[Show abstract][Hide abstract] ABSTRACT: Clinical guidelines are a constructive response to the reality that practicing physicians require assistance in assimilating and applying the exponentially expanding, often contradictory, body of medical knowledge. They attempt to define practices that meet the needs of most patients under most circumstances. Ideally, specific clinical recommendations contained within practice guidelines are systematically developed by expert panels who have access to all the available evidence, have an understanding of the clinical problem, and have clinical experience with the procedure being assessed, as well as knowledge of relevant research methods. The recent development of American Pain Society (APS) guidelines has created substantial controversy because of their perceived lack of objective analysis and recommendations perceived to be biased due to conflicts of interest.
To formally and carefully assess the APS guidelines' evidence synthesis for low back pain for therapeutic interventions using the same methodology utilized by the APS authors. The interventions examined were therapeutic interventions for managing low back pain, including epidural injections, adhesiolysis, facet joint interventions, and spinal cord stimulation.
A literature search by 2 authors was carried out utilizing appropriate databases from 1966 through July 2008. Articles in which conflicts arose were reviewed and mediated by a third author to arrive at a consensus. Selections of manuscripts and methodologic quality assessment was also performed by at least 2 authors utilizing the same criteria applied in the APS guidelines. The guideline reassessment process included the evaluation of individual studies and systematic reviews and their translation into practice recommendations.
The conclusions of APS and our critical assessment based on grading of good, fair, and poor, agreed that there is fair evidence for spinal cord stimulation in post lumbar surgery syndrome, and poor evidence for lumbar intraarticular facet joint injections, lumbar interlaminar epidural injections, caudal epidural steroids for conditions other than disc herniation or radiculitis, sacroiliac joint injections, intradiscal electrothermal therapy, endoscopic adhesiolysis, and intrathecal therapy. However, our assessment of APS guidelines for other interventional techniques, utilizing their own criteria, showed fair evidence for therapeutic lumbar facet joint nerve blocks, caudal epidural injections in disc herniation or radiculitis, percutaneous adhesiolysis in post lumbar surgery syndrome, radiofrequency neurotomy, and transforaminal epidural injections in radiculitis. Also it is illustrated that inclusion of latest literature will change the conclusions, with improved grading - caudal epidural, adhesiolysis, and lumbar facet joint nerve blocks from fair to good or poor to fair. The present critical assessment review illustrates that APS guidelines have utilized multiple studies inappropriately and have excluded appropriate studies. Our integrity assessment shows deep concerns that the APS guidelines illustrating significant methodologic failures which raise concerns about transparency, accountability, consistency, and independence.
The current reassessment, using appropriate methodology, shows evidence similar to APS guidelines for several procedures, but differs extensively from published APS guidelines for multiple other procedures including caudal epidural injections, lumbar facet joint nerve blocks, lumbar radiofrequency neurotomy, and percutaneous adhesiolysis.
[Show abstract][Hide abstract] ABSTRACT: Chronic pain affects a high percentage of the general population. Traditional therapies based upon non-steroidal anti-inflammatory drugs (NSAIDs), opioids and co-analgesic therapies, such as antidepressant or anti-epileptic drugs, are often relatively ineffective in treating chronic pain. In addition, the low therapeutic indexes and, in particular, the often-intolerable side effect profiles of conventional compounds, limit their usefulness, especially in the elderly population. Despite intensive research, until recently there was little change in the classes of drugs available to treat chronic pain clinically. This was partly due to a failure to understand which physiological processes are important in mediating clinical chronic pain. Recently, however, greater understanding of the neurophysiology critical to chronic pain development has lead to the development of numerous alternative pharmacological strategies. This review article outlines the physiological processes occurring in chronic pain, highlights some of the approaches recently developed and mentions a number of drugs currently under development that aim to provide safer and more effective analgesia for chronic pain. These include COX-2 inhibitors, gabapentin, capsaicin, new opioid strategies, neurokinin-1 (NK-1) antagonists, cannabinoid receptor agonists, neuronal nitric oxide synthase (nNOS) inhibitors and NMDA receptor antagonists, as well as a number of other therapeutic strategies in development.
No preview · Article · Feb 2005 · Expert Opinion on Emerging Drugs
[Show abstract][Hide abstract] ABSTRACT: The aims of this study were to investigate the occurrence of apoptotic cell death in the dorsal horn of the adult rat spinal cord following chronic constriction injury (CCI) to the sciatic nerve and to correlate this with behavioural responses. Six groups of six rats were used as follows: 1) CCI, 2) CCI, 3) MK801 + CCI, 4) axotomy, 5) sham, and 6) naive. Group 1 animals were behaviourally tested for thermal hyperalgesia 8 days following surgery and sacrificed and the spinal cords removed and frozen. The rest of the groups underwent the same procedure 14 days following surgery. The lumbar region of the spinal cord was cryosectioned and the incidence of apoptotic cells investigated using the TUNEL technique plus Hoechst double labelling. By 8 days post-CCI, hyperalgesia had developed in the ipsilateral paw, which was still present 14 days after the injury compared to the contralateral paw and naive and sham animals. Preemptive MK-801 prevented the onset of hyperalgesia. Significant numbers of apoptotic cells were present in the ipsilateral dorsal horn of the spinal cord 8 and 14 days following CCI compared to the contralateral side and to naive and sham animals. Preemptive treatment with MK-801 reduced the extent of apoptosis resulting from CCI to the level seen in control animals. This study demonstrates that cells undergo apoptosis as a result of CCI simultaneous with the occurrence of hyperalgesia. Furthermore, MK-801 prevents the onset of hyperalgesia and reduces the extent of apoptotic cell death, suggesting, perhaps, that apoptosis contributes to the initiation/maintenance of hyperalgesia.
No preview · Article · Apr 2001 · Journal of Neuroscience Research
[Show abstract][Hide abstract] ABSTRACT: Objective: To review the current neurophysiologic basis for the chronic pain experience, as it may apply to chronic whiplash.
Findings: There appears to be a dichotomy in our understanding of the chronic pain experience, and its cause. On the one hand, a simple physical tissue trauma that has failed to heal, does not explain what is currently observed as chronic pain behavior. Psychological problems and/or secondary gain are associated factors, suggesting the lack of a physical disorder. Recent findings on the neural mechanisms of pain, indicate that there may be some individuals whose traumatic event may have sensitized certain neurophysiologic processes to interpret as pain, from experiences of otherwise ordinary sensory-perception events. These central sensitization events could be caused or aggravated by various combinations of trauma, psychological disorders, or secondary gain and may provide at least a partial explanation of why some persons may develop chronic pain, and others will not.
No preview · Article · Jun 2000 · Journal of Musculoskeletal Pain
[Show abstract][Hide abstract] ABSTRACT: Pulse radiofrequency has been recently described as a technique to apply a relatively high voltage near a nerve but without the usual effects of a rise in temperature or subsequent nerve injury. In this set of case reports, the effect of pulsed radiofrequency (PRF) is described in patients with neuropathic pain syndromes which have been poorly controlled with other oral and invasive treatments. Whilst anecdotal, the results have been remarkable and should encourage further research into this technique. Observations from the basic science tend to support the concept that PRF may induce some sort of long-term depression in the spinal cord.
[Show abstract][Hide abstract] ABSTRACT: The unilateral sciatic nerve chronic constriction injury (CCI) model of Bennett and Xie [G.J. Bennett, Y.-K. Xie, A peripheral neuropathy in rat that produces disorders of pain sensation like those seen in man, Pain, 33 (1988) 87-108] shows features of a neuropathic pain state. We examined mechanical hyperalgesia and Fos protein staining in the lumbar spinal cord 1, 7, 14 and 28 days after unilateral CCI to the sciatic nerve or sham operation. In addition, we examined the effect of the NMDA antagonist MK-801 (0.3 mg/kg s.c. administered 30 min prior to and 6 h following operation) on Fos expression and hyperalgesia at 28 days. CCI animals were hyperalgesic compared to the sham operated animals at 14 and 28 days post injury. MK-801 reduced hyperalgesia by 68% in CCI animals on day 28 (p=0.0001). In the spinal cord, Fos positive cells were present bilaterally in deeper laminae in both sham and CCI animals at all time points examined. Relatively few Fos positive cells were present in laminae 1-2 at any time point examined. At days 1 and 7, there were increased numbers of Fos positive cells ipsilaterally in the deeper laminae of the spinal cord in CCI animals compared to sham animals, but by 14 and 28 days Fos counts were similar in sham and CCI despite the obvious behavioural differences between the two groups. Fos counts ipsilateral to the injury in laminae 3-10 correlated with hyperalgesia scores in the CCI but not sham animals. Analysis at the 28-day time point showed that MK-801 differentially affected Fos expression: MK-801 significantly reduced the Fos count bilaterally in laminae 3-10 in the CCI but not in the sham group animals. These results indicate that Fos expression is initiated by different peripheral and central mechanisms following nerve injury or sham operation.
[Show abstract][Hide abstract] ABSTRACT: Neuropeptide Y (NPY) expression in the spinal cord and dorsal root ganglia (DRG) was examined after application of colchicine, an axonal transport blocker, on the intact sciatic nerve or prior to axotomy or chronic constriction injury (CCI). Rats that underwent topical application of colchicine on the sciatic nerve showed decreased responsiveness to heat stimulation, ipsilaterally. CCI-induced hyperalgesia was prevented by prior application of colchicine. However, colchicine did not block axotomy-induced NPY increase when applied proximally to the injury. In fact, colchicine induced the expression of NPY in the DRG and spinal cord in an identical manner to axotomy. The present data indicates that the increase in NPY observed after nerve injury could be initiated by the suppression of retrograde transport of factors, possibly neurotrophins, rather than by the production of an active factor at the site of injury.
No preview · Article · Feb 1999 · Neuroscience Letters
[Show abstract][Hide abstract] ABSTRACT: Sensory neurons in neonatal rat lumbar dorsal root ganglia die after sciatic nerve axotomy, and previous studies have estimated the total cell loss to be 40–95%. We have used the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) technique, combined with immunohistochemistry, to investigate the contribution of apoptosis to the cell loss that occurs after unilaterally transecting the sciatic nerve of new-born rats.
TUNEL-positive cells were detected 1 day post-lesion, and their number peaked 3 days after the injury. Combining TUNEL labelling with immunohistochemistry, for neuron-specific neurofilament 150 kDa, or glial-specific S-100β, enabled us to identify dying neurons and dying glia. One day after axotomy, most of the TUNEL-positive cells (58%) were neurons, whereas 3 days post-injury, only a small number of dying cells (6%) were neuronal. This lower incidence was due to a decrease in neuronal death and an increase in glial death. The glia in the dorsal root ganglia therefore die subsequent to the neurons. The apoptotic nature of the cell death was confirmed by electron microscopy, with fine structural features of apoptotic cell death, e.g. chromatin compaction and membrane blebbing, being observed in both glia and neurons.
Our results confirm that extensive apoptosis occurs in the neonatal lumbar dorsal root ganglia after sciatic nerve section, and show that neurons and glial cells die with different time-courses. The results suggest a neuron-glia trophic interdependence in the dorsal root ganglia.
No preview · Article · Dec 1998 · European Journal of Neuroscience
[Show abstract][Hide abstract] ABSTRACT: We describe an updated protocol which allows the combination of the previously described TUNEL and Hoechst 33342 double-labelling (G. Whiteside, N. Cougnon, S.P. Hunt, R. Munglani, An improved method for the detection of apoptosis in tissue sections and cell culture, using the TUNEL technique combined with Hoechst stain, Brain Res. Protocols, 2, 1998, 160-164 ), with immunohistochemistry. The inclusion of the immunohistochemistry step allows identification of apoptosis in distinct cell types by using cell specific markers. It also permits investigation into the proteins expressed in cells undergoing apoptotic cell death. We have evaluated the triple staining in sections of post-axotomy neonatal dorsal root ganglia.
No preview · Article · Oct 1998 · Brain Research Protocols
[Show abstract][Hide abstract] ABSTRACT: We describe a novel procedure for combining a fluorescent variant of the TUNEL technique with Hoechst 33342 stain (bis-benzimide) to identify apoptosis in tissue sections and cell culture. The biochemical hallmark of apoptosis is internucleosomal DNA cleavage, which gives rise to oligonucleosome-sized fragments (multiples of approximately 180 bp) that can be directly visualised by labelling with biotinylated or digoxygenin-conjugated nucleosides in a reaction that employs terminal deoxynucleotide transferase (TUNEL). TUNEL and Hoechst 33342 have been used separately to identify apoptosis. TUNEL specifically labels dying cells, yet a low background makes comparison of labelled cells with surrounding normal cells difficult and causes disorientation in tissue sections. Hoechst 33342 binds all DNA therefore staining all nuclear material, allowing identification of apoptotic nuclei, but the analysis is laborious. Combining the two fluorescent labels allows the initial recognition of apoptotic cells using the TUNEL technique then, by simply changing the filter, the TUNEL positive nuclei can be compared to surrounding normal nuclei to assess changes in morphology and size. Hoechst 33342 acts as a counterstain, allowing identification of anatomical structures, and permits quantitative comparison between TUNEL positive versus normal cells. We have evaluated the technique using sections of rat embryo, post-axotomy neonatal dorsal root ganglia and adult dorsal root ganglia cell culture.
No preview · Article · Feb 1998 · Brain Research Protocols
[Show abstract][Hide abstract] ABSTRACT: Neuropeptide Y (NPY), a widely distributed peptide, has been shown to have numerous effects in both the central and peripheral nervous systems. In particular, NPY has an important role in mediating analgesia and hyperalgesia by distinct central and peripheral mechanisms. At least six NPY receptor subtypes are known to exist and the development of subtype-specific ligands targeted at NPY receptors will offer novel therapeutic agents. This article will review the involvement of NPY in diverse pathologies of the nervous system, including pain, and will propose a role for NPY in the maintenance of sympathetically maintained pain.
No preview · Article · Jul 1997 · Expert Opinion on Investigational Drugs
[Show abstract][Hide abstract] ABSTRACT: Neuropeptide Y (NPY), a widely distributed peptide neurotransmitter, is implicated in both the central and peripheral control of the cardiovascular system. Pathological changes in endogenous NPY release and receptor function may contribute to the development and maintenance of hypertension, myocardial ischaemia and cardiac failure. At least six NPY receptor subtypes are known to exist, and the activation of a certain number of these results in complex central and peripheral changes in cardiovascular function. The cloning and sequencing of NPY receptor subtypes has led to the possibility of developing subtype-specific ligands targeted at NPY receptors, and this article will consider their therapeutic potential in cardiovascular disease.
No preview · Article · May 1997 · Expert Opinion on Investigational Drugs
[Show abstract][Hide abstract] ABSTRACT: We have previously described the changes in spinal cord neuropeptides in the unilateral sciatic chronic constriction injury (CCI) model of Bennett and Xie [Pain, 33 (1988) 87-108] at 28 days, a time of maximum mechanical hyperalgesia. In this study we examine the same model 100-120 days post injury by which time resolution of the hyperalgesia and peripheral nerve injury has occurred according to previous studies. Rats underwent either CCI of the sciatic nerve (n = 12) or else sham operation (n = 8) which involved exposure but no ligation of the nerve. Mechanical hyperalgesia was assessed with a Ugo-Basile analgesymeter and immunohistochemistry performed on the spinal cord sections of the animals and quantified using a confocal microscope. At this late time point CCI rats were no longer significantly mechanically hyperalgesic compared to the sham animals (P > or = 0.09). However, examination of the lumbar spinal cord revealed the following changes. (i) The neuropeptides substance P (SP) (P < 0.0001) and galanin (P < 0.003) both showed decreases of about 30% ipsilaterally in immunoreactivity in laminae 1 and 2 of the dorsal horn compared to the sham operated animals. (ii) Calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) in laminae 1 and 2 showed no significant changes compared to sham animals. (iii) NPY levels in laminae 3 and 4 of the spinal cord showed a 15% increase in immunoreactivity compared to sham animals (P = 0.008). These results indicate that changes in neuronal markers in the spinal cord can persist after apparent resolution of a peripheral nerve injury. We suggest that these changes may form a substrate for subsequent development of abnormal pain states.
[Show abstract][Hide abstract] ABSTRACT: Since its discovery in 1982, neuropeptide Y (NPY) has been shown to have numerous effects mediated by a growing number of NPY receptors in both the CNS and peripheral nervous system. Perhaps best appreciated is the role of NPY in the control of systemic blood pressure, together with its effects on feeding, anxiety and memory. However, recent evidence increasingly supports an important role for NPY in mediating analgesia and hyperalgesia by distinct central and peripheral mechanisms. In this review we concentrate on this important aspect of NPY pharmacology and consider mechanisms controlling the expression of NPY and its receptors. In addition, we also present the more recent data describing the other possible roles for NPY-NPY agonists and antagonists may be useful in the treatment of conditions as varied as anorexia, epilepsy, anxiety, depression, hypertension and heart failure.