Effect of low-frequency dorsal root ganglion stimulation in the treatment of chronic pain.

BACKGROUND: The role of stimulation parameters, especially stimulation frequency is not well understood in dorsal root ganglion stimulation. Previous studies documented higher effectiveness for frequencies as low as 20 Hz, but there is evidence that even lower values could lead to better outcomes. In this study, we investigate the influence of low-frequency DRG-S. METHOD: This is a randomized double-blind clinical trial with a crossover design. Patients with an already implanted DRG-S system were included and randomly tested with 4 Hz, 20 Hz, 60 Hz, and sham stimulation. Amplitude was adjusted to subthreshold values for each frequency. Each frequency was tested for 5 days, followed by a 2-day washout period. Patients were assessed using VAS, McGill Pain Questionnaire, EQ-5D-5L, and Beck Depression Inventory. RESULTS: Seventeen patients were in included. Time between inclusion in this study and primary implant was 32.8 months. Baseline stimulation frequency was 20 Hz in all patients. Mean baseline pain intensity was VAS 3.2 (SD 2.2). With 4-Hz stimulation, VAS was 3.8 (SD 1.9), with 20 Hz VAS 4.2 (SD 2.0) and with 60 Hz VAS 4.6 (SD 2.7). Worst pain control was seen with sham stimulation with a VAS of 5.3 (SD 3.0). Stimulation with 4 Hz achieved lower VAS scores, but this was only statistically significant when compared to sham (p = 0.001). A similar trend favoring 4-Hz stimulation was seen using the Beck Depression Inventory, but in this case no statistical significance was found. Outcomes of McGill Pain Questionnaire and EQ-5D-5L favored 20 Hz stimulation, but again without statistical significance. CONCLUSIONS: Low-frequency stimulation was not significantly better than classic 20-Hz stimulation in relieving pain intensity; the study might however be underpowered. Longer washout and observational periods might also be necessary to show clear differences in frequency response.

Frequency dependency of therapeutic efficacy in dorsal root ganglion stimulation for neuropathic pain.

BACKGROUND: The influence of the stimulation frequency on the outcomes of dorsal root ganglion stimulation (DRG-S) to treat pain is not well understood. It is assumed that specific neural components dedicated to different tasks in the DRG can be preferably influenced at specific frequencies. The identification of frequencies designed for the type of pain and the ratio of neuropathic versus nociceptive pain might improve overall pain control and open new indications in DRG-S. METHOD: We report on a randomized double-blind clinical trial with a crossover design. Patients with a permanent DRG-S system underwent phases of stimulation with 20 Hz, 40 Hz, 60 Hz, 80 Hz, and sham in a randomized order. Each phase lasted for 4 days and was followed by a 2-day washout period. Pain intensity and quality of life were assessed with visual analog scale (VAS), McGill Pain Questionnaire (MPQ), EQ-5D, and Beck Depression Inventory (BDI). Analgesics intake was assessed. RESULTS: Overall 19 patients were included in the study. CRPS was the most frequent pain etiology (7). Five patients had a PainDetect score of 12 or lower at baseline. The mean VAS before the system was implanted was 8.6 and 3.9 at the baseline. Pain intensity was reduced to 3.7 by the stimulation with 20 Hz but increased with higher frequencies reaching 5.8 at 80 Hz. A significant difference among the groups was shown over all variables examined (VAS, MPQ, EQ-5D, BDI). The best results were seen at 20 Hz for all variables, including the smallest increase in pain medication consumption. CONCLUSIONS: The choice of the stimulation frequency shows a clear influence on pain reduction and quality of life. Lower stimulation frequencies seem to be most effective in neuropathic pain. Further studies are required to determine whether specific frequencies should be preferred based on the condition treated.

The role of periradicular infiltration in dorsal root ganglion stimulation for chronic neuropathic pain.

BACKGROUND: Targeting the correct spinal level is essential in dorsal root ganglion (DRG) stimulation. Anatomical selection of the DRG alone is not ideal since the pain area is not necessarily confined to the borders of the dermatomes. This study aims to establish the role of periradicular infiltration therapy (PRT) in the preoperative assessment of the correct level for DRG stimulation performed under general anesthesia. METHOD: We report a prospective study of 20 patients selected for DRG stimulation and submitted to a PRT for identification of the spinal level. Lead implantation for the stimulation trial occurred under general anesthesia: 19 patients experienced positive results and underwent implantation of the pulse generator. All patients suffered from chronic neuropathic pain unresponsive to best medical treatment. PRT levels were compared with the levels targeted with DRG leads. Patients were followed for up to 12 months; pain intensity and coverage of the painful area were assessed. RESULTS: In 12 patients, the trial leads were placed on the same level as previously tested positive by PRT. In 6 patients, leads were placed in the PRT target and additionally in adjacent spinal levels. In one case, the selected target for the trial diverged from the PRT target because of intense fibrosis in the chosen level. Coverage of the target area of at least 50% was achieved by two-thirds of the patients. For the six subjects with additional implanted leads as a consequence of the PRT results, 80% achieved a coverage of at least 50%. A total of 47.4% of the patients achieved sustained significant pain relief in the last follow-up. None of the patients needed a repeated surgery for implantation of additional leads. CONCLUSIONS: PRT is a helpful tool to confirm the stimulation targets. A PRT preceding the stimulation trial is an additional opportunity to optimize the coverage of the target area with stimulation-induced paresthesia for patients operated under general anesthesia.

SU-E-J-180: A Characterization of the LAP Aquarius Phantom for External LAP Laser Alignment and MR Geometric Distortion Verification for the use of SRS Patient Simulation.

PURPOSE: To explore additional application of the new Aquarius external laser alignment verification Phantom by LAP (Aq-LAP Phantom) examining geometric accuracy of magnetic resonance images (MRI) commonly used for planning intracranial stereotactic radiation surgery (ICSRS) cases. METHODS: Newly designed external patient alignment lasers were first aligned by the Aq-LAP Phantom at a Siemens Magneton Vario 3T MR unit. The scans were then performed with the T1 Axial 3D MPRAGE protocols with 0.9 mm temporal resolution, which may be used for ICSRS. They also include FLAIR, T2 BLADE and Diffusion Axial TRACE imaging acquisitions with 1 mm temporal resolution. The MRI will be fused to 1 mm cut computerized tomography (CT) images acquired by a Siemens Somatom Sensation Open©. The geometric distortions (GD) were measured against the CT in all axial, sagital, and coronal directions at different levels. RESULTS: MR images of the Aquarius Phantom indicate a distinct similarity between the nonlinear GD along the z-axis crosshair and typical magnetic field gradient nonlinearity. There is linear correlation between MR divergence datasets of distorted crosshairs (p-values from 0.57 to 0.00), and nonlinear correlation between MR divergence datasets of the distorted crosshair with the CT divergence datasets of the cross plane (p-values from 8.45×10̂-4 to 1.38×10̂-46). The margin of error exceeded no more than 0.29 mm. GDs up to about 2 mm are observed at the distal regions of the longitudinal axis in the SRS treatment planning MR images. CONCLUSIONS: Using the Aquarius Phantom, one is able to detect GD in ICSRS planning MRI acquisitions, and align the external LAP patient alignment lasers by following the LAP QA. Based on the results, one may recommend using the Aquarius Phantom to determine if margins should be included for SRS treatment planning. The Aquarius Phantom, used for laser alignment and geometric distortion detection, was provided by LAP of America.

A dose ranging study of the pharmacokinetics, safety, and preliminary efficacy of lamivudine in children and adolescents with chronic hepatitis B.

Fifty-three patients with chronic hepatitis B and active viral replication were studied for 4 weeks while on treatment and for 12 weeks after treatment with the oral nucleoside analogue lamivudine. Children aged 2 to 12 years were randomized to receive twice-daily doses of 0.35, 1.5, or 4 mg of lamivudine solution per kg of body weight or once-daily doses of 3 mg of lamivudine solution per kg. Adolescents aged 13 to 17 years received lamivudine at 100 mg (as tablets). Blood samples for pharmacokinetic assay were taken on days 1 and 28. Lamivudine was rapidly absorbed following oral administration, with the maximum concentration in serum being reached 0.5 to 1 h postdosing. Apparent oral clearance (CL/F) was higher in younger children and decreased with age, with CL/F values for adolescents reaching those seen for adults by the age of 12. All doses produced a dramatic fall in serum hepatitis B virus (HBV) DNA levels, with a median reduction of >/=99.5% after 4 weeks of treatment and with the levels returning to the baseline levels posttreatment. The correlation of dose, area under the concentration-time curve (AUC), and changes in HBV DNA levels, as measured by the Chiron Quantiplex assay, showed maximal antiviral effects (99.9% inhibition and a reduction of the amount of HBV DNA of approximately 3 log(10)) at 3 mg/kg/day, with no discernible increase in effect seen whether the drug was given at 4 mg/kg twice daily or whether it was given once daily or twice daily. The limit of detection of the assay (2.5 pg/ml) was reached for some but not all patients across the dose ranges, with the smallest number (n = 2) of those having values negative by the Chiron Quantiplex assay being in the lowest-dose group. The 13- to 17-year-olds showed a similar overall response in terms of the HBV DNA level reduction compared to that for patients younger than age 13. Analysis of the same samples by PCR, which has a lower limit of sensitivity than the Chiron Quantiplex assay, also showed average drops in HBV DNA levels of about 3 log(10) at 4 weeks for patients for which the AUC was >/=4,000 ng. h/ml, confirming the conclusions given above. Lamivudine treatment was well tolerated at all doses, with no significant adverse events or laboratory data changes. On the basis of pharmacokinetic and pharmacodynamic data, a 3-mg/kg/day dose in children (ages 2 to 12 years) with chronic hepatitis B provides levels of exposure and trough concentrations similar to those seen in adults following the receipt of doses of 100 mg. The 100-mg dose is being evaluated in a large phase III study with HBV-infected pediatric patients.

Combination alpha-interferon and lamivudine therapy for alpha-interferon-resistant chronic hepatitis B infection: results of a pilot study.

BACKGROUND/AIMS: Alpha-interferon achieves seroconversion in about one third of naive patients. Attempts to achieve seroconversion in patients who have previously failed alpha-interferon have proved disappointing. Combination chemotherapy (alpha-interferon with a nucleoside analogue) might provide a treatment alternative for these patients. We have undertaken a phase 2 study in 20 patients who had previously failed at least one course of alpha-interferon. The study was designed to assess the safety, tolerability and efficacy of the combination. METHODS: All patients were treated for 16 weeks with alpha-interferon in combination with 12 or 16 weeks of Lamivudine (3'TC). Patients were followed for 16 weeks post-treatment. Pharmacokinetic studies were performed to identify/exclude significant pharmacokinetic drug interaction. RESULTS: The combination was well tolerated, and side-effects of the combination were indistinguishable from the recognised side-effects of alpha-interferon. Pharmacokinetic studies performed on days 1 and 29 did not show any significant interaction. All patients achieved HBV DNA clearance during treatment, but 19 relapsed at the end of treatment. HBeAg/anti-HBe seroconversion was observed for four patients, but was sustained for a single patient (who also had sustained DNA clearance). CONCLUSIONS: Combination therapy with alpha-interferon and lamivudine given for 16 weeks appears safe and is well tolerated. However, for this group of patients who had previously failed interferon monotherapy, the efficacy of combination interferon/lamivudine therapy appears disappointing, and other treatment strategies should be investigated.

Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis.

BACKGROUND: Orthotopic liver transplantation in patients positive for hepatitis B virus (HBV) DNA is associated with a high reinfection rate, even with hepatitis B immunoglobulin (HBIG) prophylaxis. Nucleoside analogues that inhibit hepatitis B replication in patients with chronic hepatitis B could prevent reinfection after transplantation. The aim of this study was to analyse the efficacy and safety of prophylaxis both before and after transplantation with the nucleoside analogue lamivudine, without HBIG, in patients undergoing liver transplantation. METHODS: 17 HBsAg-positive patients with decompensated cirrhosis and previous evidence of viral replication were enrolled. 12 were HBV-DNA-positive by a signal amplification assay. Patients were treated with oral lamivudine (100 mg daily) for at least 4 weeks before transplantation and followed up for 18-90 weeks after transplantation. FINDINGS: HBV DNA became undetectable in serum before transplantation in all HBV-DNA-positive patients. Four died before transplantation from complications of cirrhosis; one patient was withdrawn from the study because of a cerebrovascular accident. The remaining 12 patients underwent transplantation. Two patients died after transplantation (one at 3 days and one [suicide] at 20 weeks). HBV DNA reappeared in one patient with histological evidence of recurrent hepatitis (72 weeks). By week 24 the nine remaining patients had lost HBsAg and remained negative for HBV DNA. INTERPRETATION: Lamivudine treatment may prove useful in preventing recurrence of hepatitis B after liver transplantation. The effect on survival of patients after transplantation remains to be assessed.