Elon Eisenberg

Spinal cord stimulation versus conventional medical management for neuropathic pain: A multicentre randomised controlled trial in patients with failed back surgery syndrome

Abstract Patients with neuropathic pain secondary to failed back surgery syndrome (FBSS) typically experience persistent pain, disability, and reduced quality of life. We hypothesised that spinal cord stimulation (SCS) is an effective therapy in addition to conventional medical management (CMM) in this patient population. We randomised 100 FBSS patients with predominant leg pain of neuropathic radicular origin to receive spinal cord stimulation plus conventional medical management (SCS group) or conventional medical management alone (CMM group) for at least 6 months. The primary outcome was the proportion of patients achieving 50% or more pain relief in the legs. Secondary outcomes were improvement in back and leg pain, health‐related quality of life, functional capacity, use of pain medication and non‐drug pain treatment, level of patient satisfaction, and incidence of complications and adverse effects. Crossover after the 6‐months visit was permitted, and all patients were followed up to 1 year. In the intention‐to‐treat analysis at 6 months, 24 SCS patients (48%) and 4 CMM patients (9%) (p < 0.001) achieved the primary outcome. Compared with the CMM group, the SCS group experienced improved leg and back pain relief, quality of life, and functional capacity, as well as greater treatment satisfaction (p ⩽ 0.05 for all comparisons). Between 6 and 12 months, 5 SCS patients crossed to CMM, and 32 CMM patients crossed to SCS. At 12 months, 27 SCS patients (32%) had experienced device‐related complications. In selected patients with FBSS, SCS provides better pain relief and improves health‐related quality of life and functional capacity compared with CMM alone.

Neurolytic celiac plexus block for treatment of cancer pain : a meta-analysis

We performed a meta-analysis of the efficacy and safety of neurolytic celiac plexus block (NCPB) for cancer pain. A literature search yielded 59 papers, but data on NCPB in two or more patients was available in only 24 papers. Twenty-one studies were retrospective, one was prospective, and two were randomized and controlled. Cancer type was stated in 1117 of 1145 patients reported (63% pancreatic, 37% nonpancreatic). A bilateral posterior approach with 150-50 mL of 50%-100% alcohol was the most common technique. Nonradiologically guided NCPB was performed in 246 patients (32%); guidance was by computed tomography (CT) in 214 (28%), radiograph in 271 (34%), fluoroscopy in 36 (5%), or ultrasound in 7 (<1%). Good to excellent pain relief was reported in 878/989 patients (89%) during the first 2 wk after NCPB. Long-term followup beyond 3 mo revealed persistent benefit. Partial to complete pain relief continued in approximately 90% of patients alive at 3 mo post-NCPB and in 70%-90% until death even if beyond 3 mo post-NCPB. Patients with pancreatic cancer responded similarly to those with other intraabdominal malignancies. Common adverse effects were transient, including local pain (96%), diarrhea (44%), and hypotension (38%); complications occurred in 2%. This analysis suggests that: 1) NCPB has long-lasting benefit for 70%-90% of patients with pancreatic and other intraabdominal cancers, regardless of the technique used; 2) adverse effects are common but transient and mild; and 3) severe adverse effects are uncommon. (Anesth Analg 1995;80:290-5)

The effects of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation

OBJECTIVEAfter randomizing 100 failed back surgery syndrome patients to receive spinal cord stimulation (SCS) plus conventional medical management (CMM) or CMM alone, the results of the 6-month Prospective Randomized Controlled Multicenter Trial of the Effectiveness of Spinal Cord Stimulation (i.e., PROCESS) showed that SCS offered superior pain relief, health-related quality of life, and functional capacity. Because the rate of crossover favoring SCS beyond 6 months would bias a long-term randomized group comparison, we present all outcomes in patients who continued SCS from randomization to 24 months and, for illustrative purposes, the primary outcome (>50% leg pain relief) per randomization and final treatment. METHODSPatients provided data on pain, quality of life, function, pain medication use, treatment satisfaction, and employment status. Investigators documented adverse events. Data analysis included inferential comparisons and multivariate regression analyses. RESULTSThe 42 patients continuing SCS (of 52 randomized to SCS) reported significantly improved leg pain relief (P < 0.0001), quality of life (P ≤ 0.01), and functional capacity (P = 0.0002); and 13 patients (31%) required a device-related surgical revision. At 24 months, of 46 of 52 patients randomized to SCS and 41 of 48 randomized to CMM who were available, the primary outcome was achieved by 17 (37%) randomized to SCS versus 1 (2%) to CMM (P = 0.003) and by 34 (47%) of 72 patients who received SCS as final treatment versus 1 (7%) of 15 for CMM (P = 0.02). CONCLUSIONAt 24 months of SCS treatment, selected failed back surgery syndrome patients reported sustained pain relief, clinically important improvements in functional capacity and health-related quality of life, and satisfaction with treatment.

Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome.

Abstract Complex regional pain syndromes (CRPS, type I and type II) are devastating conditions that can occur following soft tissue (CRPS type I) or nerve (CRPS type II) injury. CRPS type I, also known as reflex sympathetic dystrophy, presents in patients lacking a well‐defined nerve lesion, and has been questioned as to whether or not it is a true neuropathic condition with an organic basis. As described here, glabrous and hairy skin samples from the amputated upper and lower extremity from two CRPS type I diagnosed patients were processed for double‐label immunofluorescence using a battery of antibodies directed against neural‐related proteins and mediators of nociceptive sensory function. In CRPS affected skin, several neuropathologic alterations were detected, including: (1) the presence of numerous abnormal thin caliber NF‐positive/MBP‐negative axons innervating hair follicles; (2) a decrease in epidermal, sweat gland, and vascular innervation; (3) a loss of CGRP expression on remaining innervation to vasculature and sweat glands; (4) an inappropriate expression of NPY on innervation to superficial arterioles and sweat glands; and (5) a loss of vascular endothelial integrity and extraordinary vascular hypertrophy. The results are evidence of widespread cutaneous neuropathologic changes. Importantly, in these CRPS type I patients, the myriad of clinical symptoms observed had detectable neuropathologic correlates.

Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis.

PURPOSE To assess the efficacy and safety of nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of cancer pain by meta-analyses of the published randomized control trials (RCTs). PATIENTS AND METHODS Twenty-five studies met inclusion criteria for analysis. Of these, 13 tested a single-dose effect, nine multiple-dose effects, and three both single- and multiple-dose effects of 16 different NSAIDs in a total of 1,545 patients. Baseline pain intensity (when provided) of moderate or higher was indicated in 81% of patients. RESULTS Single-dose NSAID studies found greater analgesic efficacy than placebo, with rough equivalence to 5 to 10 mg of intramuscular morphine. Pain scores differed insignificantly for aspirin versus three other NSAIDs. Analgesic responses to low- and high-dose NSAIDs suggested a dose-response relationship, but this was not statistically significant. Recommended and supramaximal single doses of three NSAIDs produced comparable changes in pain scores, which indicates a ceiling analgesic effect. Common side effects included upper gastrointestinal symptoms, dizziness, and drowsiness. The incidence of side effects showed a trend to increase with dose, without a ceiling effect, and to increase with multiple doses. Single or multiple doses of weak opioids (WO) alone or in combination (WO/C) with nonopioid analgesics did not produce greater analgesia than NSAIDs alone. Single doses of WO/C analgesics produced more side effects than NSAIDs alone, although both side effect incidence and patient dropout rates were equal when multiple doses were administered. CONCLUSION These findings question whether the traditional World Health Organization (WHO) second analgesic step (addition of a weak opioid when pain is inadequately treated by a nonopioid analgesic alone) is warranted. A lack of comparable studies precluded testing the hypothesis that NSAIDs are particularly effective for malignant bone pain.

The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial

&NA; Neuropathic pain is often severe, persistent, and responds poorly to analgesic medications. Recent evidence suggests that N‐methyl‐d‐aspartate (NMDA) receptor antagonists may be effective in the treatment of neuropathic pain. The present trial was designed to test the efficacy of acute administration of the NMDA receptor antagonist amantadine in relieving surgical neuropathic pain in patients with cancer. The study sample consisted of 15 cancer patients with the diagnosis of surgical neuropathic pain. Two 500 ml infusions of either 200 mg amantadine or placebo were administered over a 3 h period, in a randomized order, 1 week apart from each other. Spontaneous and evoked pain were measured for 48 h before treatment, during treatment, and for 48 h following treatment. An average pain reduction of 85% was recorded at the end of amantadine infusion vs. 45% following placebo administration. The difference in pain relief between the two treatments was statistically significant (P=0.009). Mean pain intensity remained significantly lower during the 48 h following amantadine treatment as compared with the 48 h prior to treatment (31% reduction; P=0.006), whereas no such effect was found with the placebo (6% reduction; P=0.40). Amantadine, but not the placebo, also reduced ‘wind up’ like pain (caused by repeated pinpricking) in four patients. We conclude that amantadine infusion is a safe and effective acute treatment for surgical neuropathic pain in cancer patients. Further trials with long‐term oral or parenteral amantadine treatment should be conducted.

The individual and societal burden of chronic pain in Europe: the case for strategic prioritisation and action to improve knowledge and availability of appropriate care

BackgroundChronic pain is common in Europe and elsewhere and its under treatment confers a substantial burden on individuals, employers, healthcare systems and society in general. Indeed, the personal and socioeconomic impact of chronic pain is as great as, or greater, than that of other established healthcare priorities. In light of review of recently published data confirming its clinical and socioeconomic impact, this paper argues that chronic pain should be ranked alongside other conditions of established priority in Europe. We outline strategies to help overcome barriers to effective pain care resulting in particular from deficiencies in education and access to interdisciplinary pain management services. We also address the confusion that exists between proper clinical and scientific uses of opioid medications and their potential for misuse and diversion, as reflected in international variations in the access to, and availability of, these agents.DiscussionAs the economic costs are driven in part by the costs of lost productivity, absenteeism and early retirement, pain management should aim to fully rehabilitate patients, rather than merely to relieve pain. Accredited education of physicians and allied health professionals regarding state-of-the-art pain management is crucial. Some progress has been made in this area, but further provision and incentivization is required. We support a tiered approach to pain management, whereby patients with pain uncontrolled by non-specialists are able to consult a physician with a pain competency or a specialist in pain medicine, who in turn can recruit the services of other professionals on a case-by-case basis. A fully integrated interdisciplinary pain service should ideally be available to patients with refractory pain. Governments and healthcare systems should ensure that their policies on controlled medications are balanced, safeguarding public health without undue restrictions that compromise patient care, and that physician education programmes support these aims.SummaryStrategic prioritization and co-ordinated actions are required nationally and internationally to address the unacceptable and unnecessary burden of uncontrolled chronic pain that plagues European communities and economies. An appreciation of the ‘return on investment’ in pain management services will require policymakers to adopt a long-term, cross-budgetary approach.

Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain.

Abstract Keratinocytes are implicated in sensory transduction and can influence nociception, but whether these contribute to chronic pain is not known. In neurons, voltage‐gated sodium channels (Nav) are involved in neuropathic pain and are activated by depolarization. Since keratinocytes can also show changes in membrane potential, we used RT‐PCR, in situ hybridization, and immunohistochemistry to investigate the expression of sodium channels in these cells. Nav1.1, Nav1.6, and Nav1.8 were localized within keratinocytes in rat epidermis. In addition, sodium channels contribute to the release of ATP from rat keratinocytes in response to increased [K+]o, implicating sodium channels in keratinocyte ligand release and nociception. To examine whether keratinocytes may contribute to human pain states, we analyzed sodium channel expression in human skin biopsies from subjects with complex regional pain syndrome Type 1 (CRPS) and post‐herpetic neuralgia (PHN) using immunohistochemistry. Control skin exhibited immunolabeling for Nav1.5, Nav1.6 and Nav1.7. In contrast, painful skin from CRPS and PHN subjects displayed Nav1.1, Nav1.2, and Nav1.8 immunolabeling, in addition to substantially increased signal for Nav1.5, Nav1.6, Nav1.7. These observations lead us to propose that pathological increases in keratinocyte sodium channel expression may contribute to pain by increasing epidermal ATP release, resulting in excessive activation of P2X receptors on primary sensory axons. Consistent with this hypothesis, animal models of neuropathic pain exhibit increases in subcutaneous ATP release and activity of primary sensory neurons, and peripheral administration of P2X antagonists has been shown to reduce neuropathic pain in humans.

Quality of life, resource consumption and costs of spinal cord stimulation versus conventional medical management in neuropathic pain patients with failed back surgery syndrome (PROCESS trial)

Background: Chronic back and leg pain conditions result in patients’ loss of function, reduced quality of life and increased costs to the society.

Prevalence and characteristics of post coronary artery bypass graft surgery pain (PCP)

&NA; Coronary artery bypass grafting (CABG) is one of the most common surgical procedures performed worldwide. However, its frequent complication, the post‐CABG pain (PCP) syndrome, remains poorly documented. This retrospective cohort study was aimed to investigate the prevalence and characteristics of this syndrome. Five hundred and four of 540 subjects, who underwent CABG surgery at our institution between January 1995 and December1996 and who could be identified, were mailed questionnaires regarding the presence and characteristics of chest wall pain. Eighty of 217 patients, who were defined as having PCP based on these questionnaires, were evaluated in detail. Main outcome measures included a preliminary pain questionnaire, pain localization on a body scheme, a five‐point verbal scale and the Visual Analogue Scale (VAS) for measuring pain intensity. Pain qualities, disability and depression were measured by the McGill Pain Questionnaire (MPQ), the Pain Disability Index (PDI), and the Beck Depression Inventory (BDI), respectively. Medical and neurological examinations were also conducted, as well as quantitative thermal testing (QTT) of the chest wall. The preliminary pain questionnaires indicated that 219 of the 387 respondents (56%) reported chest wall pain, which was categorized as PCP. One hundred and forty‐two (65%) of the patients with PCP reported pain of at least moderate severity, and 151 (72%) reported that the pain interfered with their daily activities. Eighty PCP patients were available for a detailed evaluation. Left‐sided chest wall pain was noted by 53 subjects, midline scar pain by 47, and right‐sided pain by nine subjects. Pain intensity (VAS) was 35±22 (mean±SD), MPQ score was 4.9±3.7, PDI score was 2.0±0.7, and BDI score was 9.3±7.3. The neurological examination and the QTT indicated three subcategories of PCP: (1) left‐sided chest wall pain often associated with hypoesthesia, mechanical allodynia, and elevated thermal thresholds; (2) midline scar pain accompanied primarily by mechanical allodynia; (3) right‐sided, relatively infrequent pain. While the first two subcategories seem to have a neurogenic etiology, this later subcategory of pain is of a mal‐defined etiology. This study indicates that PCP is a group of pain syndromes with a high prevalence, and with a negative effect on mood and performance of daily activities. The risk of developing PCP and its potential consequences should therefore be discussed with every patient prior to CABG surgery. These results will need to be confirmed in larger, multi‐center studies.