Treatment of Refractory Low Back Pain Using Passive Recharge Burst in Patients Without Options for Corrective Surgery: Findings and Results From the DISTINCT Study, a Prospective Randomized Multicenter Controlled Trial.

OBJECTIVE: Spinal cord stimulation (SCS) is effective for relieving chronic intractable pain conditions. The Dorsal spInal cord STImulatioN vs mediCal management for the Treatment of low back pain study evaluates the effectiveness of SCS compared with conventional medical management (CMM) in the treatment of chronic low back pain in patients who had not undergone and were not candidates for lumbar spine surgery. METHODS AND MATERIALS: Patients were randomized to passive recharge burst therapy (n = 162) or CMM (n = 107). They reported severe pain and disability for more than a decade and had failed a multitude of therapies. Common diagnoses included degenerative disc disease, spondylosis, stenosis, and scoliosis-yet not to a degree amenable to surgery. The six-month primary end point compared responder rates, defined by a 50% reduction in pain. Hierarchical analyses of seven secondary end points were performed in the following order: composite responder rate (numerical rating scale [NRS] or Oswestry Disability Index [ODI]), NRS, ODI, Pain Catastrophizing Scale responder rate, Patient Global Impression of Change (PGIC) responder rate, and Patient-Reported Outcome Measure Information System-29 in pain interference and physical function. RESULTS: Intention-to-treat analysis showed a significant difference in pain responders on NRS between SCS (72.6%) and CMM (7.1%) arms (p < 0.0001). Of note, 85.2% of those who received six months of therapy responded on NRS compared with 6.2% of those with CMM (p < 0.0001). All secondary end points indicated the superiority of burst therapy over CMM. A composite measure on function or pain relief showed 91% of subjects with SCS improved, compared with 16% of subjects with CMM. A substantial improvement of 30 points was observed on ODI compared with a

Metaxalone Suppresses Production of Inflammatory Cytokines Associated with Painful Conditions in Mouse Macrophages RAW264.7 Cells in Vitro: Synergistic Effect with ß-caryophyllene.

Backgrounds and Objective: Inflammation is implicated in the pathogenesis of many diseases. Inflammatory cytokines with painful conditions are well known as biomarkers in human muscle pain, and they are produced by macrophages. Metaxalone is used as a skeletal muscle relaxant, but the mechanism by which metaxalone acts is unknown. This study was undertaken to investigate whether or not metaxalone exhibits an inhibitory effect on the activity of inflammatory macrophages in vitro. METHODS: Mouse macrophage RAW264.7 cells were cultured in Dulbecco's Modification of Eagle's Medium containing 10% fetal bovine serum in the presence of metaxalone. Cell growth was assayed by counting the number of cells attached to culture dishes. Inflammatory cytokines released into the culture medium were analyzed with the ELISA kit. RESULTS: Metaxalone (1-100 µM) was found to decrease the number of macrophages by inhibiting the proliferation and stimulating the death of RAW264.7 cells in vitro. The combination of metaxalone (0.1 or 1 µM) and ß-caryophyllene (10 or 50 µM), which alone did not have a significant effect on the cell number, caused potential effects on the growth and death of RAW264.7 cells. Mechanistically, molecular levels of mitogenactivated protein kinase were decreased by treatment with metaxalone or ß- caryophyllene, and each effect was enhanced by their combination. Furthermore, levels of caspase-3 were increased by metaxalone or ß-caryophyllene and enhanced by their combination. Notably, productions of inflammatory cytokines, including tumor necrosis factor-α, interleukin-6 or prostaglandin E2, which were enhanced by lipopolysaccharide (LPS), were repressed by culturing with metaxalone. Levels of cyclooxygenase (COX)-1, COX-2 and nuclear factor kappa B, which were increased by LPS treatment, were reduced by metaxalone. CONCLUSION: Metaxalone was found to suppress the activity of inflammatory macrophages in vitro.

A Systematic Literature Review of Spine Neurostimulation Therapies for the Treatment of Pain.

OBJECTIVE: To conduct a systematic literature review of spinal cord stimulation (SCS) for pain. DESIGN: Grade the evidence for SCS. METHODS: An international, interdisciplinary work group conducted literature searches, reviewed abstracts, and selected studies for grading. Inclusion/exclusion criteria included randomized controlled trials (RCTs) of patients with intractable pain of greater than one year's duration. Full studies were graded by two independent reviewers. Excluded studies were retrospective, had small numbers of subjects, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria. RESULTS: SCS has Level 1 evidence (strong) for axial back/lumbar radiculopathy or neuralgia (five high-quality RCTs) and complex regional pain syndrome (one high-quality RCT). CONCLUSIONS: High-level evidence supports SCS for treating chronic pain and complex regional pain syndrome. For patients with failed back surgery syndrome, SCS was more effective than reoperation or medical management. New stimulation waveforms and frequencies may provide a greater likelihood of pain relief compared with conventional SCS for patients with axial back pain, with or without radicular pain.

Long-term safety and efficacy of closed-loop spinal cord stimulation to treat chronic back and leg pain (Evoke): a double-blind, randomised, controlled trial.

BACKGROUND: Spinal cord stimulation has been an established treatment for chronic back and leg pain for more than 50 years; however, outcomes are variable and unpredictable, and objective evidence of the mechanism of action is needed. A novel spinal cord stimulation system provides the first in vivo, real-time, continuous objective measure of spinal cord activation in response to therapy via recorded evoked compound action potentials (ECAPs) in patients during daily use. These ECAPs are also used to optimise programming and deliver closed-loop spinal cord stimulation by adjusting the stimulation current to maintain activation within patients' therapeutic window. We aimed to examine pain relief and the extent of spinal cord activation with ECAP-controlled closed-loop versus fixed-output, open-loop spinal cord stimulation for the treatment of chronic back and leg pain. METHODS: This multicentre, double-blind, parallel-arm, randomised controlled trial was done at 13 specialist clinics, academic centres, and hospitals in the USA. Patients with chronic, intractable pain of the back and legs (Visual Analog Scale [VAS] pain score ≥60 mm; Oswestry Disability Index [ODI] score 41-80) who were refractory to conservative therapy, on stable pain medications, had no previous experience with spinal cord stimulation, and were appropriate candidates for a spinal cord stimulation trial were screened. Eligible patients were randomly assigned (1:1) to receive ECAP-controlled closed-loop spinal cord stimulation (investigational group) or fixed-output, open-loop spinal cord stimulation (control group). The randomisation sequence was computer generated with permuted blocks of size 4 and 6 and stratified by site. Patients, investigators, and site staff were masked to the treatment assignment. The primary outcome was the proportion of patients with a reduction of 50% or more in overall back and leg pain with no increase in pain medications. Non-inferiority (δ=10%) followed by superiority were tested in the intention-to-treat population at 3 months (primary analysis) and 12 months (additional prespecified analysis) after the permanent implant. This study is registered with ClinicalTrials.gov, NCT02924129, and is ongoing. FINDINGS: Between Feb 21, 2017, and Feb 20, 2018, 134 patients were enrolled and randomly assigned (67 to each treatment group). The intention-to-treat analysis comprised 125 patients at 3 months (62 in the closed-loop group and 63 in the open-loop group) and 118 patients at 12 months (59 in the closed-loop group and 59 in the open-loop group). The primary outcome was achieved in a greater proportion of patients in the closed-loop group than in the open-loop group at 3 months (51 [82·3%] of 62 patients vs 38 [60·3%] of 63 patients; difference 21·9%, 95% CI 6·6-37·3; p=0·0052) and at 12 months (49 [83·1%] of 59 patients vs 36 [61·0%] of 59 patients; difference 22·0%, 6·3-37·7; p=0·0060). We observed no differences in safety profiles between the two groups. The most frequently reported study-related adverse events in both groups were lead migration (nine [7%] patients), implantable pulse generator pocket pain (five [4%]), and muscle spasm or cramp (three [2%]). INTERPRETATION: ECAP-controlled closed-loop stimulation provided significantly greater and more clinically meaningful pain relief up to 12 months than open-loop spinal cord stimulation. Greater spinal cord activation seen in the closed-loop group suggests a mechanistic explanation for the superior results, which aligns with the putative mechanism of action for spinal cord stimulation and warrants further investigation. FUNDING: Saluda Medical.

Neuromodulation of the Dorsal Root Ganglion for Chronic Postsurgical Pain.

OBJECTIVE: The objective of this study is to review the available evidence for dorsal root ganglion (DRG) stimulation for the treatment of complex regional pain syndrome type II (CRPS II; peripheral causalgia) associated with chronic neuropathic postsurgical pain (NPP). DESIGN: Available literature was identified through a search of the US National Library of Medicine's Medline database, PubMed.gov. References from published articles also were reviewed for relevant citations. RESULTS: The data published to date support the use of DRG stimulation to treat chronic NPP of the groin, knee, and foot. NPP following procedures such as thoracotomy, hernia surgery, and knee replacement surgery were identified as some of the conditions for which DRG stimulation is likely to be effective. CONCLUSION: DRG stimulation is known to be an effective treatment for focal neuropathic pain. Currently, NPP of the foot, groin, and knee all appear to be the conditions with the most clinical experience, backed by a limited but growing body of evidence. However, prospective studies lag behind real-world clinical experience and are needed to confirm these findings.

The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines.

INTRODUCTION: Pain treatment is best performed when a patient-centric, safety-based philosophy is used to determine an algorithmic process to guide care. Since 2007, the International Neuromodulation Society has organized a group of experts to evaluate evidence and create a Polyanalgesic Consensus Conference (PACC) to guide practice. METHODS: The current PACC update was designed to address the deficiencies and innovations emerging since the previous PACC publication of 2012. An extensive literature search identified publications between January 15, 2007 and November 22, 2015 and authors contributed additional relevant sources. After reviewing the literature, the panel convened to determine evidence levels and degrees of recommendations for intrathecal therapy. This meeting served as the basis for consensus development, which was ranked as strong, moderate or weak. Algorithms were developed for intrathecal medication choices to treat nociceptive and neuropathic pain for patients with cancer, terminal illness, and noncancer pain, with either localized or diffuse pain. RESULTS: The PACC has developed an algorithmic process for several aspects of intrathecal drug delivery to promote safe and efficacious evidence-based care. Consensus opinion, based on expertise, was used to fill gaps in evidence. Thirty-one consensus points emerged from the panel considerations. CONCLUSION: New algorithms and guidance have been established to improve care with the use of intrathecal drug delivery.

The Polyanalgesic Consensus Conference (PACC): Recommendations for Intrathecal Drug Delivery: Guidance for Improving Safety and Mitigating Risks.

INTRODUCTION: Intrathecal therapy is an important part of the pain treatment algorithm for chronic disease states. The use of this option is a viable treatment strategy, but it is inherent for pain physicians to understand risk assessment and mitigation. In this manuscript, we explore evidence and mitigating strategies to improve safety with intrathecal therapy. METHODS: A robust literature search was performed covering January 2011 to October 9, 2016, in PubMed, Embase, MEDLINE, Biomed Central, Google Scholar, Current Contents Connect, and International Pharmaceutical Abstracts. The information was cross-referenced and compiled for evidence, analysis, and consensus review, with the intent to offer weighted recommendations and consensus statements on safety for targeted intrathecal therapy delivery. RESULTS: The Polyanalgesic Consensus Conference has made several best practice recommendations to improve care and reduce morbidity and mortality associated with intrathecal therapy through all phases of management. The United States Prevention Service Task Force evidence level and consensus strength assessments are offered for each recommendation. CONCLUSION: Intrathecal therapy is a viable and relatively safe option for the treatment of cancer- and noncancer-related pain. Continued research and expert opinion are required to improve our current pharmacokinetic and pharmacodynamic model of intrathecal drug delivery, as this will undoubtedly improve safety and efficacy.

The combination of ß-caryophyllene, baicalin and catechin synergistically suppresses the proliferation and promotes the death of RAW267.4 macrophages in vitro.

ß-caryophyllene, which is a constituent of many essential oils, has been known to be a selective agonist of the cannabinoid receptor type-2 and to exert cannabimimetic anti-inflammatory effects in animals. The effects of ß-caryophyllene on macrophages have not been investigated to date. This study was undertaken to determine whether ß-caryophyllene exerts suppressive effects on mouse RAW267.4 macrophages in vitro in comparison with other botanical molecules that exert antioxidant and anti-inflammatory effects. The proliferation of RAW267.4 cells was suppressed by culture with ß-caryophyllene (50, 100 and 200 µg/ml of medium) or curcumin (100 and 200 µg/ml). Culture with baicalin (1-200 µg/ml) or (+)-catechin (1-200 µg/ml) did not exert an effect on RAW267.4 cells. The combination of ß-caryophyllene (1 or 10 µg/ml) with either curcumin (1 or 10 µg/ml), baicalin (1 or 10 µg/ml) or (+)-catechin (1 or 10 µg/ml) did not exert any suppressive effects on cell proliferation. Of note, the combination of all three agents, ß-caryophyllene, baicalin and (+)-catechin at the concentration of either 1 or 10 µg/ml was found to exert synergistic suppressive effects on cell proliferation. Moreover, the combination of ß-caryophyllene, baicalin and (+)-catechin synergistically promoted the death of RAW267.4 cells. Such an effect was blocked by culture with caspase-3 inhibitor. The combination of the three agents decreased the protein levels of Akt, mitogen-activated protein kinase (MAPK) and cyclooxygenase (COX)-1 or -2. On the whole, this study demonstrates that the combination of ß-caryophyllene, baicalin and (+)-catechin exerts synergistic suppressive effects on macrophages in vitro. This composition may be a useful as an anti-inflammatory treatment strategy.

A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas.

One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m(2) IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m(2) PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m(2) on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycles post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor.

ß-Caryophyllene promotes osteoblastic mineralization, and suppresses osteoclastogenesis and adipogenesis in mouse bone marrow cultures in vitro.

Osteoporosis is induced by the reduction in bone mass through decreased osteoblastic osteogenesis and increased osteoclastic bone resorption, and it is associated with obesity and diabetes. Osteoblasts and adipocytes are derived from bone marrow mesenchymal stem cells. The prevention of osteoporosis is an important public health concern in aging populations. ß-caryophyllene, a component of various essential oils, is a selective agonist of the cannabinoid receptor type 2 and exerts cannabimimetic anti-inflammatory effects in animals. The present study aimed to identify the effect of ß-caryophyllene on adipogenesis, osteoblastic mineralization and osteoclastogenesis in mouse bone marrow cell cultures in vitro. Bone marrow cells obtained from mouse femoral tissues were cultured in the presence of ß-caryophyllene (0.1-100 µM) in vitro. The results revealed that ß-caryophyllene stimulated osteoblastic mineralization, and suppressed adipogenesis and osteoclastogenesis. Thus, ß-caryophyllene may be used as a therapeutic agent for the prevention and treatment of osteoporosis.

The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications. METHODS: The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar. RESULTS: Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated. CONCLUSIONS: Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation.

Interventional management of neuropathic pain: NeuPSIG recommendations.

Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long-term studies, and head-to-head comparisons among different interventional and noninterventional treatments.

Phase I study of arsenic trioxide and temozolomide in combination with radiation therapy in patients with malignant gliomas.

To evaluate the toxicity and maximum tolerated dose (MTD) of arsenic trioxide (ATO) in combination with temozolomide (TMZ) and radiation therapy (RT) in malignant gliomas. A 3 + 3 dose escalation study was performed in patients with newly diagnosed glioblastoma, anaplastic astrocytoma (AA), and anaplastic oligoastrocytoma (AOA). All patients received RT 59-61 Gy in 28-33 fractions, TMZ for 42 days, and ATO 1-2 h prior to RT for 5 days during the first week, then twice weekly until completing RT. Dose levels (DL) were: (1) TMZ 60 mg/m(2)/ATO 0.2 mg/kg; (2) TMZ 75 mg/m(2)/ATO 0.2 mg/kg; (3) TMZ 75 mg/m(2)/ATO 0.25 mg/kg. Dose-limiting toxicity (DLT) was defined as grade 3 non-hematologic toxicity or grade 4 toxicity of any type from enrollment until 3 weeks after finishing RT. 17 patients (13 glioblastoma, 4 AA/AOA) were accrued. Median age was 52 (range 25-80). Median KPS was 90 %. DLT's occurred at DL 2 (grade 4 transaminase elevation) and DL 3 (grade 4 neutropenia and grade 3 QTc prolongation). The MTD of TMZ 75 mg/m(2)/ATO 0.2 mg/kg was safe and well tolerated. A phase II study evaluating the efficacy of this combination is underway.

5-Lipoxygenase metabolic contributions to NSAID-induced organ toxicity.

Cyclooxygenase (COX)-1, COX-2, and 5-lipoxygenase (5-LOX) enzymes produce effectors of pain and inflammation in osteoarthritis (OA) and many other diseases. All three enzymes play a key role in the metabolism of arachidonic acid (AA) to inflammatory fatty acids, which contribute to the deterioration of cartilage. AA is derived from both phospholipase A(2) (PLA(2)) conversion of cell membrane phospholipids and dietary consumption of omega-6 fatty acids. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the COX enzymes, but show no anti-5-LOX activity to prevent the formation of leukotrienes (LTs). Cysteinyl LTs, such as LTC(4), LTD(4), LTE(4), and leukoattractive LTB(4) accumulate in several organs of mammals in response to NSAID consumption. Elevated 5-LOX-mediated AA metabolism may contribute to the side-effect profile observed for NSAIDs in OA. Current therapeutics under development, so-called "dual inhibitors" of COX and 5-LOX, show improved side-effect profiles and may represent a new option in the management of OA.

Comprehensive consensus based guidelines on intrathecal drug delivery systems in the treatment of pain caused by cancer pain.

BACKGROUND: Chronic persistent pain as a result of terminal illness, either as a consequence of the disease or the necessary treatment, is common in patients with cancer. For these patients with moderate-to-severe intractable pain, intrathecal (IT) drug delivery systems may represent an effective option for pain management. Thus, IT drug delivery is a viable treatment strategy for both neuropathy and nociceptive pain in the cancer population. However, there is a scarcity of comprehensive guidelines in implanting IT drug delivery systems in the treatment of pain caused by cancer. OBJECTIVE: This article outlines consensus guidelines for the implementation of intrathecal therapy in patients with cancer-related pain and other end of life states causing pain. We highlight the multidisciplinary criteria that warrant careful consideration to ensure meaningful analgesia. METHODS: Evidence was compiled, ranked, and strength considered by an invited panel of well-published and innovative clinician research leaders in pain medicine. Based on that analysis, an accumulation of evidence from observational and randomized prospective trials supports the use of intrathecal (IT) drug delivery to provide effective analgesia for patients with cancer-related pain, including individuals at the end of life. Although not all patients are candidates for this invasive treatment modality, clinicians can determine the appropriateness of proceeding with device implantation by carefully evaluating the individual's overall medical status, psychological stability, social support system, and prognosis of disease. Further, consumption of health care resources and cost-effective treatment is becoming more of a priority; not only is this therapy appropriate medically, but also economically. This multifaceted approach to patient selection assists in maximizing treatment effect and avoiding unintended consequences of therapy. LIMITATIONS: The limitations of these guidelines include that these are of expert panel guidelines. The literature describes appropriate preparation of guidelines based on evidence derived from randomized trials and systematic reviews. However, there is also value for consensus-based guidelines due to non-availability of evidence from either systematic reviews of randomized trials or randomized trials alone. In addition, the evidence is not available on many aspects of intrathecal infusion systems even with observational studies and case reports. Thus, the present approach with expert consensus guidelines is acceptable. CONCLUSIONS: These consensus guidelines are intended to assist clinicians in identifying the candidacy of patients with cancer-related pain and end of life diseases causing pain that may benefit from intrathecal drug delivery. With careful consideration of the patient's medical comorbidities and prior therapies, communication with the oncologist, proper psychological evaluation, and appropriate trialing technique, clinicians can effectively optimize the use of IT therapy for cancer pain. The panel advocates for a much wider application of IT therapy to provide meaningful analgesia for patients with cancer pain, including those at the end of life from a variety of causes.

Peripheral neuromodulation for migraine headache.

Extremely high prevalence among general population along with the high percentage of treatment-refractory cases makes migraine headaches one of the potentially largest indications for neuromodulation. Cranial peripheral nerve stimulation targeting the occipital nerve(s) alone or in combination with others appears to be both safe and efficacious for the treatment of medically intractable migraine headaches. Although initial reports of occipital nerve stimulation for migraine headaches were very encouraging, this clinical benefit was not clearly confirmed in larger-scale prospective randomized trials. Moreover, the exact mechanism of neuromodulation effect in migraine treatment remains unclear. Significant further investigation needs to be performed to optimize our knowledge concerning patient selection, stimulation targets and parameters and device programming, and further improve clinical results. At present, neurostimulation for migraine headache pain is performed in the United States on an 'off-label' basis, but based upon our experience and the increasing evidence in the medical literature, we look forward to its approval by the FDA in the near future so that patients suffering from severe, medically intractable headache pain may gain access to these potentially important therapies.

Bing-Neel syndrome: an illustrative case and a comprehensive review of the published literature.

Waldenstrom's macroglobulinemia (WM) is a chronic lymphoproliferative disorder within the spectrum of lymphoplasmacytic lymphoma characterized by proliferation of plasma cells, small lymphocytes, and plasmacytoid lymphocytes. Central nervous system involvement is very rare (Bing-Neel [BN] syndrome). We present the case of a 62-year-old woman previously diagnosed with WM who presented with Bing-Neel syndrome and review the published literature which consists of only case reports. We performed a Medline search using the terms "Waldenstrom's macroglobulinemia and central nervous system" and "Bing-Neel" collecting data on presentation, evaluation, treatment, and outcome and summarizing these findings in the largest pooled series to date. Central nervous system manifestations are localization related. Serum laboratory testing reflects systemic disease. Cerebrospinal fluid analysis may show lymphocytic pleocytosis, elevated protein, and IgM kappa or lambda light chain restriction; cytology results are variable. Imaging is frequently abnormal. Biopsy confirms the diagnosis. Treatment data are limited, but responses are seen with radiation and/or chemotherapy. BN syndrome is a very rare complication of WM that should be considered in patients with neurologic symptoms and a history of WM. Treatment should be initiated as responses do occur that may improve quality of life and extend it when limited or no active systemic disease is present.