Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury.

The most obvious impairments associated with spinal cord injury (SCI) are loss of sensation and motor control. However, many subjects with SCI also develop persistent neuropathic pain below the injury which is often severe, debilitating and refractory to treatment. The underlying mechanisms of persistent neuropathic SCI pain remain poorly understood. Reports in amputees describing phantom limb pain demonstrate a positive correlation between pain intensity and the amount of primary somatosensory cortex (S1) reorganization. Of note, this S1 reorganization has also been shown to reverse with pain reduction. It is unknown whether a similar association between S1 reorganization and pain intensity exists in subjects with SCI. The aim of this investigation was to determine whether the degree of S1 reorganization following SCI correlated with on-going neuropathic pain intensity. In 20 complete SCI subjects (10 with neuropathic pain, 10 without neuropathic pain) and 21 control subjects without SCI, the somatosensory cortex was mapped using functional magnetic resonance imaging during light brushing of the right little finger, thumb and lip. S1 reorganization was demonstrated in SCI subjects with the little finger activation point moving medially towards the S1 region that would normally innervate the legs. The amount of S1 reorganization in subjects with SCI significantly correlated with on-going pain intensity levels. This study provides evidence of a link between the degree of cortical reorganization and the intensity of persistent neuropathic pain following SCI. Strategies aimed at reversing somatosensory cortical reorganization may have therapeutic potential in central neuropathic pain.

Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial.

OBJECTIVE: To evaluate pregabalin in central neuropathic pain associated with spinal cord injury. METHODS: A 12-week, multicenter study of patients randomized to either flexible-dose pregabalin 150 to 600 mg/day (n = 70) or placebo (n = 67), administered BID. Patients were allowed to remain on existing, stable pain therapy. The primary efficacy variable was the endpoint mean pain score, derived from patients' last 7 days daily pain diary entries. Key secondary endpoints included pain responder rates, the SF-MPQ, sleep interference, mood, and the patient global measure of change. RESULTS: The mean baseline pain score was 6.54 in the pregabalin group and 6.73 in the placebo group. The mean endpoint pain score was lower in the pregabalin group (4.62) than the placebo group (6.27; p < 0.001), with efficacy observed as early as week 1 and maintained for the duration of the study. The average pregabalin dose after the 3-week stabilization phase was 460 mg/day. Pregabalin was significantly superior to placebo in endpoint assessments on the SF-MPQ. The > or =30% and > or =50% pain responder rates were higher with pregabalin than placebo (p < 0.05). Pregabalin was associated with improvements in disturbed sleep (p < 0.001) and anxiety (p < 0.05), and more patients reported global improvement at endpoint in the pregabalin group (p < 0.001). Mild or moderate, typically transient, somnolence and dizziness were the most common adverse events. CONCLUSIONS: Pregabalin 150 to 600 mg/day was effective in relieving central neuropathic pain, improving sleep, anxiety, and overall patient status in patients with spinal cord injury.

Direct clinical evidence for spinal hyperalgesia in a patient with irritable bowel syndrome.

OBJECTIVE: Our objective was to evaluate GI motor and sensory function and spinal cord testing in a patient with severe irritable bowel syndrome. METHODS: A patient is described who underwent an extensive assessment of GI motor and sensory function including transit studies, colonic and rectal barostat studies, sensory and manometric studies of the small bowel, and colon and anorectal physiology testing. The patient also underwent testing with spinal cord stimulation and spinal drug delivery as part of a pain management assessment. RESULTS: The viscerosomatic referral pain pattern resulting from rectal distention was consistent with spinal hyperalgesia. The patient underwent testing for spinal cord stimulation and spinal drug delivery. CONCLUSION: This novel finding provides direct clinical evidence for the presence of spinal hyperalgesia in a patient with irritable bowel syndrome, consistent with the existing indirect clinical evidence and animal data.

Chronic pain in Australia: a prevalence study.

This study reports chronic pain prevalence in a randomly selected sample of the adult Australian population. Data were collected by Computer-Assisted Telephone Interview (CATI) using randomly generated telephone numbers and a two-stage stratified sample design. Chronic pain was defined as pain experienced every day for three months in the six months prior to interview. There were 17,543 completed interviews (response rate=70.8%). Chronic pain was reported by 17.1% of males and 20.0% of females. For males, prevalence peaked at 27.0% in the 65--69 year age group and for females, prevalence peaked at 31.0% in the oldest age group (80--84 years). Having chronic pain was significantly associated with older age, female gender, lower levels of completed education, and not having private health insurance; it was also strongly associated with receiving a disability benefit (adjusted OR=3.89, P<0.001) or unemployment benefit (adjusted OR=1.99, P<0.001); being unemployed for health reasons (adjusted OR=6.41, P<0.001); having poor self-rated health (adjusted OR=7.24, P<0.001); and high levels of psychological distress (adjusted OR=3.16, P<0.001). Eleven per cent of males and 13.5% of females in the survey reported some degree of interference with daily activities caused by their pain. Prevalence of interference was highest in the 55--59 year age group in both males (17.2%) and females (19.7%). Younger respondents with chronic pain were proportionately most likely to report interference due to pain, affecting 84.3% of females and 75.9% of males aged 20--24 years with chronic pain. Within the subgroup of respondents reporting chronic pain, the presence of interference with daily activities caused by pain was significantly associated with younger age; female gender; and not having private health insurance. There were strong associations between having interfering chronic pain and receiving disability benefits (adjusted OR=3.31, P<0.001) or being unemployed due to health reasons (adjusted OR=7.94, P<0.001, respectively). The results show that chronic pain impacts upon a large proportion of the adult Australian population, including the working age population, and is strongly associated with markers of social disadvantage.

The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury.

We performed a double-blinded, randomized, controlled trial in 15 patients to determine the efficacy of intrathecal morphine or clonidine, alone or combined, in the treatment of neuropathic pain after spinal cord injury. The combination of morphine and clonidine produced significantly more pain relief than placebo 4 h after administration; either morphine or clonidine alone did not produce as much pain relief. In addition, lumbar and cervical cerebrospinal fluid (CSF) concentrations, sampled at these levels at different times after administration were examined for a relationship between pain relief and CSF drug concentration. Lumbar CSF drug concentrations were initially several orders of magnitude larger than those in cervical CSF. After 1-2 h, the concentrations of morphine in cervical CSF markedly exceeded those of clonidine. The concentration of morphine in the cervical CSF and the degree of pain relief correlated significantly. We conclude that intrathecal administration of a mixture of clonidine and morphine is more effective than either drug administered alone and is related to the CSF-borne drug concentration above the level of spinal cord injury. If there is pathology that may restrict CSF flow, consideration should be given to intrathecal administration above the level of spinal cord damage to provide an adequate drug concentration in this region.

The effect of diclofenac on the expression of spinal cord c-fos-like immunoreactivity after ischemia-reperfusion-induced acute hyperalgesia in the rat tail.

Ischemia-reperfusion of the rat tail for 20 min induces local acute hyperalgesia of approximately 1-h duration. We studied how this stimulus affected the expression of c-fos-like immunoreactivity (c-fos-LI) labeling of neurons of the sacral spinal cord, and how diclofenac pretreatment influenced the outcome. After ischemia, the number of c-fos-LI-labeled neurons was significantly increased when assessed at 60, 90, and 120 min after reperfusion (to 183%, 283%, and 164% of control, respectively; all P < 0.01). At 90 min, the number of regional c-fos-LI-labeled neurons was increased to 585% in laminae I-II, 183% in laminae III-IV, 270% in laminae V-X, and 286% in total, compared with respective control values (all P < 0.01). After diclofenac pretreatment (subcutaneous 40 mg/Kg, 30 min before insult) the number of c-fos-LI-labeled neurons at 90 min was increased to 424% in laminae I-II, 150% in laminae III-IV, 142% in laminae V-X, and 183% in total (all P < 0.01). Thus diclofenac pretreatment partially prevented the insult-induced increase in total and regional neuronal c-fos-LI. This acute nociceptive model involves only natural algogens. However, the results were similar to acute chemically induced or chronic adjuvant induced arthritic inflammatory pain models in which increases in c-Fos were partially inhibited by nonsteroidal antiinflammatory drugs.

Lack of secondary hyperalgesia and central sensitization in an acute sheep model.

BACKGROUND AND OBJECTIVES: We aimed to determine the following in an experimental acute pain model in sheep: (1) whether multimodal analgesia with intravenous fentanyl and ketorolac was more effective than fentanyl alone; (2) whether secondary hyperalgesia (central sensitization) occurred in adjacent (foreleg) dermatomes after thoracic surgery; (3) whether ketorolac used preemptively influenced the development of secondary hyperalgesia after surgery. METHODS: Changes in primary nociception were measured by increases to tolerated pressure, applied to the foreleg by a blunt pin, before foreleg withdrawal occurred. Changes to breath-to-breath interval and estimated end-tidal CO2 were used as indices of respiratory effects. Study 1 (n = 6) compared the paired responses to acute nociception after ketorolac (90 mg) or saline (control) pretreatment, followed by fentanyl (graded, 0 mg to 1.5 mg). Study 2 (n = 6) used a cross-over of ketorolac (90 mg) or saline (control) 24 hours and 1 hour, respectively, before a standardized thoracotomy incision, followed by antinociceptive testing with ketorolac (90 mg) and fentanyl (0.6 mg) daily over 4 days. RESULTS: In study 1, fentanyl produced naloxone-antagonizable antinociception and respiratory depression. Ketorolac did not affect fentanyl antinociception, except for prolonging antinociception at the highest dose; it did not affect the respiratory effects. In study 2, preemptive ketorolac had no effect on the postoperative antinociceptive or respiratory effects of fentanyl. The pharmacokinetics of fentanyl were unaltered by ketorolac. CONCLUSIONS: The results obtained in this acute pain model found no significant evidence of a fentanyl-ketorolac interaction, of central sensitization as shown by secondary hyperalgesia, or of a preemptive analgesic effect.

Microdialysis study of the blood-brain equilibration of thiopental enantiomers.

Thiopental is a racemate of equimolar R- and S-thiopental enantiomers that have different potencies in laboratory experiments. We measured concentrations of R- and S-thiopental in plasma, tissues and brain microdialysate of rats after computer-controlled infusion of thiopental i.v. to a plasma concentration of 40 micrograms ml-1 for 20 min in two pharmacokinetic studies. In study 1, animals were found to maintain their target plasma concentrations, which then decayed biphasically after infusion. Brain microdialysate concentrations of both enantiomers increased from about 3% of corresponding plasma concentrations at 1 min to 9% at 20 min. In study 2, thiopental concentrations were found to be highest at 20 min in CNS tissue, at 30 min in muscle and at 60 min in fat. Tissue:plasma distribution coefficients of R-thiopental were greater than those of S-thiopental when calculated from total or unbound plasma concentrations. We found no pharmacokinetic evidence to support differences between the thiopental enantiomers in rates of equilibration across the blood-brain barrier after infusion of rac-thiopental.

Glutamate and kynurenate in the rat central nervous system following treatments with tail ischaemia or diclofenac.

Kynurenate is an endogenous antagonist at the allosteric glycine site on the N-methyl-D-aspartate (NMDA) receptor, and may have a role in ameliorating nociceptive processes through modulation of NMDA receptor function. While antinociceptive effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are mediated peripherally and possibly centrally through inhibition of prostaglandin synthesis, there is also evidence for centrally mediated prostaglandin-independent antinociceptive effects that may result from increased central nervous system (CNS) concentrations of kynurenate. We have investigated the effects of the NSAID diclofenac, (40 mg kg(-1), s.c.; administered to rats 1 h before killing) or the exposure of rats to noxious stimulation (tail ischaemia for 20 min before killing), on the concentrations of glutamate and kynurenate in discrete CNS regions. Regional CNS tissue concentrations of diclofenac were between 3.0-3.8 nmolg(-1). The corresponding regional glutamate concentrations ranged between 4.8-10.6 micromol g(-1), and were significantly lower in the ischaemia group when compared with both control (15%, P < 0.05) and diclofenac-treated (19%, P < 0.002) groups. Kynurenate concentrations in these CNS regions ranged between 3.3-45.8 pmol g(-1). Pairwise comparisons between the control and diclofenac-treated groups found significant increases in kynurenate concentrations in the diencephalon and lumbo-sacral regions of the CNS (P = 0.05). Noxious stimulation from tail ischaemia appeared to be associated with increased release of glutamate. Additionally, NSAIDs appeared to increase kynurenate concentrations in the spinal cord and diencephalon. Antagonism by kynurenate of glutamate effects at NMDA receptors may contribute to the antinociceptive effects of NSAIDs.

Lack of whole-body pharmacokinetic differences of halothane enantiomers in the rat.

BACKGROUND: Halothane is made and used as a racemate (an equimolar mixture of R- and S- enantiomers). This study was initiated to determine whether there were demonstrable enantiomeric differences in the whole-body pharmacokinetics of halothane that might have significance for studies in which racemate is used. METHODS: Adult male Wistar rats were exposed to halothane vaporized in the atmosphere of a closed constant volume chamber supplied with O2 commensurate with CO2 production. Concentrations of halothane enantiomers were measured by a specific gas chromatography-mass spectrometry method. Experiments were performed at four initial concentrations of halothane (0.1%, 0.5%, 1.0%, and 1.5% vol/vol). Enantiomeric differences in whole-body pharmacokinetics were assessed indirectly from the relative chamber atmosphere concentrations of halothane enantiomers. RESULTS: Concentrations of halothane decreased biphasically. The initial more rapid decrease was interpreted as incorporating absorption, distribution, and clearance; the slower decrease was interpreted as principally incorporating metabolic clearance. The ratio of concentrations of the two halothane enantiomers and of the ratios of the respective areas under the concentration-time curves remained constant without differing from unity at any time at any concentration of halothane. The dose-normalized areas under the concentration-time curves for the concentrations 0.1%, 0.5%, and 1.0% did not differ; that for 1.5% was significantly greater, suggesting nonlinear clearance, but the values did not differ significantly between enantiomers at any concentration. CONCLUSIONS: As there were no significant differences in concentrations of the two enantiomers in the chamber atmosphere, enantioselectivity was not demonstrated in the whole-body pharmacokinetics of halothane.

Cardiovascular and pulmonary effects of epidural anaesthesia.

Epidural anaesthesia has been used since the early 1900s. Consequently the general characteristics of these procedures have been well defined. More studies have provided a better understanding of the cardiopulmonary changes produced by epidural anaesthesia. The cardiovascular effects observed with epidural anaesthesia are complex and variable, depending on a multitude of factors. The extent of sympathetic denervation, balance of sympathetic and parasympathetic activity, the pharmacological effect of systemically absorbed local anaesthetic agents, inclusion of adrenaline in the anaesthetic solution, the distribution of blood in relation to cardiac filling and cardiovascular function of the patient must be taken into account when considering the circulatory effects of epidural anaesthesia. Individual cardiovascular response to different levels of sympathetic blockade varies widely, depending on the degree of sympathetic tone before the block. Epidural anaesthesia that is restricted to the level of the low thoracic and lumbar region (T5-L4) results in a "peripheral" sympathetic blockade with vascular dilatation in the pelvis and lower limbs. High thoracic epidural anaesthesia, from the first to fifth thoracic, blocks the cardiac afferent and efferent sympathetic fibres with loss of chronotropic and inotropic drive to the myocardium. Thoracic epidural anaesthesia appears to at least partly reverse the diaphragmatic dysfunction that is a major determinant of the decrease in lung volumes observed after upper abdominal surgery. This article summarizes cardiovascular and pulmonary responses to epidural anaesthesia. Details of clinical management are not included in the review.

Neuropathic orofacial pain. Part 2-Diagnostic procedures, treatment guidelines and case reports.

Neuropathic orofacial pain can be difficult to diagnose because of the lack of clinical and radiographic abnormalities. Further difficulties arise if the patient exhibits significant distress and is a poor historian regarding previous diagnostic tests and treatments, such as somatosensory local anaesthetic blockade. Valuable information can be obtained by utilising the McGill Pain Questionnaire that allows the patient to choose words that describe the qualities of his/her pain in a number of important dimensions (sensory and effective). Basal pain intensity should be measured with the visual analogue scale, a simple instrument that can evaluate the efficacy of subsequent treatments. The dentist or endodontist can employ sequential analgesic blockade with topical anaesthetics and perineural administration of plain local anaesthetic to ascertain sites of neuropathology in the PNS. These can be performed in the dental chair and in a patient blinded manner. Other, more specific, tests necessitate referral to a specialist anaesthetist at a multidisciplinary pain clinic. These tests include placebo controlled lignocaine infusions for assessing neuropathic pain, and placebo controlled phentolamine infusions for sympathetically maintained pain. The treatment/management of neuropathic pain is multidisciplinary. Medication rationalisation utilises first-line antineuropathic drugs including tricyclic antidepressants such as amitriptyline and nortriptyline, and possibly an anticonvulsant such as carbamazepine, sodium valproate, or gabapentin if there are sharp, shooting qualities to the pain. Mexiletine, an antiarrhythmic agent and lignocaine analogue, may be considered following a positive patient response to a lignocaine infusion. All drugs need to be titrated to achieve maximum therapeutic effect and minimum side effects. Topical applications of capsaicin to the gingivae and oral mucosa are a simple and effective treatment in two out of three patients suffering from neuropathic orofacial pain. Temporomandibular disorder is present in two thirds of patients and should be assessed and treated with physiotherapy and where appropriate, occlusal splint therapy. Attention to the patient's psychological status is crucial and requires the skill of a clinical psychologist and/or psychiatrist with pain clinic experience. Psychological variables include distress, depression, expectations of treatment, motivation to improve, and background environmental factors. Unnecessary dental treatment to "remove the pain" with dental extractions is contraindicated and aggravates neuropathic orofacial pain.

Neuropathic orofacial pain part 1--prevalence and pathophysiology.

Neuropathic pain is defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system". Neuropathic orofacial pain has previously been known as "atypical odontalgia" (AO) and "phantom tooth pain". The patient afflicted with neuropathic oral/orofacial pain may present to the dentist with a persistent, severe pain, yet there are no clearly identifiable clinical or radiographic abnormalities. Accordingly, multiple endodontic procedures may be instigated to remove the likely anatomical source of the pain, yet the pain persists. There have been few studies and limited patient numbers investigating the condition. Two retrospective studies revealed the incidence of persistent pain following endodontic treatment to be 3-6% and 5% of patients; one author with wide experience in assessing the condition estimated its prevalence at 125,000 individuals in the USA alone. In one study, 50% of neuropathic orofacial pain patients reported persistent pain specifically following endodontic treatment. Patients predisposed to the condition may include those suffering from recurrent cluster or migraine headaches. Neuropathic pain states include postherpetic neuralgia (shingles) and phantom limb/stump pain. The aberrant developmental neurobiology leading to this pain state is complex. Neuropathic pain serves no protective function, in contrast to physiological pain that warns of noxious stimuli likely to result in tissue damage. The relevant clinical features of neuropathic pain include: (i) precipitating factors such as trauma or disease (infection), and often a delay in onset after initial injury (days-months), (ii) typical complaints such as dysaesthesias (abnormal unpleasant sensations), pain that may include burning, and paroxysmal, lancinating or sharp qualities, and pain in an area of sensory deficit, (iii) on physical examination there may be hyperalgesia, allodynia and sympathetic hyperfunction, and (iv) the pathophysiology includes deafferentation, nerve sprouting, neuroma formation and sympathetic efferent activity.

Toward a canon of the pain and analgesia literature: a citation analysis.

UNLABELLED: The purpose of this study was to use citation analysis to identify major themes and contributors to the pain and analgesia literature over the past two decades. A citation analysis was performed on a database of more than 110,000 articles in the biomedical literature from January 1981 through June 1997, and in the interval from January 1988 through June 1997. Articles and authors related to pain and analgesia research and practice were identified by searching approximately 7,700 journals. The 20 articles and 20 authors with the most citations were then checked by hand to ensure relevance to pain or analgesia. Most of the high-impact articles identified pertained to research on basic pain pathways. Nearly all the articles concerned opioids, nonsteroidal antiinflammatory drugs, and consequences of analgesic use. None of the highest-impact articles address assessment of clinical pain. Few women were first authors of any most frequently cited paper. Citation analysis is a useful tool in identifying important contributions to the biomedical literature. Recent and continuing research trends include the use of nonsteroidal antiinflammatory drugs, opioid mechanisms, and persistent pain disorders. Current trends expected to become stronger include description of pain from the patient's perspective and mechanisms of the transition from acute to chronic pain. IMPLICATIONS: We performed a citation analysis to identify important contributions and contributors to the biomedical literature. Recent pain and analgesia research has been focused on mechanisms of pain, but evidence suggests the importance of understanding the pain experience from the patient's perspective and the transition from acute to chronic pain.