Richard L. Boortz-Marx

Randomized Clinical Trial of an Implantable Drug Delivery System Compared With Comprehensive Medical Management for Refractory Cancer Pain: Impact on Pain, Drug-Related Toxicity, and Survival

PURPOSE Implantable intrathecal drug delivery systems (IDDSs) have been used to manage refractory cancer pain, but there are no randomized clinical trial (RCT) data comparing them with comprehensive medical management (CMM). PATIENTS AND METHODS We enrolled 202 patients on an RCT of CMM versus IDDS plus CMM. Entry criteria included unrelieved pain (visual analog scale [VAS] pain scores >/= 5 on a 0 to 10 scale). Clinical success was defined as >/= 20% reduction in VAS scores, or equal scores with >/= 20% reduction in toxicity. The main outcome measure was pain control combined with change of toxicity, as measured by the National Cancer Institute Common Toxicity Criteria, 4 weeks after randomization. RESULTS Sixty of 71 IDDS patients (84.5%) achieved clinical success compared with 51 of 72 CMM patients (70.8%, P =.05). IDDS patients more often achieved >/= 20% reduction in both pain VAS and toxicity (57.7% [41 of 71] v 37.5% [27 of 72], P =.02). The mean CMM VAS score fell from 7.81 to 4.76 (39% reduction); for the IDDS group, the scores fell from 7.57 to 3.67 (52% reduction, P =.055). The mean CMM toxicity scores fell from 6.36 to 5.27 (17% reduction); for the IDDS group, the toxicity scores fell from 7.22 to 3.59 (50% reduction, P =.004). The IDDS group had significant reductions in fatigue and depressed level of consciousness (P <.05). IDDS patients had improved survival, with 53.9% alive at 6 months compared with 37.2% of the CMM group (P =.06). CONCLUSION IDDSs improved clinical success in pain control, reduced pain, significantly relieved common drug toxicities, and improved survival in patients with refractory cancer pain.

Prevention and management of intrathecal drug delivery and spinal cord stimulation system infections.

FULLY implantable devices or drug–device combinations, such as intrathecal drug delivery (DD) systems and spinal cord stimulation (SCS) systems, increasingly are used for the treatment of chronic intractable pain. Another approved indication for intrathecal DD systems is the administration of intrathecal baclofen (ITB) to treat medically intractable spasticity of spinal or cerebral origin. Although patients with cancer, spinal cord injuries, or cerebral palsy have a reduced life expectancy, the majority of intrathecal drug administration devices— and nearly all SCS devices—are implanted in patients with painful non–cancer-related disorders that are associated with a normal life span. Therefore, long-term implantable devices used for the treatment of pain and spasticity should have a relatively benign safety record. Device-related infection is the most common, potentially reducible, serious adverse event associated with intrathecal DD or SCS devices. Reducing the number of implantable DD and SCS device infections is important for various reasons. One is that treatment of an established infection often involves temporary or permanent removal of the device, which causes cessation of drug or stimulation therapy. Therapy cessation (with or without eventual device replacement) increases the risks, discomfort, inconvenience, and expenses of patients who experience infectious complications. Abrupt cessation of intrathecal drug therapy may precipitate drug withdrawal symptoms and, in the case of ITB, can have fatal consequences. In rare cases, device-associated infections can progress to fatal sepsis, meningitis, or both. Available data indicate that implantable DD and SCS device infections share important features with other surgical site infections (SSIs), including those that affect cerebrospinal fluid (CSF) shunts and electrophysiologic cardiac devices such as implantable pacemakers and cardioverter–defibrillators (ICDs). Management of infections associated with DD and SCS systems typically involves administration of antibiotics and explantation of the devices. Measures that reduce the incidence of other SSIs also should reduce the infection rate associated with the implantation of SCS and intrathecal DD devices.

μ-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer.

Background: Preclinical studies suggest that opioids may promote tumor growth. Genetic polymorphisms have been shown to affect opioid receptor function and to modify the clinical effects of morphine. In this study we assessed the association between six common polymorphisms in the &mgr;-opioid receptor gene, including the well known A118G polymorphism, and breast cancer survival. Methods: A total of 2,039 women ages 23–74 yr (38% African-American, 62% European-American, 55% postmenopausal) diagnosed with breast cancer between 1993–2001 were followed through 2006. Genotyping was performed using the TaqMan platform (Applied Biosystems Inc., Foster City, CA). Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models were used to examine the association between each genotype and survival. Results: After Bonferroni correction for multiple testing, patient genotype at A118G was associated with breast cancer-specific mortality at 10 yr. Women with one or more copies of the G allele had decreased breast cancer-specific mortality (P < 0.001). This association was limited to invasive cases only; effect size appeared to increase with clinical stage. Cox regression model adjusted for age and ethnicity also showed decreased mortality in A/G and G/G genotypes compared with A/A genotype (hazard ratio = 0.57 [0.38, 0.85] and 0.32 [0.22, 0.49], respectively; P = 0.006). Conclusions: These results suggest that opioid pathways may be involved in tumor growth. Further studies examining the association between genetic variants influencing opioid system function and cancer survival are warranted.

Sneddon’s Syndrome With Granulomatous Leptomeningeal Infiltration

BACKGROUND There is limited neuropathologic information available from cases of Sneddons syndrome in which strokes are associated with livedo reticularis. Pathogenesis of the syndrome is controversial, although current opinion favors a coagulopathy, often with antiphospholipid antibodies. We describe a case lacking antiphospholipid antibodies but having a granulomatous infiltration of the leptomeninges. CASE DESCRIPTION The patient presented at age 29 with stroke, livedo reticularis, essential hypertension, and Raynauds phenomenon. Assessment uncovered no underlying disease, including absent antiphospholipid antibodies. A leptomeningeal biopsy showed granulomatous infiltration. CONCLUSIONS The findings suggest that an inflammatory process plays a role in at least some cases of Sneddons syndrome.

Factors affecting intracranial pressure: a descriptive study.

&NA; This study examined the effects of 365 occurrences on the intracranial pressure (ICP) of four patients with severe head injuries and a Glasgow Coma Score below five. The occurrences were in: 1) health care activities, 2) patient‐initiated activities, and 3) environmental stimuli. The health care activities that increased intracranial pressure were suctioning, turning, and flexion of the head; decreases were realized by elevating the head of the bed and repositioning the patient. The patient‐initiated activities that increased intracranial pressure were flexion of extremities, rotation of the neck, and coughing. In contrast to previous reports, environmental stimuli did not affect intracranial pressure and bathing increased it. Recommendations for nursing care include: turning patients more slowly to less acute angles; proper head/neck positioning; and more direct psychosocial interactions with families of patients who have low Glasgow Coma Scores.

Spinal Cord Stimulation Therapy for Patients With Refractory Angina Who Are Not Candidates for Revascularization

Objectives:  The aim of this study was to evaluate the safety and efficacy of spinal cord stimulation (SCS) for refractory angina.

Stellate ganglion blockade for the treatment of refractory ventricular arrhythmias: A systematic review and meta-analysis: FUDIM et al .

Treatment refractory ventricular arrhythmias (VAs) are often driven and exacerbated by heightened sympathetic tone. We aim to conduct a systematic review and meta‐analysis of published studies of a temporary percutaneous stellate ganglion block (SGB) on VA burden and defibrillation episodes in patients with treatment refractory VAs.

Splanchnic nerve block for decompensated chronic heart failure: splanchnic-HF

Division of Cardiology, Department of Medicine, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC 27705, USA; Division of Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, 2301 Erwin Road, Durham, NC 27710, USA; and Department of Biostatistics and Bioinformatics and Duke Clinical Research Institute, Duke University School of Medicine, 2424 Erwin Road, Durham, NC 27710, USA

Through the Looking Glass: Specialty Influence on SCS Outcomes: SPECIALTY INFLUENCE ON SCS OUTCOMES

To the Editor: It was with great interest that we read the article by Lad et al. (1) which tested the hypothesis that spinal cord stimulator outcomes, defined as a trial to permanent conversion, can be determined based on specialty demographics of the surgeon. Specifically, specialties traditionally trained in surgical implantation of spinal cord stimulation systems may have a higher trial-to-permanent conversion rate, and, therefore, improve health care economics and better utilize healthcare resources. The magnitude of this effect, deviating from previous work (2), and the possible ramifications for training or policy decisions warrants closer inspection of their methods and data, as it seems the conclusions are flawed and irresponsible. To better describe this assertion of a difference of success among specialties, let us look to the recent randomized controlled trials published in our space: the DRG study (3) and the spinal cord stimulation high frequency 1000 Hz study (4). Each supported a trial to permanent ratio above 80%. Among the authors (and the implanters), 25 of the 26 physicians for the DRG study and 15 of the 15 physicians for the HF10 study were not orthopedic spine or neurosurgeons. This poses an interesting scenario when looking at market scan analysis vs. the innovation introduction to our space. Many of the assumptions within Lad’s work can be only described as a poorly described methodology. Overly simplified, Lad et al. has defined success as a trial to permanent ratio. This statistic is outdated and not representative of the current benchmark for sustainability of the therapy. Further, the physician groups described in the article are not adequate and fail to identify to describe formal neuromodulation training or tenure. With closer inspection, there are questions regarding the analysis that need to be clarified to better understand the authors’ conclusions. First, there are many variables noted in Tables 1 and 2 on the univariate regression analysis that demonstrate statistically significant differences among the patients seen by the different specialties. “Anesthesiology” providers saw older patients, with a higher Medicare/Medicaid mix, and with more difficult to treat pain pathologies such as CRPS. The authors do not include all these significantly different variables in the multiple regression analysis. They do not discuss why they chose to include or exclude the variables they did use, even though they published on the impact of these variables previously (2). Certainly this oversight makes it impossible to make any meaningful conclusions. The inclusion of those significant variables in the analysis would properly control for the differences in the populations and, more importantly, the procedure being done on the dependent variable of trial conversion. Validating this assertion is that explants among the categories defined in this analysis demonstrated a similar explant rate across all specialties, and with aforementioned argument, one could make the argument non-orthopedic or neurosurgeons faired better. As highlighted in the Neuromodulation Appropriateness Consensus Committee on Safety Guidelines for the Reduction of Severe Neurological Injury, published in January of 2017 (5), Petraglia et al. published their investigation of spinal cord injury following percutaneous and surgical paddle leads (6), with no statistical difference amongst lead type (and very likely specialty). A closer analysis of Table 1 suggests the most likely source of the large variation in conversion rate is due to the lead type, with surgical specialists primarily using a combination of paddle and percutaneous implants. For implants, 50–70% of surgical specialist implants were a combination as compared with 4–6% in the other groups. As paddle leads are more traumatic for placement but have been shown to have higher success rates (7), this large variation likely skews the conversion rate rapidly, yet lead type is not included in the multiple variable analysis. Furthermore, the use of combined paddle and percutaneous leads for the implant suggests the majority of surgically placed implants are being done as combination dorsal column stimulation with additional off-label field stimulation, which would greatly complicate any conclusions from this work. Oddly, the authors also noted but chose not to correct for their recently noted volume-effect from this same dataset (8). It has already been suggested that centers of excellence be established to better improve healthcare outcomes and utilization (9). This suggestion was popularized by Malcom Gladwell with his work “Outliers” and the “10,000 hour rule” (10). Further, it is already well described that approximately 20% of the implanting physicians in the United States are performing approximately 80% of the SCS volume. Does a neurosurgical specialist who does a low volume of SCS cases perform better than a PM&R specialist who does a high volume? These highly confounding variables are something the authors could readily have corrected for in their multiple variable analyses, but they did not, and the most recent accepting reviewers must not have asked them to. Overall, we suspect that the Neuromodulation readership would agree that there is a need to increase the utilization of these technologies to those suffering from chronic pain. It is also necessary to identify patient, technology, and provider factors that predict success. We can agree that anesthesiology, internal medicine, neurology, physical medicine and rehabilitation, radiology, orthopedic, and neurosurgical providers have varying amounts of training and

Fatal Pain Relief

This case discusses a synergistic pharmacodynamic interaction between morphine and bupivacaine, resulting in death. This drug pair eliminated both central and peripheral respiratory drive.