Reduces Capsaicin-evoked Hyperalgesia but Not Pain in Normal Skin in Humans

Background Animal studies suggest that [small alpha, Greek]‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid‐kainate (AMPA‐KA) receptors are involved in pain processing. The effects of the competitive AMPA‐KA antagonist LY293558 in two types of experimental pain in human volunteers, brief pain sensations in normal skin, and mechanical allodynia‐pinprick hyperalgesia were studied after the injection of intradermal capsaicin. Methods Brief intravenous infusions of the competitive AMPA‐KA antagonist LY293558 were given to 25 healthy volunteers to examine acute toxicity and analgesic effects. Fifteen volunteers then entered a double‐blinded, three‐period crossover study. In a Phase II study, LY293558 infusions (100% maximally tolerated dose vs. 33% maximally tolerated dose vs. placebo) began 10 min after intradermal injection of 250 [micro sign]g capsaicin in volar forearm. Spontaneous pain, areas of mechanical allodynia and pinprick hyperalgesia, and side effects were determined every 5 min for 60 min. Results The median maximally tolerated dose was 1.3 +/− 0.4 (range, 0.9‐2.0) mg/kg. Tests of cognitive and neurological function were unchanged. Dose‐limiting side effects were hazy vision in 95% of volunteers and sedation in 40%. There were no significant changes in electrical or warm‐cool detection and pain thresholds or heat pain thresholds. LY293558 had little effect on brief pain sensations in normal skin. Both high and low doses of LY293558 significantly reduced pain intensity, pain unpleasantness, and the area in which light brush evoked pain after intradermal capsaicin. There was a trend toward a dose‐response effect of LY293558 on the area in which pinprick evoked pain after intradermal capsaicin, which did not reach statistical significance. Conclusions The authors infer that AMPA‐KA receptor blockade reduces the spinal neuron sensitization that mediates capsaicin‐evoked pain and allodynia. The low incidence of side effects at effective doses of LY293558 suggests that this class of drugs may prove to be useful in clinical pain states.

The Role of Fluoroscopy in Cervical Epidural Steroid Injections : An Analysis of Contrast Dispersal Patterns

Study Design. A multicenter, retrospective analysis of cervical epidurograms. Objectives. To determine the effectiveness of the loss of resistance (LOR) technique in identifying the cervical epidural space. To delineate the pattern of epidural contrast spread during cervical epidural steroid injections. Background. Previous studies have shown that if performed without fluoroscopy, the LOR technique can result in inaccurate needle placement in up to 30% of lumbar epidural steroid injections. To date, no study has examined accuracy of LOR technique and pattern of radiographic contrast spread in cervical epidural levels. Methods. Epidurograms of 38 cervical epidural steroid injections in 31 patients were reviewed. The number of LOR attempts and pattern of contrast spread was analyzed. The effects of age, gender, MRI results, previous cervical laminectomy, and the physician’s level of training were correlated with results. Results. The authors found a 53% rate of false LOR during the first attempt to enter the epidural space. Unilateral epidural contrast spread was found in 51% and ventral epidural spread was found in 28% of cases. The average number of cervical vertebral levels covered with 2 mL of contrast was 3.14, with significantly wider spread noted in those patients who had not undergone previous cervical laminectomy. Other variables did not influence the accuracy of needle placement and pattern of epidural contrast spread. Conclusions. The loss of resistance technique may not be an adequate method for ensuring accurate needle placement in blindly performed cervical epidural injections. The use of epidurography can improve the accuracy of needle placement and medication delivery to targeted areas of pathology.

The Technical Aspects of Epidural Steroid Injections: A National Survey

UNLABELLED Although epidural steroid injections (ESIs) are a common treatment for chronic pain conditions, it is not clear whether there is consensus on their technical aspects. The current literature suggests that variations in technical aspects may affect ESI outcomes. The goal of the survey was to help establish a standard frame of reference for the performance of ESIs. We analyzed survey results from 68 academic anesthesia programs and 28 private practices in the United States. The main finding in this survey is that there is no clear-cut consensus as to the ideal method to perform ESI. There is a wide variation among individual practices in almost every technical aspect of ESI. Private practices use significantly more fluoroscopy than academic centers. The large difference was found in the cervical region where 73% of private practices and only 39% of academic institutions polled perform the ESIs with fluoroscopic guidance (P = 0.005). A similar discrepancy was found in approaches to the epidural space after laminectomy where 61% of private practices, but only 15% of academic centers, use the transforaminal approach. The study results indicate that there is no consensus, and that there is a wide variation in current practices. IMPLICATIONS A national survey of practices performing epidural steroid injections was conducted. The purpose was to establish whether consensus exists on technical aspects of this procedure. The study results indicate that there is no consensus, and that there is a wide variation in current practices.

Duloxetine for the Management of Diabetic Peripheral Neuropathic Pain: Evidence-Based Findings from Post Hoc Analysis of Three Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Studies

OBJECTIVE This post hoc analysis was aimed to summarize the efficacy and tolerability of duloxetine as represented by number needed to treat (NNT) and number needed to harm (NNH) to provide a clinically useful assessment of the position of duloxetine among current agents used to treat diabetic peripheral neuropathic pain (DPNP). METHODS Data were pooled from three 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which patients received 60 mg duloxetine either QD or BID or placebo. NNT was calculated based on rates of response (defined as >or=30% and >or=50% reductions from baseline in the weekly mean of the 24-hour average pain severity scores); NNH was calculated based on rates of discontinuation due to adverse events (AEs). RESULTS Patients receiving duloxetine 60 mg QD and 60 mg BID had NNTs (95% CI) of 5.2 (3.8-8.3) and 4.9 (3.6-7.6), respectively, based on last observation carried forward; NNTs of 5.3 (3.8-8.3) for 60 mg QD and 5.7 (4.1-9.7) for 60 mg BID were obtained based on baseline observations carried forward. The NNHs (95% CI) based on discontinuation due to AEs were 17.5 (10.2-58.8) in the duloxetine 60-mg QD group and 8.8 (6.3-14.7) in the 60-mg BID group. CONCLUSION These post hoc results suggest that duloxetine was effective and well tolerated for the management of DPNP and further support the importance of duloxetine as a treatment option for clinicians and patients to assist with the management of DPNP.

Capsaicin-evoked mechanical allodynia and hyperalgesia cross nerve territories. Evidence for a central mechanism.

Background The finding in some patients with neuropathic pain that mechanical allodynia (pain evoked by light touch) and hyperalgesia (supranormal pain evoked by painful stimuli) extend beyond the territory of a single nerve or spinal sensory root (extraterritorial pain) often prompts a diagnosis of psychiatric illness. The hypothesis that focal nociceptive input in a single nerve territory can result in allodynia and hyperalgesia in a nerve territory adjacent to the input was investigated in normal human subjects. Methods On separate days, 13 healthy volunteers each received left radial and ulnar nerve blocks. After block of either nerve, sensation remaining for three classes of afferents (A beta low-threshold mechanoreceptors, A delta nociceptors, and C polymodal nociceptors) allowed inference of the nerve territory of the adjacent nerve, and the area of overlapping innervation. On a third day, 1,000 micro gram intradermal capsaicin was administered into a site such that C-nociceptor input was confined to the ulnar nerve territory. Areas of brush allodynia and pinprick hyperalgesia were determined. Results Spread of brush allodynia beyond all three borders of the ulnar nerve territory occurred in 9 of 13 patients (for these subjects, range 5-28 mm), whereas spread of pinprick hyperalgesia beyond all borders of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm). Spread of brush allodynia beyond the A beta border of the ulnar nerve territory occurred in 10 of 13 subjects (range 4-35 mm); and spread of pinprick hyperalgesia beyond the A delta border of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm). Conclusions It is concluded that activation of C-nociceptors evokes a state of central sensitization that may manifest itself by the appearance of extraterritorial pain abnormalities.

Etiologic factors in renovascular fibromuscular dysplasia. A case-control study.

The role of several factors that have been suggested as being of etiologic importance in renovascular fibromuscular dysplasia was examined in a case-control study of 33 patients with angiographically demonstrated fibromuscular dysplasia and 61 renal transplant donor control subjects with normal renal arteries. The factors studied included use of oral contraceptive agents or markers of sex hormone dysfunction, mechanical stress to the renal artery wall, human lymphocytic antigen (HLA) type, cigarette smoking, history of hypertension for more than 5 years, and family history of cardiovascular disease. The risk of fibromuscular dysplasia was significantly (p = 0.003) increased (odds ratio = 4.1, 95% confidence interval = 1.5-10.9) among cigarette smokers. A significant (p less than 0.001) dose-response relation was noted between cigarette use and the risk of fibromuscular dysplasia developing (odds ratio = 8.6 for those who had smoked more than 10 pack-years). Personal history of hypertension more than 5 years was also associated (odds ratio = 5.0, 95% confidence interval = 1.1-22.8) with a significantly (p = 0.036) increased risk for the development of fibromuscular dysplasia. HLA-DRw6 antigen was more common in the 33 fibromuscular dysplasia patients than in the 61 renal transplant donor control subjects (odds ratio = 3.00, p = 0.067) or a second group of 934 ambulatory control subjects (odds ratio = 2.51, p = 0.031). Adjustment for cigarette smoking increased the odds ratio to 5.0 (95% confidence interval = 1.3-19.6). There was a positive though not statistically significant (odds ratio = 1.7, p = 0.175) association noted between family history of cardiovascular disease and fibromuscular dysplasia.(ABSTRACT TRUNCATED AT 250 WORDS)