The dorsal root ganglion in chronic pain and as a target for neuromodulation: a review.

BACKGROUND: In the not-too-distant past, the dorsal root ganglion (DRG) was portrayed as a passive neural structure without involvement in the development or maintenance of chronic neuropathic pain (NP). The DRG was thought of as a structure that merely "supported" physiologic communication between the peripheral nervous system (PNS) and the central nervous system (CNS). Newer scientific information regarding the anatomic and physiologic changes that occur within the DRG as a result of environmental pressures has dispelled this concept and suggests that the DRG is an active participant in the development of NP. This new information, along with new clinical data showing that stimulation of the DRG reduces intensity of pain, suggests that the DRG can be a robust target for neuromodulation therapies. METHODS: A review of the anatomical and physiological literature regarding the role of the DRG in the development of NP was performed utilizing SciBase, PubMed, and Google Scholar. The information gathered was used to lay an anatomic and physiologic foundation for establishing the DRG as a relevant target for neuromodulation therapies and to formulate a hypothesis as to how electrical stimulation of the DRG might reverse the process and perception of NP. CONCLUSIONS: The DRG is an active participant in the development of NP. DRG stimulation has multiple effects on the abnormal changes that occur within the DRG as a result of peripheral afferent fiber injury. The sum total of these stimulation effects is to stabilize and decrease hyperexcitability of DRG neurons and thereby decrease NP.

The role of the dorsal root ganglion in the development of neuropathic pain.

BACKGROUND: The dorsal root ganglion (DRG), in the not too distant past, had been thought of as a passive organ not involved in the development of abnormal aberrent neuropathic pain (NP), but merely metabolically "supporting" physiologic functions between the peripheral nervous system (PNS) and the central nervous system (CNS). New information regarding metabolic change within the DRG has dispelled this supportive passive role and suggests that the DRG is an active, not a passive, organ, in the process of the development of chronic pain. METHODS: A review of the anatomic and physiologic literature utilizing PubMed and Google Scholar was performed to create a review of the anatomic and physiologic foundations for the development of NP after peripheral afferent fiber injury. CONCLUSIONS: The DRG is as involved in the process of generating NP as is the nociceptor and the dorsal horn of the spinal cord.

A history of intraspinal analgesia, a small and personal journey.

INTRODUCTION: There is a large and robust literature on the spinal use of opioids and non-opioids alike, but unless one is my age and older, very few persons know how we got here. This small history offering tells us how we got to where we are today regarding the science, clinical uses, and management of intraspinal analgesia. METHODS: I have reviewed the literature bases of Google Scholar and the National Library of Medicine using the key words: history, opium, spinal analgesia, spinal morphine, intrathecal (IT), opioid receptors, endogenous opioids, IT delivery of opioids, and IT side-effects/complications. RESULTS: In this personal review of the history of intraspinal analgesia, I relate my own early and later experiences of the science and clinical uses of intraspinal morphine, other opioids, and non-opioids alike to a historical context. This review outlines a rather small history of opium, the historical use of opium and its various compounds, and the search for and answer to the question, "why was the poppy created for wondrous medicinal uses for mankind?" This search led to the discovery of endogenous opioid like chemicals, the discovery of opiate receptors for these endogenous opioids, the first uses of intraspinal opioids in animal models and man, and, finally, our understanding of the appropriate and inappropriate clinical uses of intraspinal analgesia. Within this paper, I acknowledge the works of my colleagues and the "heroes" who have laid the foundation for our understanding of intraspinal analgesia. CONCLUSIONS: The history of the use of intraspinal analgesia is rich and guides us to advance the science and clinical use of intraspinal analgesia without reinventing the wheel.

Using the SAFE principles when evaluating electrical stimulation therapies for the pain of failed back surgery syndrome.

OBJECTIVE: In this paper we review the literature on failed back surgery syndrome (FBSS) and use principles of Safety, Appropriateness, Fiscal Neutrality, and Effectiveness (SAFE) to determine the appropriate place for spinal cord stimulation (SCS) for the treatment of FBSS. METHODS AND RESULTS: We analyzed the most recent literature regarding treatments of pain due to FBSS and used the SAFE principles to reprioritize pain treatments, particularly electrical stimulation therapies, for FBSS in a more appropriate, relevant, and up to date continuum of care. CONCLUSIONS: Based on this review and analysis of the safety, appropriateness, cost-effectiveness, and efficacy of treatments for the pain of FBSS, relegating SCS to a last resort therapy is no longer justifiable. SCS should be considered before submitting a patient to either long-term systemic opioid therapy or repeat spinal surgery for chronic pain resulting from FBSS.

"On the shoulders of giants": a history of the understandings of pain, leading to the understandings of neuromodulation.

The history of the use of electrical stimulation for pain is a cavalcade of research and innovation of many great scholars, scientists, and physicians over centuries that continues up to the present day. The legacy of this philosophy, research, and innovation is the field of neuromodulation for pain control. Today, patients with chronic pain from damage to the nervous system and chronic pain of the extremities, the axial low back, and neck, the face, and the viscera, all derive benefit from these early pioneers that have led to the expanding field of neuromodulation ... "on the shoulders of giants." We present here a history of the understandings of pain from the ancients to the present, which has led to our understandings of the use of electricity to cure disease and release patients from their suffering, generating the new, exciting, and expanding field of neuromodulation.

Successful long-term outcomes of spinal cord stimulation despite limited pain relief during temporary trialing.

Objectives. In spinal cord stimulation (SCS) therapy, limited pain relief during the temporary trial period is generally considered to be predictive of poor long-term benefit. To validate or refute this perception, the long-term outcomes of subjects who reported less than 50% pain relief during a temporary SCS trial were examined. Materials and Methods. Twelve subjects with intractable pain underwent implantation of trial SCS systems. After a trial period in which they reported less than 50% pain relief, they each received a permanent SCS implant. Pain ratings and complications were tracked for 6-18 months. Results. At the end of the temporary trial period, the average pain relief was 21%; no subject reported 50% or better pain relief. More favorable outcomes were reported after activation of the permanent system, however. At all follow-up time points, at least a third of the subjects reported better than 50% pain relief, and the average pain relief varied over time between 44% and 83%. All complications were readily resolved and no subjects withdrew from the study. Conclusions. Although SCS provided limited pain relief during the trial period, efficacy was more satisfactory after permanent implantation. Several subjects went on to experience nearly complete pain relief for up to 18 months (the maximum follow-up visit for study purposes), and no subject chose to discontinue SCS therapy. SCS appears to be a viable treatment option for patients who fail trials, raising some doubt as to the predictive sensitivity and specificity of the trial period. Thus, although outcome of a temporary trial period may be suggestive of later efficacy with SCS, it may not be the sole predictor of success. Alternatively, the arbitrary benchmark of 50% pain relief that is typically used to define the success of a temporary trial may be too stringent and unreliable.

Management of intrathecal catheter-tip inflammatory masses: an updated 2007 consensus statement from an expert panel.

Background. Expert panel of physicians and nonphysicians, all expert in intrathecal (IT) therapies, convened in the years 2000 and 2003 to make recommendations for the rational use of IT analgesics based on the preclinical and clinical literature known up to those times, presentations of the expert panel, discussions on current practice and standards, and the result of surveys of physicians using IT agents. An expert panel of physicians and convened in 2007 to review previous recommendations and to form recommendations for the rational use of IT agents as they pertain to new scientific and clinical information regarding the etiology, prevention and treatment for IT granuloma. Method. A review of preclinical and clinical literature from 2000 to 2006 was undertaken and disseminated to an expert panel of physicians. Focused discussions concerning the rational use of IT agents and its relationship to the etiology of, prevention of, and treatment of IT granuloma were held. Results. This report presents here new knowledge of the etiology of catheter tip granuloma and guidelines for its prevention and treatment.

Future directions for intrathecal pain management: a review and update from the interdisciplinary polyanalgesic consensus conference 2007.

Background. Expert panels of physicians and nonphysicians, all expert in intrathecal (IT) therapies, convened in the years 2000 and 2003 to make recommendations for the rational use of IT analgesics, based on the preclinical and clinical literature known up to those times, presentations of the expert panels, discussions on current practice and standards, and the result of surveys of physicians using IT agents. An expert panel of physicians and nonphysicians has convened in 2007 to update information known regarding IT therapies and to update information on new and novel opioid and nonopioid analgesic compounds that might show promise for IT use. Methods. A review of preclinical and clinical published relevant studies from 2000 to 2006 was undertaken and disseminated to a convened expert panel of physicians and nonphysicians to discuss new and novel analgesic agents for IT use. Results. The panelists identified several agents that were worthy of future studies for the clinical and rational use of IT agents that are presented in this article. Conclusions. A list of nonopioid IT analgesics, including gabapentin, adenosine, octreotide, the χ-conopeptide, Xen2174, the conopeptide, neurotensis 1 agonist, CGX-1160, the ω-conotoxin, AM-336, and physostigmine, were identified as worthy of future research by the panelists.

Spinal cord stimulation has comparable efficacy in common pain etiologies.

Objectives. The probability of success with spinal cord stimulation (SCS) depends largely on appropriate patient selection. Here, we have assessed the predictive value of pain etiology as it relates to pain relief with SCS as part of a prospective multicenter clinical trial. Methods. Sixty-five subjects with chronic and intractable pain tested an epidural SCS system. Subjects reported pain ratings (visual analog scale) with stimulation off and stimulation on at scheduled follow-up visits for up to 18 months after activation of the system. Visual analog scale scores were averaged and stratified by dominant pain etiologies, comprising failed back surgery syndrome, complex regional pain syndrome, and a subgroup of subjects with miscellaneous other pain etiologies. Results. More than 70% of subjects in each subgroup had successful outcomes during the temporary trial period and similar percentages of subjects from each etiology subgroup subsequently went on to permanent implantation. After permanent implantation, all subgroups reported more than 50% pain relief, on average, at each follow-up time point. No predictive value of pain etiology was observed. Conclusions. Spinal cord stimulation is an effective therapy for neuropathic pain arising from a variety of causes. Failed back surgery syndrome, complex regional pain syndrome, and pain of other etiologies responded equally well to SCS.

Spinal Cord Stimulation Modulates Visceral Nociception and Hyperalgesia via the Spinothalamic Tracts and the Postsynaptic Dorsal Column Pathways: A Literature Review and Hypothesis.

Introduction. Early animal and human evidence existed for a postsynaptic dorsal column (PSDC) pathway for visceral nociception that, when lesioned, decreased pain of terminal illness. There have been recent anecdotal reports in the literature that spinal cord stimulation (SCS) reduces pain of visceral nociception. We present here a review of the literature supporting a hypothesis that SCS might work by modulating information through the spinothalamic tracts (STT) and PSDC. Methods. A review of the relevant literature regarding nociception, nociceptive transmission, visceral sensitization, and the "brain-gut" axis; and SCS was performed as a foundation for this hypothesis. Key words used for this review of databases and nonindexed relevant journals included visceral pain, visceral nociception, visceral hyperalgesia, visceral neuropathic pain, visceral sensitization, "brain-gut" axis, SCS, PSDC pathway, and STTs. Results. An abundance of both clinical and scientific literature suggests the neuropathic and sensitized nature of chronic visceral nociception. There is also evidence that there may be an interaction between the PSDC pathway and lateral spinothalamic tracts (LSTT) that might be operant in the preclinical and anecdotal clinical evidence that SCS ameliorates the pain of visceral nociception. Conclusions. Chronic visceral nociception may be secondary to visceral sensitization and hyperalgesia and can be affected by the spinal cord and brain, the "brain-gut" axis. There is preclinical evidence and clinical anecdotes that this nociceptive information is transmitted in the central nervous system through the PSDC pathway and LSTT and that SCS decreases pain of visceral nociception. It may be that SCS works by modulation of the above pathways.

A new spinal cord stimulation system effectively relieves chronic, intractable pain: a multicenter prospective clinical study.

Objectives. A prospective, open label, multicenter clinical trial confirmed the functionality of a new spinal cord stimulation (SCS) system for the treatment of chronic, intractable pain of the trunk and/or limbs. Materials and Methods. Sixty-five subjects tested a rechargeable 16-channel SCS system with individual current control of each contact on one or two percutaneous eight-contact epidural leads. After baseline measurements, subjects were tracked on pain ratings and complication rates for up to 18 months. Results. After a trial period, 75% of subjects underwent permanent implantation of the entire SCS system. More than one-half the implanted subjects experienced 50% or greater relief of pain after permanent implantation; some subjects reported relief of 90% or more of their pain. The most common complications after permanent implantation were lead migration, uncomfortable stimulation, and component failure; most resolved after reprogramming or device replacement. Conclusions. The new SCS system provided good pain relief to a majority of subjects, and the results confirm a favorable safety and efficacy profile for the SCS system.

Polyanalgesic consensus conference 2007: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.

Background. Expert panels of physicians and nonphysicians in the field of intrathecal therapies convened in 2000 and 2003 to make recommendations for the rational use of intrathecal analgesics based on the preclinical and clinical literature known up to those times. An expert panel of physicians convened in 2007 to update previous recommendations and to form guidelines for the rational use of intrathecal opioid and nonopioid agents. Methods. A review of preclinical and clinical published relevant studies from 2000 to 2006 was undertaken and disseminated to a convened expert panel of physicians and nonphysicians. Focused discussions were held on the rational use of intrathecal agents and a survey asking questions regarding intrathecal therapies management was given to the panelists. Results. The panelists, after review of the literature from 2000 to 2006 and discussion, created an updated algorithm for the rational use of intrathecal opioid and nonopioid agents in patients with nonmalignant and end-of-life pain. Of note is that the panelists felt that ziconotide, based on new and relevant literature and experience, should be updated to a line one intrathecal drug.

Technique that better localizes the dura mater during intrathecal catheterization should reduce inadvertent multiple dural punctures and reduce complications.

We present here a technique to mitigate the complication of multiple needle entries into the thecal sac when attempting to place an intrathecal catheter into the thecal sac. Our technique of injecting radio-opaque contrast material after entering the epidural space and before entering the thecal sac allows for visualization of the thecal sac within the spinal canal, thus obviating the technique of "fell and pop" to enter the sac. In our hands, this technique has improved outcomes for our patients and has decreased the incidence of post dural puncture headache, neural trauma and technical failures.

The effect of spinal cord stimulation, overall, and the effect of differing spinal cord stimulation technologies on pain, reduction in pain medication, sleep, and function.

Background. Spinal cord stimulation (SCS) is effective in reducing pain from a number of differing medical conditions that are refractory to other, more conservative treatments. Much is written in the literature regarding efficacy and safety of SCS; however, no one to our knowledge has compared and reported safety and efficacy of SCS when using differing manufactured SCS devices. We undertook such a preliminary evaluation. Methods. Charts from the years 2001-2005 of our clinic's patients who had undergone trials and placement of permanent SCS systems were selected for review. All patients who had received either an Advanced Bionics SCS system (Advanced Bionics, Valencia, CA, USA), an Advanced Neuromodulation Systems (ANS) SCS system (ANS, Plano, TX, USA), or a Medtronic SCS system (Medtronic, Inc., Minneapolis, MN, USA) were given a survey to complete for data analysis. Patients were categorized into three groups: those patients having received a Medtronic (Mdt) SCS system, those patients having received an Advance Bionics (ABi) SCS system, and those patients having received an Advance Neuromodulation Systems (ANS) SCS system. Data, limited to volunteers, who gave their written consent, were analyzed for efficacy and complications. Differences in outcomes and safety were analyzed overall and according to manufacturer. Results. Eighty surveys were mailed out to 80 patients and 30 surveys were completed and returned, a return and completion rate of 37.5%. All patients showed improvement in all aspects including pain relief, sleep, functional activities, and medication use for pain control. When comparing outcomes of SCS from the three different companies, there was no significant statistical difference in average percentage pain relief, sleep improvement, and medication needed for pain control. However, there was a statistically different less change in functional improvement in the ABi group when compared to patients in the Mdt and ANS groups. Conclusions. Spinal cord stimulation improves pain, sleep, and function in patients with intractable pain. Because of the low number of patients evaluable in this study, we believe that conclusions should not be made regarding the effect of technology on outcomes or safety. We believe that an analysis of this type in larger populations is warranted to understand the role, if any, that present-day technology has on outcomes of SCS.

Polyanalgesic Consensus Conference 2003: an update on the management of pain by intraspinal drug delivery-- report of an expert panel.

Intraspinal drug infusion using fully implantable pump and catheter systems is a safe and effective therapy for selected patients with chronic pain. The options for this approach are increasing, as drugs that are commercially available for systemic administration are adapted to this use and other drugs that are in development specifically for intraspinal administration become available. In 2000 a Polyanalgesic Consensus Conference was organized to evaluate the existing literature and develop guidelines for drug selection. The major outcome of this effort, an algorithm for drug selection, was based on the best available evidence at the time. Rapid changes have occurred in the science and practice of intraspinal infusion and a Polyanalgesic Consensus Conference 2003 was organized to pursue the following goals: 1) to review the literature on intraspinal drug infusion since 1999, 2) to revise the 2000 drug-selection algorithm, 3) to develop guidelines for optimizing drug dosage and concentration, 4) to create a process for documenting minimum evidence supporting the use of a drug for intraspinal infusion, and 5) to clarify issues pertaining to compounding of drugs. Based on the best available evidence and expert opinion, consensus recommendations were developed in all these areas. The panel's conclusions may provide a foundation for clinical practice and a rational basis for new research.