Percutaneous Neuromodulation of the Brachial Plexus and Sciatic Nerve for the Treatment of Acute Pain Following Surgery: Secondary Outcomes From a Multicenter, Randomized, Controlled Pilot Study.

OBJECTIVES: We recently reported that percutaneous peripheral nerve stimulation (PNS or "neuromodulation") decreased pain and opioid consumption within the first two weeks following ambulatory surgery. However, the anatomic lead locations were combined for the analysis, and benefits for each location remain unknown. We therefore now report the effects of percutaneous PNS for brachial plexus and sciatic nerve leads separately. MATERIALS AND METHODS: Before surgery, leads were implanted percutaneously to target the brachial plexus (N = 21) for rotator cuff repair or sciatic nerve (N = 40) for foot/ankle surgery, followed by a single injection of local anesthetic. Postoperatively, subjects were randomized in a double masked fashion to 14 days of electrical stimulation (N = 30) or sham/placebo (N = 31) using an external pulse generator. The primary outcome of interest was opioid consumption and pain scores evaluated jointly. Thus, stimulation was deemed effective if superior on either outcome and at least noninferior on the other. RESULTS: For brachial plexus leads, during the first seven postoperative days pain measured with the numeric rating scale in participants given active stimulation was a median [interquartile range] of 0.8 [0.5, 1.6] versus 3.2 [2.7, 3.5] in patients given sham (p < 0.001). For this same group, opioid consumption in participants given active stimulation was 10 mg [5, 20] versus 71 mg [35, 125] in patients given sham (p = 0.043). For sciatic nerve leads, pain scores for the active treatment group were 0.7 [0, 1.4] versus 2.8 [1.6, 4.6] in patients given sham (p < 0.001). During this same period, participants given active stimulation consumed 5 mg [0, 30] of opioids versus 40 mg [20, 105] in patients given sham (p = 0.004). Treatment effects did not differ statistically between the two locations. CONCLUSIONS: Ambulatory percutaneous PNS of both the brachial plexus and sciatic nerve is an effective treatment for acute pain free of systemic side effects following painful orthopedic surgery.

Percutaneous Peripheral Nerve Stimulation (Neuromodulation) for Postoperative Pain: A Randomized, Sham-controlled Pilot Study.

BACKGROUND: Percutaneous peripheral nerve stimulation is an analgesic technique involving the percutaneous implantation of a lead followed by the delivery of electric current using an external pulse generator. Percutaneous peripheral nerve stimulation has been used extensively for chronic pain, but only uncontrolled series have been published for acute postoperative pain. The current multicenter study was undertaken to (1) determine the feasibility and optimize the protocol for a subsequent clinical trial and (2) estimate the treatment effect of percutaneous peripheral nerve stimulation on postoperative pain and opioid consumption. METHODS: Preoperatively, an electrical lead was percutaneously implanted to target the sciatic nerve for major foot/ankle surgery (e.g., hallux valgus correction), the femoral nerve for anterior cruciate ligament reconstruction, or the brachial plexus for rotator cuff repair, followed by a single injection of long-acting local anesthetic along the same nerve/plexus. Postoperatively, participants were randomized to 14 days of either electrical stimulation (n = 32) or sham stimulation (n = 34) using an external pulse generator in a double-masked fashion. The dual primary treatment effect outcome measures were (1) cumulative opioid consumption (in oral morphine equivalents) and (2) mean values of the "average" daily pain scores measured on the 0 to 10 Numeric Rating Scale within the first 7 postoperative days. RESULTS: During the first 7 postoperative days, opioid consumption in participants given active stimulation was a median (interquartile range) of 5 mg (0 to 30) versus 48 mg (25 to 90) in patients given sham treatment (ratio of geometric means, 0.20 [97.5% CI, 0.07 to 0.57]; P < 0.001). During this same period, the average pain intensity in patients given active stimulation was a mean ± SD of 1.1 ± 1.1 versus 3.1 ± 1.7 in those given sham (difference, -1.8 [97.5% CI, -2.6 to -0.9]; P < 0.001). CONCLUSIONS: Percutaneous peripheral nerve stimulation reduced pain scores and opioid requirements free of systemic side effects during at least the initial week after ambulatory orthopedic surgery.

Ultrasound-Guided Percutaneous Peripheral Nerve Stimulation: A Pragmatic Effectiveness Trial of a Nonpharmacologic Alternative for the Treatment of Postoperative Pain.

BACKGROUND: Percutaneous peripheral nerve stimulation (PNS) is an analgesic modality involving the insertion of a lead through an introducer needle followed by the delivery of electric current after needle withdrawal. This modality has been used extensively to treat chronic pain, but only small series have been published involving postoperative pain. The ultimate objective of this study is to determine the postoperative effects of percutaneous PNS following moderately to severely painful ambulatory surgery within a real-world clinical practice setting. The primary hypothesis is that surgical pain and opioid consumption during the initial 7 days after surgery will be reduced by percutaneous PNS compared with usual and customary analgesia (dual primary outcome measures). DESIGN: A multicenter pragmatic effectiveness trial. We are randomizing participants having painful orthopedic surgical procedures of the upper and lower extremity to receive 14 days of either 1) electrical stimulation or 2) sham in a double-masked fashion. End points are being assessed at various time points over 12 postoperative months. SUMMARY: The postoperative experience will be much improved if percutaneous PNS provides potent analgesia while concurrently decreasing opioid requirements following painful surgery. Because this modality can be administered for up to 60 days at home, it may provide postoperative analgesia that outlasts surgical pain yet has relatively few risks and, unlike opioids, has no systemic side effects or potential for abuse, addiction, and overdose. Percutaneous PNS has the potential to revolutionize postoperative analgesia as it has been practiced for the past century. This study will inform key stakeholders regarding an evidence-based nonpharmacologic approach to the management of postoperative pain.

Prognostic value of hypersensitivity reactions on epidural steroid injection outcomes: a phenotypic signature? A prospective cohort study.

BACKGROUND: Studies have found that diffuse pain, indicative of central sensitization, portends poor interventional outcomes. Multiple chemical sensitivities are associated with signs of central sensitization. We sought to prospectively determine whether hypersensitivity reactions (HR) were associated with epidural steroid injection (ESI) outcomes. METHODS: HR were classified as immune-related or non-immune-related and categorized by number (0=low, 1 or 2=intermediate, ≥3=high). The primary outcome measure was mean reduction in average leg pain score 1 month post-procedure. A positive outcome was defined as a two-point or greater decrease in average leg pain accompanied by satisfaction 1 month post-procedure. RESULTS: The mean number of immune-mediated and non-immune-mediated HR were 0.6±1.2 and 0.8±1.4, respectively. Individuals in the high (n=24) total HR group had a mean reduction in average leg pain of 0.1±2.7, compared with those in the low (n=61; 1.8±2.1, p=0.025) and intermediate groups (n=52; 1.6±3.1, p=0.060). For back pain and categorical successful outcome, those with fewer HR experienced greater benefit. There were no differences in outcomes when patients were stratified by immune-related HR. Among participants in the low, intermediate and high non-immune-mediated HR groups, the mean reductions in average leg pain scores were 1.7±2.5, 1.6±3.0, and -0.2±2.3, respectively (p = 0.002). 51%, 35%, and 12% of people with low, intermediate and high numbers of non-immune-mediated HR experienced a positive categorical outcome, respectively (p=0.007). CONCLUSIONS: Non-immune-related HR were inversely correlated with some ESI outcome measures.

Epidural steroids, etanercept, or saline in subacute sciatica: a multicenter, randomized trial.

BACKGROUND: Perineural inhibitors of tumor necrosis factor have recently generated intense interest as an alternative to epidural steroid injections for lumbosacral radiculopathy. OBJECTIVE: To evaluate whether epidural steroids, etanercept, or saline better improves pain and function in adults with lumbosacral radiculopathy. DESIGN: A multicenter, 3-group, randomized, placebo-controlled trial conducted from 2008 to 2011. Randomization was computer-generated and stratified by site. Pharmacists prepared the syringes. Patients, treating physicians, and nurses assessing outcomes were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00733096) SETTING: Military and civilian treatment centers. PATIENTS: 84 adults with lumbosacral radiculopathy of less than 6 months' duration. INTERVENTION: 2 epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by 2 weeks. MEASUREMENTS: The primary outcome measure was leg pain 1 month after the second injection. All patients had 1-month follow-up visits; patients whose condition improved remained blinded for the 6-month study period. RESULTS: The group that received epidural steroids had greater reductions in the primary outcome measure than those who received saline (mean difference, -1.26 [95% CI, -2.79 to 0.27]; P = 0.11) or etanercept (mean difference, -1.01 [CI, -2.60 to 0.58]; P = 0.21). For back pain, smaller differences favoring steroids compared with saline (mean difference, -0.52 [CI, -1.85 to 0.81]; P = 0.44) and etanercept (mean difference, -0.92 [CI,-2.28 to 0.44]; P = 0.18) were observed. The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments: steroids vs. etanercept (mean difference, -16.16 [CI, -26.05 to -6.27]; P = 0.002), steroids vs. saline (mean difference, -5.87 [CI, -15.59 to 3.85]; P = 0.23), and etanercept vs. saline (mean difference, 10.29 [CI, 0.55 to 20.04]; P = 0.04). More patients treated with epidural steroids (75%) reported 50% or greater leg pain relief and a positive global perceived effect at 1 month than those who received saline (50%) or etanercept (42%) (P = 0.09). LIMITATION: Short-term follow-up, small sample size, and a possibly subtherapeutic dose of etanercept. CONCLUSION: Epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, but larger studies with longer follow-up are needed to confirm their benefits. PRIMARY FUNDING SOURCE: The John P. Murtha Neuroscience and Pain Institute, International Spinal Intervention Society, and Center for Rehabilitation Sciences Research.

Does sensory stimulation threshold affect lumbar facet radiofrequency denervation outcomes? A prospective clinical correlational study.

BACKGROUND: Radiofrequency facet denervation is one of the most frequently performed procedures for chronic low back pain. Although sensory stimulation is generally used as a surrogate measure to denote sufficient proximity of the electrode to the nerve, no study has examined whether stimulation threshold influences outcome. METHODS: We prospectively recorded data in 61 consecutive patients undergoing lumbar facet radiofrequency denervation who experienced significant pain relief after medial branch blocks. For each nerve lesioned, multiple attempts were made to maximize sensory stimulation threshold (SST). Mean SST was calculated on the basis of the lowest stimulation perceived at 0.1-V increments for each medial branch. A positive outcome was defined as a ≥50% reduction in back pain coupled with a positive satisfaction score lasting ≥3 months. The relationship between mean SST and denervation outcomes was evaluated via a receiver's operating characteristic (ROC) curve, and stratifying outcomes on the basis of various cutoff values. RESULTS: No correlation was noted between mean SST and pain relief at rest (Pearson's r=-0.01, 95% confidence interval [CI]: -0.24 to 0.23, P=0.97), with activity (r=-0.17, 95% CI: -0.40 to 0.07, P=0.20), or a successful outcome. No optimal SST could be identified. CONCLUSIONS: There is no significant relationship between mean SST during lumbar facet radiofrequency denervation and treatment outcome, which may be due to differences in general sensory perception. Because stimulation threshold was optimized for each patient, these data cannot be interpreted to suggest that sensory testing should not be performed, or that high sensory stimulation thresholds obtained on the first attempt should be deemed acceptable.

Influencing leadership perceptions of patient safety through just culture training.

There are differences in perceptions of safety culture between healthcare leaders and staff. Evidence suggests that an organization's actual safety performance is more closely reflected in staff perceptions suggesting that frontline staff may be more aware than the leadership of actual patient safety challenges within their organization. Closing the perception gap between healthcare leaders and staff is critical to aligning the resources and strategies required to create a true culture of safety.

Incidence and root cause analysis of wrong-site pain management procedures: a multicenter study.

BACKGROUND: Medical errors exact an inordinate toll on healthcare costs. One of the most publicized and analyzed type of medical error is wrong-site surgery. Yet, despite the burgeoning number of procedures performed, no literature exists on wrong-site pain management injections. The purpose of this study was to estimate the relative incidence and determine the causes of wrong-site pain management procedures. METHODS: Quality improvement records were examined during a 2-yr period from four civilian academic teaching hospitals, three military treatment facilities, and three private practices, for "sentinel" events involving wrong-site pain management procedures. A total of 13 cases (incidence 0.027%; 95% CI 0.01-0.05%) were identified from approximately 48,941 collective procedures of which 52.4% were deemed to be "at risk" for the occurrence. Root cause analyses were then conducted to determine the origin of each error. RESULTS: The 13 cases included five wrong-side transforaminal epidural steroid injections, six other wrong-side injections, and two wrong-level minimally invasive surgical procedures. In only one case was the "universal protocol" completely followed, and in nine procedures, multiple lapses occurred in protocol. Three patients had bilateral pathology, and in seven cases, the patient knew at the time that the wrong side was being injected. In no instance did any technical, legal, or professional consequences ensue from the error. CONCLUSIONS: Wrong-site nerve blocks occur more frequently in pain management centers than has previously been acknowledged. Adaptation of the universal protocol to nerve blocks and strict adherence to widely accepted guidelines may prevent wrong-site interventional pain procedures.

Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica.

BACKGROUND: Recent evidence implicates the inflammatory cytokine tumor necrosis factor as a major cause of radiculopathy. Yet, whereas open-label studies with systemically delivered tumor necrosis factor inhibitors have yielded positive results, a placebo-controlled study failed to demonstrate efficacy. One variable that may have contributed to poor outcomes is low drug levels at the site of nerve inflammation. To date, no studies have evaluated the efficacy or safety of epidurally administered anti-tumor necrosis factor agents. METHODS: A double-blind, placebo-controlled, dose-response study was conducted to evaluate an epidural tumor necrosis factor inhibitor. Twenty-four patients with subacute lumbosacral radiculopathy were randomly assigned to receive two transforaminal epidural injections of 2, 4, or 6 mg of entanercept 2 weeks apart in successive groups of eight. In each group, two patients received epidural saline. A parallel epidural canine safety study was conducted using the same injection doses and paradigm as in the clinical study. RESULTS: The animal and human safety studies revealed no behavioral, neurologic, or histologic evidence of drug-related toxicity. In the clinical arm, significant improvements in leg and back pain were collectively noted for the etanercept-treated patients, but not for the saline group, one month after treatment. One patient in the saline group (17%), six patients in the 2-mg group (100%), and four patients each in the 4-mg and 6-mg groups (67%) reported at least 50% reduction in leg pain and a positive global perceived effect one month after treatment. Six months after treatment, the beneficial effects persisted in all but one patient. CONCLUSION: Epidural entanercept holds promise as a treatment for lumbosacral radiculopathy.

A double-blind, placebo-controlled, dose-response pilot study evaluating intradiscal etanercept in patients with chronic discogenic low back pain or lumbosacral radiculopathy.

BACKGROUND: In recent years, convincing evidence has emerged implicating tumor necrosis factor alpha as a causative factor in radiculopathy and discogenic back pain. But although preliminary open-label studies demonstrated promising results for the treatment of low back pain with tumor necrosis factor-alpha inhibitors, early optimism has been tainted by a controlled study showing no significant benefit in sciatica. To determine whether outcomes might be improved by a more direct route of administration, the authors evaluated escalating doses of intradiscal etanercept in 36 patients with chronic lumbosacral radiculopathy or discogenic low back pain. METHODS: A double-blind, placebo-controlled pilot study was conducted whereby six patients received 0.1, 0.25, 0.5, 0.75, 1.0, or 1.5 mg etanercept intradiscally in each pain-generating disc. In each escalating dose group of six patients, one received placebo. A neurologic examination and postprocedure leukocyte counts were performed in all patients at 1-month follow-up visits. In patients who experienced significant improvement in pain scores and function, follow-up visits were conducted 3 and 6 months after the procedure. RESULTS: At 1-month follow-up, no differences were found for pain scores or disability scores between or within groups for any dose range or subgroup of patients. Only eight patients remained in the study after 1 month and elected to forego further treatment. No complications were reported, and no differences were noted between preprocedure and postprocedure leukocyte counts. CONCLUSIONS: Although no serious side effects were observed in this small study, a single low dose of intradiscal etanercept does not seem to be an effective treatment for chronic radicular or discogenic low back pain.

Presentation, diagnoses, mechanisms of injury, and treatment of soldiers injured in Operation Iraqi Freedom: an epidemiological study conducted at two military pain management centers.

UNLABELLED: In recent military conflicts the major source of soldier attrition has not been battle injuries but more mundane causes similar to those encountered in civilian life. In an effort to determine the pain conditions affecting soldiers during wartime, we conducted an observational study among 162 soldiers medically evacuated from Operation Iraqi Freedom who were referred to 2 large pain treatment centers located outside the theaters of combat. Fifty-three percent of soldiers presented with either radicular (n = 49) or axial (n = 37) low back pain, with lumbar herniated disk being the most frequently diagnosed condition (24%). The two most implicated etiologies were exacerbation of a previous pain condition treated with surgery (15%) and motor vehicle accidents(12%). Only 17% of patients were injured during battle. Seventy-two percent of soldiers received at least one nerve block/injection, the most common of which was lumbar epidural steroid administration (22%). Nonsteroidal antiinflammatory drugs were prescribed to 56% of patients, opioids to 49%, and some form of alternative therapy to 17%. Among the 49 patients in whom data were available, only 2% returned to combat duty in Iraq. With the exception of battle-related injuries, the pain conditions suffered during modern warfare seem to be similar to those encountered in civilian pain clinics. To improve the return-to-duty rate, better preventive measures and more aggressive treatment conducted in forward-deployed medical units are recommended. IMPLICATIONS: We conducted an observational study at two large military pain treatment centers among soldiers injured in Operation Iraqi Freedom. Fifty-three percent of soldiers presented with low back pain, with lumbar herniated disk being the most common diagnosis. Only 2% of patients returned to combat duty in Iraq. To improve the return-to-duty rate, better preventive measures and more aggressive treatment in forward-deployed medical units are recommended.

Hemorrhagic shock in swine: nitric oxide and potassium sensitive adenosine triphosphate channel activation.

BACKGROUND: To determine the role of nitric oxide and adenosine triphosphate-sensitive potassium (KATP) vascular channels in vascular decompensation during controlled hemorrhagic shock in swine. METHODS: Thirty instrumented, anesthetized adolescent Yorkshire swine were subjected to controlled isobaric hemorrhage to a mean arterial pressure of 40 mmHg for 2 h (n = 6) or 4 h (n = 10) or 50 mmHg for 4 h (n = 8). An additional six animals were used as anesthetized instrumented time controls. During controlled hemorrhage, plasma and tissue samples were obtained every 30 to 60 min. Before euthanasia, tissue (carotid artery, lung, liver, and aorta) was obtained for analysis of nitrate concentrations and nitric oxide synthase activity. Isolated carotid artery ring reactivity to norepinephrine was also determined with and without glibenclamide. RESULTS: Animals hemorrhaged to 40 mmHg decompensated earlier than animals hemorrhaged to 50 mmHg. Plasma nitrate concentrations and nitric oxide synthase activity rose consistently throughout hemorrhage in both groups. However, they were substantially higher in the mean arterial pressure 40 group. Constitutive nitric oxide synthase activity was the major contributor to total nitric oxide synthase activity throughout the protocol with only the animals maintained at 40 mmHg for 4 h showing evidence of inducible nitric oxide synthase activity. Profound KATP channel activation and hyporeactivity of isolated vessel rings to norepinephrine was not observed until 4 h after the initiation of hemorrhagic shock. Only those animals with inducible nitric oxide synthase activity showed a decreased response to norepinephrine, and this hyporeactivity was reversed with the KATP channel inhibitor, glibenclamide. CONCLUSIONS: The data indicate that profound KATP activation associated with increased nitric oxide concentrations and inducible nitric oxide synthase induction is a key factor in vascular smooth muscle hyporeactivity characteristic of the late decompensatory phase of hemorrhagic shock in swine.

Crystal structure of human L-isoaspartyl methyltransferase.

The enzyme l-isoaspartyl methyltransferase initiates the repair of damaged proteins by recognizing and methylating isomerized and racemized aspartyl residues in aging proteins. The crystal structure of the human enzyme containing a bound S-adenosyl-l-homocysteine cofactor is reported here at a resolution of 2.1 A. A comparison of the human enzyme to homologs from two other species reveals several significant differences among otherwise similar structures. In all three structures, we find that three conserved charged residues are buried in the protein interior near the active site. Electrostatics calculations suggest that these buried charges might make significant contributions to the energetics of binding the charged S-adenosyl-l-methionine cofactor and to catalysis. We suggest a possible structural explanation for the observed differences in reactivity toward the structurally similar l-isoaspartyl and d-aspartyl residues in the human, archael, and eubacterial enzymes. Finally, the human structure reveals that the known genetic polymorphism at residue 119 (Val/Ile) maps to an exposed region away from the active site.

Protein repair methyltransferase from the hyperthermophilic archaeon Pyrococcus furiosus. Unusual methyl-accepting affinity for D-aspartyl and N-succinyl-containing peptides.

Protein l-isoaspartate-(d-aspartate) O-methyltransferases (EC ), present in a wide variety of prokaryotic and eukaryotic organisms, can initiate the conversion of abnormal l-isoaspartyl residues that arise spontaneously with age to normal l-aspartyl residues. In addition, the mammalian enzyme can recognize spontaneously racemized d-aspartyl residues for conversion to l-aspartyl residues, although no such activity has been seen to date for enzymes from lower animals or prokaryotes. In this work, we characterize the enzyme from the hyperthermophilic archaebacterium Pyrococcus furiosus. Remarkably, this methyltransferase catalyzes both l-isoaspartyl and d-aspartyl methylation reactions in synthetic peptides with affinities that can be significantly higher than those of the human enzyme, previously the most catalytically efficient species known. Analysis of the common features of l-isoaspartyl and d-aspartyl residues suggested that the basic substrate recognition element for this enzyme may be mimicked by an N-terminal succinyl peptide. We tested this hypothesis with a number of synthetic peptides using both the P. furiosus and the human enzyme. We found that peptides devoid of aspartyl residues but containing the N-succinyl group were in fact methyl esterified by both enzymes. The recent structure determined for the l-isoaspartyl methyltransferase from P. furiosus complexed with an l-isoaspartyl peptide supports this mode of methyl-acceptor recognition. The combination of the thermophilicity and the high affinity binding of methyl-accepting substrates makes the P. furiosus enzyme useful both as a reagent for detecting isomerized and racemized residues in damaged proteins and for possible human therapeutic use in repairing damaged proteins in extracellular environments where the cytosolic enzyme is not normally found.