John D. Loeser

Pharmacologic management of neuropathic pain: evidence-based recommendations.

Abstract Patients with neuropathic pain (NP) are challenging to manage and evidence‐based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically‐sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first‐line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel α2‐δ ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second‐line treatments that can be considered for first‐line use in select clinical circumstances. Other medications that would generally be used as third‐line treatments but that could also be used as second‐line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N‐methyl‐d‐aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long‐term studies, head‐to‐head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.

The Kyoto protocol of IASP Basic Pain Terminology

Around the same time that representatives of national governments met in Bali to discuss the world climate and the Kyoto protocol on carbon dioxide emissions, IASP council, at its annual meeting held in Kyoto in November 2007, approved the publication of modifications to the IASP Basic Pain Terminology on its website. These modifications were prepared by the IASP Task Force on Taxonomy and were reviewed by the entire Editorial Board of the journal, Pain. The debate at IASP council was less heated than the political one that addressed the earth’s climate, but like its predecessors, the 2008 IASP Pain Terminology is likely to provoke a continuing debate among clinicians and researchers. In this Topical review, we briefly outline the rationale for the modifications in terminology.

A new definition of neuropathic pain

1. IntroductionIASP has recently published a new definition of neuropathic pain according to which neuropathic pain is defined as “pain caused by a lesion or disease of the somatosensory system” (www.iasp-pain.org/resources/painDefinition). This definition replaces the 17-year old definition that ap

Towards a mechanism-based classification of pain?

It is self evident that the recent explosive growth in our understanding of the molecular, cellular and system’s mechanisms responsible for nociception and pain has important implications for the clinical diagnosis and treatment of pain. A small group of independent basic scientists and clinicians met in New York in January 1998, for a wide ranging discussion on the possible need for and implications of a mechanism-based classification of pain. The group believed that acceptance of a mechanism-based classification could have profound implications: drugs may be developed which target distinct mechanisms, basic scientists may have new guidelines for experimental design, and clinicians may be eventually armed with more reliable and valid diagnostic tools for treatment and clinical investigation. Furthermore, a mechanism-based classification for clinical syndromes might generate testable hypotheses for selecting treatments which interact with specific mechanisms. We wish to initiate a wide debate on this important topic by highlighting what we consider to be some of the key issues. In general, taxonomies can be either natural or artificial. Examples of each, respectively, are the division of objects into animate or inanimate groups (which reflects order in nature) and a telephone book (which is merely a conventional way of listing peoples’ numbers and addresses). Natural taxonomies are based on theoretical ideas of how the world is organized. Artificial taxonomies provide convenient or practical methods for organizing the world. Consequently they do not easily facilitate the development of new ideas. A mechanism-based classification of pain requires a conceptual understanding of organization in nature, and would, therefore, set a framework for scientific development. Current methods of classifying pain have, we believe, a number of major limitations. Pain syndromes are identified by parts of the body, duration, and causative agent. We believe that an anatomical-based classification of pain is limiting because the innervation of distinct anatomical regions is often analogous, bearing in mind differences of target organ innervated (e.g. skin vs. viscera), length of axon, myelination, etc. To the extent that universal mechanisms can be identified, anatomical differences should be disregarded in favor of mechanisms that apply to all parts of the body. The acute/chronic dichotomy is also not helpful. Acute and chronic do not readily differentiate mechanisms. The benign/malignant dichotomy too has no mechanistic basis for pain, although it will influence treatment strategies. Greater care needs also to be taken with the definition of terms such as allodynia and hyperalgesia. Both terms are a description of clinical symptoms and do not imply a mechanism. Allodynia (pain evoked by normally non-painful stimuli) is often used in the clinical context to refer to Ab-fiber mediated brush-evoked mechanical pain or an altered processing of sensory information in the CNS. However, there are several other distinct types of mechanical hypersensitivity that do not involve A b fibers and probably no significant central reorganization, but which present as pain evoked by commonly non-painful stimuli. Reduction in threshold is not, therefore, useful by itself, for a mechanistic classification. From a practical perspective, clinicians use classification systems to predict treatment responses as well as prognosis and to search for risk factors and morbidities. Ultimately any classification system must be judged on its utility for clinical practice and research. The most powerful systems could be organized by mechanism, by disease or etiology. In the neuropathic disease category, at least, the disease classification system was considered by the group to fail to Pain 77 (1998) 227–229

Morbidity and mortality in association with operations on the lumbar spine. The influence of age, diagnosis, and procedure.

We examined the rates of postoperative complications and mortality, as recorded in a hospital discharge registry for the State of Washington for the years 1986 through 1988, for patients who had had an operation on the lumbar spine. When patients who had had a malignant lesion, infection, or fracture are excluded, there were 18,122 hospitalizations for procedures on the lumbar spine, 84 per cent of which involved a herniated disc or spinal stenosis. The rates of morbidity and mortality during hospitalization, as well as the hospital charges, increased with the ages of the patients. The rate of complications was 18 per cent for patients who were seventy-five years or older. Nearly 7 per cent of patients who were seventy-five years old or more were discharged to nursing homes. Complications were most frequent among patients who had spinal stenosis, but multivariate analysis suggested that the complications associated with procedures for this condition were primarily related to the patients age and the type of procedure. Complications, length of hospitalization, and charges were higher for patients who had had a spinal arthrodesis than for those who had not. Over-all, operations for conditions other than a herniated disc were associated with more complications and greater use of resources, particularly when arthrodesis was performed, than were operations for removal of a herniated disc. No data on symptoms or functional results were available.

Mechanosensitivity of dorsal root ganglia and chronically injured axons: A physiological basis for the radicular pain of nerve root compression

&NA; The radicular pain of sciatica was ascribed by Mixter and Barr to compression of the spinal root by a herniated intervertebral disc. It was assumed that root compression produced prolonged firing in the injured sensory fibers and led to pain perceived in the peripheral distribution of those fibers. This concept has been challenged on the basis that acute peripheral nerve compression neuropathies are usually painless. Furthermore, animal experiments have rarely shown more than several seconds of repetitive firing in acutely compressed nerves or nerve roots. It has been suggested that “radicular pain” is actually pain referred to the extremity through activation of deep spinal and paraspinal nociceptors. Our experiments on cat lumbar dorsal roots and rabbit sural nerves have confirmed that acute compression of the root or nerve does not produce more than several seconds of repetitive firing. However, long periods of repetitive firing (5–25 min) follow minimal acute compression of the normal dorsal root ganglion. Chronic injury of dorsal roots or sural nerve produces a marked increase in mechanical sensitivity; several minutes of repetitive firing may follow acute compression of such chronically injured sites. Such prolonged responses could be evoked repeatedly in a population of both rapidly and slowly conducting fibers. Since mechanical compression of either the dorsal root ganglion or of chronically injured roots can induce prolonged repetitive firing in sensory axons, we conclude that radicular pain is due to activity in the fibers appropriate to the area of perceived pain.

Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications.

&NA; We conducted a systematic review of the literature on the effectiveness of spinal cord stimulation (SCS) in relieving pain and improving functioning for patients with failed back surgery syndrome and complex regional pain syndrome (CRPS). We also reviewed SCS complications. Literature searches yielded 583 articles, of which seven met the inclusion criteria for the review of SCS effectiveness, and 15 others met the criteria only for the review of SCS complications. Two authors independently extracted data from each article, and then resolved discrepancies by discussion. We identified only one randomized trial, which found that physical therapy (PT) plus SCS, compared with PT alone, had a statistically significant but clinically modest effect at 6 and 12 months in relieving pain among patients with CRPS. Similarly, six other studies of much lower methodological quality suggest mild to moderate improvement in pain with SCS. Pain relief with SCS appears to decrease over time. The one randomized trial suggested no benefits of SCS in improving patient functioning. Although life‐threatening complications with SCS are rare, other adverse events are frequent. On average, 34% of patients who received a stimulator had an adverse occurrence. We conclude with suggestions for methodologically stronger studies to provide more definitive data regarding the effectiveness of SCS in relieving pain and improving functioning, short‐ and long‐term, among patients with chronic pain syndromes.

Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society.

Study Design. Clinical practice guideline. Objective. To develop evidence-based recommendations on use of interventional diagnostic tests and therapies, surgeries, and interdisciplinary rehabilitation for low back pain of any duration, with or without leg pain. Summary of Background Data. Management of patients with persistent and disabling low back pain remains a clinical challenge. A number of interventional diagnostic tests and therapies and surgery are available and their use is increasing, but in some cases their utility remains uncertain or controversial. Interdisciplinary rehabilitation has also been proposed as a potentially effective noninvasive intervention for persistent and disabling low back pain. Methods. A multidisciplinary panel was convened by the American Pain Society. Its recommendations were based on a systematic review that focused on evidence from randomized controlled trials. Recommendations were graded using methods adapted from the US Preventive Services Task Force and the Grading of Recommendations, Assessment, Development, and Evaluation Working Group. Results. Investigators reviewed 3348 abstracts. A total of 161 randomized trials were deemed relevant to the recommendations in this guideline. The panel developed a total of 8 recommendations. Conclusion. Recommendations on use of interventional diagnostic tests and therapies, surgery, and interdisciplinary rehabilitation are presented. Due to important trade-offs between potential benefits, harms, costs, and burdens of alternative therapies, shared decision-making is an important component of a number of the recommendations.

Lumbar spinal fusion: A cohort study of complications, reoperations, and resource use in the medicare population

Regional variations in lumbar spinal fusion rates suggest a poor consensus on surgical indications. Therefore, complications, costs, and reoperation rates were compared for elderly patients undergoing surgery with or without spinal fusion. Subjects were Medicare recipients who underwent surgery in 1985, with 4 years of subsequent follow-up. There were 27,111 eligible patients, of whom 5.6% had fusions. Mean age was 72 years. Patients undergoing fusion had a complication rate 1.9 times greater than those who had surgery without fusion. The blood transfusion rate was 5.8 times greater, nursing home placement rate 2.2 times greater, and hospital charges 1.5 times higher (all P < 0.0005). Six-week mortality was 2.0 times greater for patients undergoing fusions (P = 0.025). Reoperation rates at 4 years were no lower for patients who had fusion surgery and results were similar in most diagnostic subgroups. Indications for fusion among older patients require better definition, preferably based on outcomes from prospective controlled studies.

Surgery for low back pain: A review of the evidence for an American pain society clinical practice guideline

Study Design. Systematic review. Objective. To systematically assess benefits and harms of surgery for nonradicular back pain with common degenerative changes, radiculopathy with herniated lumbar disc, and symptomatic spinal stenosis. Summary of Background Data. Although back surgery rates continue to increase, there is uncertainty or controversy about utility of back surgery for various conditions. Methods. Electronic database searches on Ovid MEDLINE and the Cochrane databases were conducted through July 2008 to identify randomized controlled trials and systematic reviews of the above therapies. All relevant studies were methodologically assessed by 2 independent reviewers using criteria developed by the Cochrane Back Review Group (for trials) and Oxman (for systematic reviews). A qualitative synthesis of results was performed using methods adapted from the US Preventive Services Task Force. Results. For nonradicular low back pain with common degenerative changes, we found fair evidence that fusion is no better than intensive rehabilitation with a cognitive-behavioral emphasis for improvement in pain or function, but slightly to moderately superior to standard (nonintensive) nonsurgical therapy. Less than half of patients experience optimal outcomes (defined as no more than sporadic pain, slight restriction of function, and occasional analgesics) following fusion. Clinical benefits of instrumented versus noninstrumented fusion are unclear. For radiculopathy with herniated lumbar disc, we found good evidence that standard open discectomy and microdiscectomy are moderately superior to nonsurgical therapy for improvement in pain and function through 2 to 3 months. For symptomatic spinal stenosis with or without degenerative spondylolisthesis, we found good evidence that decompressive surgery is moderately superior to nonsurgical therapy through 1 to 2 years. For both conditions, patients on average experience improvement either with or without surgery, and benefits associated with surgery decrease with long-term follow-up in some trials. Although there is fair evidence that artificial disc replacement is similarly effective compared to fusion for single level degenerative disc disease and that an interspinous spacer device is superior to nonsurgical therapy for 1- or 2-level spinal stenosis with symptoms relieved with forward flexion, insufficient evidence exists to judge long-term benefits or harms. Conclusion. Surgery for radiculopathy with herniated lumbar disc and symptomatic spinal stenosis is associated with short-term benefits compared to nonsurgical therapy, though benefits diminish with long-term follow-up in some trials. For nonradicular back pain with common degenerative changes, fusion is no more effective than intensive rehabilitation, but associated with small to moderate benefits compared to standard nonsurgical therapy.