bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraplantar zymosan as a reliable, quantifiable model of thermal and mechanical hyperalgesia in the rat
Authors: Meller S.T. , Gebhart G.F.
Published: February 2004

The study of the mechanisms of thermal and mechanical hyperalgesia produced in human inflammatory conditions is dependent on a reliable, consistent model. The present investigation shows that the intraplantar administration of zymosan in the rat hindpaw produces a reliable and quantifiable thermal and mechanical hyperalgesia accompanied by oedema that closely mimics the symptoms of inflammation in man.

Prior to the intraplantar injection of zymosan, there was no significant difference in withdrawal latencies, mechanical withdrawal thresholds or paw thickness between the left and right hindpaws. The intraplantar injection of zymosan (0.313–6.25 mg), an extract from yeast, produced a dose‐ and time‐dependent thermal and mechanical hyperalgesia, a robust oedema and, at the greatest doses, produced evidence of spontaneous pain. At the least dose of zymosan tested (0.313 mg), there was a slight oedema; oedema was greatest at dosages 2.5 mg and was always maximal by 30 min postinjection, irrespective of the dose. On the other hand, thermal and mechanical hyperalgesia showed a more complex dose‐ and time‐dependence. Mechanical hyperalgesia did not appear until dosages 1.25 mg and was maximal by 5 mg. In addition, mechanical hyperalgesia showed a time‐dependent progressive onset so that hyperalgesia was maximal by the 4‐h testing time‐point. In contrast, thermal hyperalgesia showed a biphasic nature with two apparent maximal time‐points (30 min and 4 h). There was an early‐phase thermal hyperalgesia (maximal by 30 min) that was dose‐dependent at dosages 2.5 mg (not apparent at lower dosages) and a late‐phase (maximal by 4 h) that was dose‐dependent at dosages 0.0625 mg. At the greatest doses administered (5 and 6.25 mg), there was evidence of spontaneous pain from the time of injection for up to 4 h that was characterized by occasional spontaneous flicking of the hindpaw, but more usually by holding the paw in an elevated position for extended periods of time. In addition, at the greatest dose tested (6.25 mg), all rats showed evidence of licking, biting and shaking of the injected hindpaw for up to 30–45 min after injection.

These data demonstrate that the intraplantar injection of zymosan is a reliable and quantifiable model of tonic pain characterized by a dose‐ and time‐dependent thermal and mechanical hyperalgesia accompanied by a robust oedema. This model is likely to be a useful, reliable model in which to study further the central and peripheral mechanisms of hyperalgesia.
Incidence of mononeuropathy in rats is influenced by pre‐emptive alteration of spinal excitability
Authors: Cui J.‐C. , Linderoth B. , Meyerson B.A.
Published: February 2004

Both clinical and experimental data support the notion that the development of neuropathic pain is related to the state of excitability at the time of nerve injury. The present study was performed to investigate whether altering spinal excitability immediately before creation of a chronic constriction nerve injury in rats can influence the incidence of tactile hypersensitivity (‘allodynia';) by using pre‐emptive: (1) intrathecal injection of a GABAB agonist or antagonists; (2) intrathecal lidocaine; or (3) C‐fibre activation by electric stimulation. The incidence of tactile hypersensitivity was significantly reduced by the GABAB agonist baclofen while it was markedly enhanced by the administration of the GABAB antagonists 5‐AVA and CGP 55845, as well as by C‐fibre stimulation. Intrathecal administration of lidocaine did not influence the incidence of hypersensitivity. The results suggest that GABAergic mechanisms play an important role in the development of tactile hypersensitivity, and suggest that GABAB receptor agonists may be used as pre‐emptive treatment to prevent the development of postinjury neuropathic pain.
Quantification of local and referred pain in humans induced by intramuscular electrical stimulation
Authors: Laursen R.J. , Graven‐Nielsen T. , Jensen T.S. , Arendt‐Nielsen L.
Published: February 2004

The basic knowledge related to referred muscle pain is limited. To study referred pain, an experimental model using intramuscular electrical stimulation has been developed.

Four experiments were performed: (1) the thresholds for eliciting local (LPT) and referred pain (RPT) were determined; (2) stimulus‐response functions relating stimulus intensity, pain intensity ratings and size of pain areas were determined; (3) inter‐ and intrasession variabilities were assessed; and (4) prolonged stimulations were given with a duration of 10 min to evaluate temporal aspects of the referred muscle pain.

Intramuscular electrical stimulation of the tibialis anterior muscle elicited pain at the stimulation site in 94% of the subjects, and referred pain in 78% of the subjects. Referred pain was located in the anterior part of the ankle. The mean RPT was 72% higher than the mean LPT (p≤0.01). Correlation was found between stimulus intensity, sensory/pain rating scores and size of pain areas (0.74≤r≤0.98, p<0.04). Size of pain areas and sensation/pain rating scores were correlated (0.86≤r≤0.97, p<0.01). Intersession variability showed that the LPTs were not significantly different (p>0.16), but the RPTs were disparate (p<0.02). Intrasession values revealed a significant difference between the five LPTs, RPTs, local and referred pain rating scores. The size of the local and referred pain areas remained constant. Prolonged stimulation at 150% of RPT showed that the onset (the first occurrence of pain) of referred pain occurred significantly later (43 s ± 80 s) than at the local pain site (p<0.03).

This study showed that local and referred muscle pain can be elicited by intramuscular electrical stimulation, and indicated that temporal and spatial summation may be involved in the elicitation of referred muscle pain.
Cutaneous norepinephrine application in complex regional pain syndrome
Authors: Birklein F. , Riedl B. , Claus D. , Neundörfer B. , Handwerker H.O.
Published: February 2004

Patients with complex regional pain syndrome (CRPS) (n=20) were examined in order to evaluate cutaneous reactions to norepinephrine (NE) on both the affected and the unaffected limb in comparison to healthy controls. Sixteen female and four male patients suffering from very acute and therefore untreated CRPS with a mean duration of 5.5 weeks were included in this study. Two groups of healthy volunteers served as control groups: the first group (n =18) according to the same study protocol as CRPS patients, and the second group (n =10) after warming up one limb. Norepinephrine was iontophoresized (0.2 mA, 120 s) and vasoconstriction was recorded by laser‐doppler flowmetry. Pain sensations were simultaneously rated on a visual analogue scale (VAS). Five patients underwent a second trial with higher intracutaneous NE concentrations in order to study possible dose‐dependent effects of NE on pain sensation. After acclimatization, skin temperature was recorded by infra‐red thermography.

The NE‐induced reduction of skin blood flow was significantly higher in the affected limb in the patient group (33.0 vs 11.2%, p<0.005). None of the patients reported pain or hyperalgesia. The skin temperature of CRPS patients was significantly higher in the affected limb (34.7 vs 32.5°C, p<0.001). The first control group did not show any difference between left and right sides concerning NE‐induced vasoconstriction or skin temperature. The second control group had an increased unilateral skin temperature after warming up (35.0 vs 34.3°C, p<0.006) and demonstrated a significantly increased vasoconstriction on the warmer side (52.0 vs 20.2%, p<0.03) corresponding to findings in patients with acute CRPS.

The present study proves that there are signs of decreased sympathetic activity in the affected limb in very acute CRPS. However, no indication was found for increased sensitivity of vascular α‐receptors in the very acute stages of CRPS, and there was also no indication for a significant direct contribution of the sympathetic nervous system to pain in very acute CRPS.
The pharmacokinetics of lignocaine in humans during a computer‐controlled infusion
Authors: Dyck J.B. , Wallace M.S. , Lu J.Q. , Rossi S.S. , Yaksh T.L.
Published: February 2004

Several types of chronic pain syndromes are effectively treated with sodium channel blockers such as lignocaine. Further investigation of this therapeutic modality would be facilitated by refinement of the parameters describing lignocaine distribution and elimination. This would allow precise lignocaine infusion by a computer‐controlled infusion to attain and maintain stable target lignocaine concentrations.

Arterial blood samples were obtained at frequent intervals during a computer‐controlled infusion of lignocaine in 12 adult human volunteers. Plasma lignocaine concentrations of 1, 2, 3, 4 and 5μg/ml were targeted for 15 min at each concentration. A three‐compartment mammillary pharmacokinetic model best described the resulting concentration vs time profile. A population pharmacokinetic analysis was performed using three different techniques; the two‐stage, pooled and mixed effects modelling.

There was marked overshoot of the plasma concentration above the target prior to refinement of the pharmacokinetic parameters. The best parameters of a three‐compartment mammillary model fit to the measured concentration using the pooled data approach were: V1 = 7.44, V2 =11.5 and V3 = 97.71; Cl1 = 0.585, Cl2 = 2.23 and Cl3 =1.64 Umin. Similarly calculated parameters using NONMEM were V1 = 6.99, V2 =12.2 and V3 =1341; Cl1 = 0.703, Cl2 =1.24 and Cl3 =1.49 Umin. The addition of age as a covariate of the pharmacokinetic parameters improved the model in both cases. Height, lean body mass and body surface area as covariates of the pharmacokinetic parameters did not improve the predicted value of the model. Prospective testing of the pharmacokinetic parameters will be required to define whether they function well.

The refinement of pharmacokinetic parameters for the computer‐controlled intravenous infusion of lignocaine will facilitate further research in pain therapy. Published lignocaine pharmacokinetic values have a relatively large central volume of distribution, and hence, when implemented as a computer‐controlled infusion, result in dramatic overshoot shortly after targeting a higher plasma concentration. In light of the long‐lasting pain relief provided by sodium channel blockade in neuropathic pain states, overshoot of plasma concentrations must be avoided if the concentration vs effect relationship is to be defined.
Morphine‐3‐glucuronide prevents tolerance to morphine‐6‐glucuronide in mice
Authors: Faura C.C. , Olaso M.J. , Horga J.F.
Published: February 2004

Daily subcutaneous (s.c.) pretreatment with morphine‐3‐glucuronide (6 mg/kg) was found to reduce morphine‐6‐glucuronide (4 mg/kg s.c.)‐induced antinociception, with no decrease in the effect over 5 days. Morphine‐6‐glucuronide administration (4 mg/kg s.c.) on Day 6, without morphine‐3‐glucorinide pretreatment, results in a significant increase in antinociception (from 24% on Day 5 to 70%; p≤0.05). Morphine‐3‐glucuronide may prevent tolerance to morphine‐6‐glucuronide by reducing morphine‐6‐glucuronide‐induced antinociception.
Anatomical basis for the dynamic processing of nociceptive input
Authors: Lima Deolinda
Published: February 2004

The involvement of the lamina I, or marginal zone, of the spinal cord dorsal horn in pain processing has been extensively demonstrated. Its neuronal population comprises four structurally distinct neuronal groups, which were shown to be present in species as different as the rat, cat and pigeon. In the rat, each neuronal type presents a particular neurochemical nature and supraspinal projection pattern. In addition, there is recent evidence that supraspinal modulatory actions may affect differentially cells of different types. By combining retrograde tracing with noxious‐evoked induction of the c fos proto‐oncogene, it was verified that activation of different neuronal groups varies as a function of the brain site they target and the nature of the stimulus. These data suggest that the responsiveness of lamina I neurones is under controlling mechanisms which reflect the stimulus characteristics. Accordingly, both the spinal GABAergic and opioidergic anti‐nociceptive actions appear to differ when different kinds df input are being processed. Moreover, supraspinal pain‐modulatory circuits are also likely to control the excitability of each cell group. Not only reciprocal connections between the spinal cord and various pain‐control centres have been identified, but also a correlation between the number of cfos positive projecting cells and the pain‐inhibitory or facilitating role of their target has been observed. It is proposed that the compound nature of the nociceptive system serves a dynamic interplay between the spinal cord and the brain, which, by controlling the activation of distinct projection neurones, modulates the nociceptive signal while integrating nociceptive processing with several brain functions.
Tramadol and its enantiomers differentially suppress c‐fos‐like immunoreactivity in rat brain and spinal cord following acute noxious stimulus
Authors: Kovelowski C.J. , Raffa R.B. , Porreca F.
Published: February 2004

Tramadol hydrochloride, (1RS, 2RS)‐2‐[(dimethylamino)methyl]‐1‐(3‐methoxyphenyl)‐cyclohexanol hydrochloride, is an orally‐active, centrally‐acting analgesic with a putative dual mechanism of action, including an opioid and non‐opioid component. The analgesic properties of tramadol and the possible co‐existence of dual mechanisms has been postulated to be due to complementary and interactive pharmacologies of its enantiomers. We examined the ability of tramadol, its enantiomers, and morphine as reference to suppress c‐fos‐like immunoreactivity (c‐fos‐ir) in rat spinal cord and brain regions following a noxious stimulus (i.p. administration of 3.5% acetic acid). c‐fos‐ir was measured by immunocytochemistry and the stained cells in each region were counted 2 h after the acetic‐acid injection (2:25 h after tramadol or morphine). Equi‐analgesic doses of s.c. morphine (10 mg/kg) or tramadol (30 mg/kg) significantly suppressed c‐fos‐ir in all areas examined, except dorsal central gray of the spinal cord. The enantiomers of tramadol had distinctive patterns of suppression, neither one suppressed c‐fos‐ir in all of the regions, and hence neither one alone accounted for the suppression produced by the racemate. These findings support differential and complementary effects of tramadol enantiomers in sub‐populations of spinal and supraspinal nociceptive neurons, consistent with the proposed antinociceptive interaction between the enantiomers.
Ridit scores for analysis and interpretation of ordinal pain data
Authors: Donaldson Gary W.
Published: February 2004

Pain studies frequently generate outcome data in the form of ordered categorical responses. Measurement properties of such ordinal variables do not permit straightforward numeric treatment, yet purely categorical (nominal) procedures fail to incorporate the ordered nature of the pain response. This paper describes analysis of ordered categorical data by means of ridit analysis, a simple, yet statistically valid and efficient, technique that yields a highly intuitive interpretation of a treatment effect. The mean ridit comparison of two treatments estimates the probability that a randomly‐selected patient from one will have higher pain than a randomly‐selected patient from the other. Ridit analysis is illustrated with two examples from a clinical trial involving patients with painful bony metastases subsequent to hormone‐refractory prostate cancer.
Memantine attenuates responses of spinothalamic tract cells to cutaneous stimulation in neuropathic monkeys
Authors: Carlton Susan M. , Rees Huw , Tsuruoka Masayoshi , Willis William D.
Published: February 2004

Several lines of evidence indicate that N‐methyl‐D‐aspartate (NMDA) receptors play an important role in nociception in general and in pathological pain in particular. It has been previously demonstrated in behavioral studies that NMDA receptor antagonists attenuate pathological pain in humans and nociceptive behaviors in animals. In the present study, we investigated the effect of the NMDA receptor antagonist memantine (MEM) on the responses of spinothalamic tract (STT) cells in normal and neuropathic monkeys. Memantine was delivered into the spinal cord through a microdialysis fiber acutely implanted into the dorsal horn. Responses of STT cells to peripheral stimulation within their receptive fields were recorded before and after MEM infusion. In normal animals (n = 7), 10 mm MEM did not affect STT cell (n = 7) baseline activity or responses to mechanical stimuli (brush, press or pinch). In neuropathic animals (n = 6), 1.0, 3.0, 10.0 and 100 mm MEM did not affect baseline activity of STT cells (n = 7); however, in a dose‐dependent fashion, it significantly reduced responses of these cells to all cutaneous stimuli. The data suggest that MEM can have a direct effect on STT cells, blocking NMDA receptors known to be present on this cell population and, furthermore, may be a therapeutic agent for chronic pain.
Controlled‐release oxycodone compared with controlled‐release morphine in the treatment of cancer pain: A randomized, double‐blind, parallel‐group study
Authors: Mucci‐LoRusso Patricia , Berman Barry S. , Silberstein Peter T. , Citron Marc L. , Bressler Linda , Weinstein Sharon M. , Kaiko Robert F. , Buckley Barbara J. , Reder Robert F.
Published: February 2004

Controlled‐release oral formulations of oxycodone and morphine are both suitable analgesics for moderate to severe pain. They were compared in cancer‐pain patients randomized to double‐blind treatment with controlled‐release oxycodone (n = 48) or controlled‐release morphine (n = 52) every 12 h for up to 12 days. Stable analgesia was achieved by 83% of controlled‐release oxycodone and 81% of controlled‐release morphine patients in 2 days (median). Following titration to stable analgesia, pain intensity (0/none to 3/severe) decreased from baseline within each group (p≤ 0.005), from 1.9 (0.1) to 1.3 (0.1), mean (SE), with controlled‐release oxycodone, and from 1.6 (0.1) to 1.0 (0.1) with controlled‐release morphine (no significant between‐group differences). Typical opioid adverse experiences were reported in both groups. Hallucinations were reported only with controlled‐release morphine (n = 2). Visual analog scores (VAS) for ‘itchy’ and ‘scratching’ were lower with controlled‐release oxycodone (p≤ 0.044), as was peak‐to‐trough fluctuation in steady‐state plasma concentration (p = 0.004). The correlation between plasma concentration and dose was stronger (p = 0.026) for oxycodone (0.7) than morphine (0.3). The relationship between pain intensity (VAS) and plasma concentration was more positive for oxycodone (p = 0.046). There was a positive relationship between morphine‐6‐glucuronide concentrations and urea nitrogen and creatinine levels (p = 0.0001). Controlled‐release oxycodone was as effective as controlled‐release morphine in relieving chronic cancer‐related pain, and as easily titrated to the individual's need for pain control. While adverse experiences were similar, controlled‐release oxycodone was associated with less itching and no hallucinations. Controlled‐release oxycodone provides a rational alternative to controlled‐release morphine for the management of moderate to severe cancer‐related pain.
Increased non‐articular tenderness in patients on steroid therapy
Authors: Buskila Dan , Schleifer Elena , Odes H. Selvyn , Neumann Lily
Published: February 2004

Increased non‐articular tenderness and tender shins have been suggested to be associated with steroid therapy in patients with lupus. The aim of the present study was to extend this observation in a different disease, inflammatory bowel disease (IBD), and to examine the relationship between tenderness, dosage and duration of steroid therapy.

Eighty‐seven patients with 11313, 23 of them on steroid therapy, were assessed for disease activity and nonarticular tenderness. A count of 18 tender points was conducted by thumb palpation, and tenderness thresholds were assessed by dolorimetry at four shin sites, nine tender point sites and four control point sites. Patients on steroids were significantly more tender than subjects not on steroids: their mean tender point counts were 13.3 and 6.7 (p<0.001), respectively, and the dolorimetry thresholds at all three sites were significantly lower in the steroid group (p<0.001). Increased tenderness was also associated with increased steroid dosage. However, tenderness was not related to duration of steroid therapy, to gender, or to previous steroid therapy being discontinued at least a year ago. Disease activity was neither related to tenderness nor to steroid treatment.

The demonstration of increased tenderness in IBD patients on steroid therapy, in addition to earlier observations in lupus, may suggest that such a relationship is not disease specific. The recognition of this association is important to physicians treating patients with steroids and will prevent misinterpretations of complaints about tender shins and diffuse tenderness as part of the disease entity itself.
Orphanin‐FQ/nociceptin: Lack of antinociceptive, hyperalgesic or allodynic effects in acute thermal or mechanical tests following intracerebroventricular or intrathecal administration to mice or rats
Authors: Vanderah Todd W. , Raffa Robert B. , Lashbrook Jason , Burritt Andrew , Hruby Victor , Porreca Frank
Published: February 2004

A recent review calls attention to the discrepant results resulting from studies that have examined the nociceptive or antinociceptive properties of orphanin‐FQ/nociceptin (Phe‐Gly‐Gly‐Phe‐Thr‐Gly‐Ala‐Arg‐Lys‐Ser‐Ala‐ArgLys‐Leu‐Ala‐Asn‐Gln; OFQ/N), the heptadecapeptide isolated from rat (nociceptin) and pig (orphanin FQ) brain that binds with high affinity to the opioid ‘orphan’ receptor (a seven transmembrane protein with sequence homology to opioid receptors), but exhibits only low affinity binding with conventional opioid ligands. Some of the discrepancy might result from differences in species, test, route of administration or time‐course. We undertook a comprehensive examination of the effects of spinal (i.t.) or supraspinal (i.c.v.) administration of OFQ/N in mice and rats. Mice treated with OFQ/N either i.t. or i.c.v. demonstrated no significant nociceptive effect in the hot plate, warm‐water or radiant heat tail‐flick tests (except for the highest and most sedative dose of 10 nmol i.c.v. in the mouse warm‐water tail‐flick test). Pretreatment with the opioid antagonist naloxone or with peptidase inhibitors did not enhance the nociceptive effects of OFQ/N peptide in the warm‐water tail‐flick test. The motor activity in mice administered OFQ/N i.c.v. decreased significantly compared to controls. Rats administered i.c.v. or i.t. OFQ/N displayed no significant difference from vehicle‐treated animals in similar noxious stimulus tests and OFQ/N‐treated rats did not exhibit allodynia in a paw‐withdrawal test. Overall, OFQ/N was ineffective in significantly altering response to noxious stimuli, regardless of whether the peptide was given at supraspinal or spinal sites in mice or in rats. In addition, i.c.v. or i.t. application of antisense or mismatch ODN to the orphan receptor did not modify tail‐flick latency in either mice or rats, arguing against a tonic nociceptive tone mediated via the OFQ/N receptor.
Predictors for outcome of a multi‐modal cognitive behavioural treatment program for low back pain patients — a 12‐month follow‐up study
Authors: Haldorsen E.M.H. , Kronholm K. , Skouen J.S. , Ursin H.
Published: February 2004

Low back pain patients (n=142) on sick leave for at least 8 weeks were given a multi‐modal cognitive behavioural treatment program (MMCBT) that lasted for 4 weeks. Before treatment, all patients were tested with a comprehensive test battery. The outcome at 12‐month follow‐up was predictable from the pretest, but only when combining medical and psychological data. Patients who returned to work (Returners, 50%) in the MMCBT group were characterised by less pain, more psychological strength, were evaluated by the physiotherapist as having a good prognosis for return to work, and were less educated. Patients who did not return to work (Non‐returners) in the MMCBT group felt tense and unfit, felt hopelessness concerning the future, were less physically active, thought their complaints would worsen if they continued working, and reported fewer difficulties driving a car. Returners to work (58%) in the randomised control group (n=81), who received ordinary physical therapy, were characterised by high levels of energy, less subjective health complaints, less exhaustion for a condition test, and did not work in positions giving a constant load on the back. There was no significant differences between number of patients who had returned to work in the MMCBT and the control group. Non‐returners in the control group lacked energy, trained less regularly, worked in occupations that gave an almost constant load on the back, and did not expect to be back to work in the course of a couple of weeks. It seems to be important to develop further diagnostic tools to identify those who might benefit from extensive or specific treatments.
Anxiety and coping in patients with chronic work‐related muscular pain and patients with fibromyalgia
Authors: Hallberg Lillemor R.‐M. , Carlsson Sven G.
Published: February 2004

The aims of this study were: (1) to compare two groups of patients with chronic pain conditions (work‐related muscular pain, mainly low back pain, and fibromyalgia) in general coping and pain‐specific coping; (2) to examine the relationship between general and pain‐specific coping and, (3) to examine the influence of state‐trait anxiety on general and pain‐specific coping. The sample included 80 individuals (range = 19–70 years; mean = 47; SD = 9.9), who were patients at two pain management clinics for examination of their physical and psychosocial health conditions and consideration on disability pension. The patients were asked to respond to the Strategies to Handle Stress Questionnaire, the Coping Strategies Questionnaire and the State‐Trait Anxiety Inventory. Patients with fibromyalgia scored significantly higher on T‐anxiety and adopted ‘problem‐solving’ (p<0.01) and ‘catharsis’ (p<0.05) less often and ‘religion’ more often (p<0.01) than patients with work‐related muscular pain in coping with stressful situations in general. No differences were revealed in pain‐related coping between the groups. T‐anxiety was positively correlated to pain‐related “catastrophizing” (p<0.001) and negatively to abilities to control and reduce pain (p<0.05 and p<0.01, respectively). The correlation between general and pain‐specific coping was weak to moderate. In conclusion, patients with fibromyalgia scored significantly higher on trait‐anxiety and seem to interpret stressful situations as more threatening than patients with work‐related muscular pain. Anxiety seems to be of central importance for coping with chronic pain. Anxiety‐prone patients with fibromyalgia might benefit from psychological support in the process of coping with pain.
The NMDA (N‐methyl‐D‐aspartate) receptor antagonist memantine in the treatment of postherpetic neuralgia: A double‐blind, placebo‐controlled study
Authors: Eisenberg Elon , Kleiser Ana , Dortort Ariela , Haim Tamar , Yarnitsky David
Published: February 2004

A double‐blind, randomized, placebo‐controlled trial was conducted to study the analgesic efficacy of the NMDA (N‐methyl‐D‐aspartate) receptor antagonist memantine (1‐amino‐3,5‐dimethyladamantane hydrochloride) in relieving postherpetic neuralgia (PHN). Memantine (or an identical‐looking placebo; n=12/group) was administered at a dose of 10 mg/day for one week, and 20 mg/day for an additional 4 weeks. All patients were required to record their pain level twice daily during the entire study period, with the use of a 0–10 numerical pain scale (NPS). The McGill Pain Questionnaire (MPQ), spontaneous pain, and a series of mechanical and thermal stimuli‐induced pain were measured with the use of a 0–100 visual analogue scale (VAS), on six office visits. Quantitative thermal testing (QTT) and routine blood tests were performed at the beginning and at the end of the study. Although reduction in spontaneous pain, mechanical and cold allodynia, mechanical hyperalgesia, and ‘wind‐up’ like pain were found in both groups, there were no significant differences between memantine and the placebo on any of the outcome measures. No changes were found in either group in MPQ scores or in quantitative thermal thresholds. Although three patients were withdrawn from the memantine group and only one from the control group, no differences in incidence of adverse effects between the two groups were found. Study results show that memantine is ineffective in reducing spontaneous and evoked pain in patients with PHN.
The importance of stimulus configuration for temporal summation of first and second pain to repeated heat stimuli
Authors: Nielsen Jesper , Arendt‐Nielsen Lars
Published: February 2004

Temporal summation of pain is suggested to be an important factor during various clinical conditions. Controversies exist as to whether temporal summation exists for A8 fibre‐mediated first pain. The aim of the present human experimental study was to investigate the importance of stimulus configuration (intensity, interpulse interval, location) for temporal summation of radiant (laser)‐ and contact‐heat‐induced pain. Consecutive stimuli were applied to the same or to adjacent skin locations. Both stimulation techniques evoked rapid temperature changes, which is an important parameter for recruitment of specific cutaneous nociceptors (Aδ and C fibres). Psychophysical thresholds and intensity ratings were used to assess the pain evoked by repeated stimuli applied to the hairy skin of nine volunteers. Inter‐pulse interval (IPI) and stimulus intensity were important and interrelated parameters for temporal summation of pain. An increase in IPI resulted in a decreased summation, whereas increased stimulus intensity resulted in increased summation. Brief heat pulses evoked both first and second pain, and summation of the different pain qualities was investigated. Taking the latency from stimulation to perception into consideration, we were able to differentiate and find summation of first (A8 fibre‐mediated) and second pain (C fibre‐mediated). Summation of first pain was more pronounced for high (38°C) than for low (30–32°C) baseline temperature.
Interactions in the antinociceptive effect of tramadol in mice: An isobolographic analysis
Authors: Pinardi Gianni , Pelissier Teresa , Miranda Hugo F.
Published: February 2004

Tramadol is a widely‐used analgesic for pre‐ and post‐operative pain which has a different pharmacological profile to that of classical opioids, since it does not induce respiratory depression, constipation, sedation, tolerance or dependence. However, tramadol frequently produces nausea and vomiting as side‐effects. In the present study, the interactions between tramadol and several adrenergic and serotonergic compounds with antinociceptive activity were studied by isobolographic analysis. Antinociceptive activity was evaluated using the acetic acid writhing test in mice. Dose‐response curves for the antinociceptive effect of tramadol, prazosin, clonidine, xylamine, clomipramine and cyproheptadine were obtained, and ED50S were calculated for isobolographic analysis, which was performed by administration of fixed‐ratios of tramadol with each of these drugs, given both systemically and intrathecally. The isobolograms of all combinations tested, either systemically or intrathecally showed superadditivity. The synergies observed with these combinations suggest a complex modulation of the descending noradrenergic and serotonergic systems that exert inhibitory influences on the transmission of nociceptive information, probably in addition to effects on receptors in the primary neurons of the spinal cord. The co‐administration of analgesic drugs that produce superadditivc effects constitutes a significant new avenue for the treatment of pain, since a similar level of antinociception can be obtained with considerable reductions in the dose of each analgesic.
Scoring the mouse formalin test: Validation study
Authors: Sufka Kenneth J. , Watson G. Stennis , Nothdurft Rebeccah E. , Mogil Jeffrey S.
Published: February 2004

The formalin test is a well‐established model for assessing nociceptive processes and analgesic drug effects. Previous studies have provided statistical validation of optimal procedures for conducting and scoring the rat formalin test. In the mouse model, formalin concentration has been subjected to validation studies. The present research extended previous work by subjecting two additional parameters — the behaviors that should be scored and the optimal interval for second‐phase formalin response — to empirical validation. Five behavioral (formalin‐induced favoring, lifting, and biting/licking, rearing and locomotion) and two physiological measures (paw weight and paw thickness increases reflective of formalin‐induced inflammation) were examined under four formalin concentrations (Exp. 1: 0.5, 1.0, 5.0, and 10.0%/25 μl formalin) or under four morphine doses (Exp. 2: 0.0, 1.0, 5.0, and 10.0 mg/kg, s.c. with 5% formalin concentration). Multiple regression analyses defined the optimal second‐phase formalin response in outbred, Swiss‐Webster mice as 15–35 min post formalin injection, and revealed that the second‐phase response is best characterized by the cumulative time spent biting/licking the injected paw. Finally, paw physiological measures provided convergent evidence of nociceptive and antinociceptive processes in the mouse formalin test.
The contribution of spinal neuronal changes to development of prolonged, tonic nociceptive responses of the cat induced by subcutaneous bee venom injection
Authors: Chen Jun , Luo Ceng , Li Hui‐Li
Published: February 2004

To elucidate neurophysiological mechanisms of persistent pain induced by tissue injury, the present study was designed to investigate the effects of s.c. bee venom injection on responses of the dorsal horn nociceptive neurons and those of behavior in anesthetized and awake cats, respectively. A parallel comparative study was also performed to compare the effects of s.c. bee venom and formalin injections on neuronal responses by using an extracellular single‐unit recording technique. The present results showed that s.c. bee venom injection into the peripheral cutaneous receptive field resulted in a protracted, tonic monophase of increase in spike responses of wide‐dynamic‐range (WDR) neurons for more than 1 h, while injection of the same volume of vehicle did not have such an effect. The mean number of spikes during the 60‐min period after bee venom was 6.74±2.58 spikes/s (n/10), which showed a significant increase in firing rate over the background activity (2.23±0.96 spikes/s). Behavioral observations showed that s.c. bee venom injection into the dorsum of a hind paw also produced a prolonged, tonic single phase of response indicative of pain, suggesting that central neuronal changes may contribute to development of bee venom‐induced prolonged, tonic pain in cats. The increased neuronal firing induced by s.c. bee venom could be suppressed by a single dose of i.v. morphine and resumed by naloxone. Blockade of the sciatic nerve with lidocaine resulted in a complete suppression of the bee venom‐induced neuronal firing, suggesting that the central neuronal changes following s.c. bee venom are peripherally‐dependent. Comparative studies showed that the duration and frequency of the bee venom‐induced neuronal responses were comparable to those induced by s.c. formalin; however, responses of WDR neurons to mechanical stimuli applied to the injection site of the two chemical agents were quite different. Bee venom produced a significant enhancement of mechanical responses of WDR neurons, while, on the contrary, formalin produced a desensitization of sensory receptors in the injection site, suggesting that the two tonic pain models may have different underlying mechanisms.
Different direct pathways of locus coeruleus to medial prefrontal cortex and centrolateral thalamic nucleus: Electrical stimulation effects on the evoked responses to nociceptive peripheral stimulation
Authors: Condés‐Lara M.
Published: February 2004

Projections from the locus coeruleus (LC) to the centrolateral thalamus (C1) and the medial prefrontal cortex (PfCx) were studied using orthodromic and antidromic stimulation techniques. The LC is a major noradrenergic source in the central nervous system, and its descending projections provide an important source of pain suppression at spinal level. Previously, the author has described a cortico‐thalamic loop involved in pain modulation. The present paper reports on a study of the participation of LC as part of an ascending pain‐control system acting on the cortico‐thalamic loop.

Rats were anaesthetized with halothane, and single unit recordings were made in LC using glass micropipettes. Stainless steel electrodes were placed in cortex and thalamus for electrical stimulation.

Stimulation in PfCx or C1 produces antidromic responses in neurons in LC. The latencies, conduction velocity and location of neurons in LC projecting to PfCx or Cl structures are described. Separate projections to both structures have significantly different conducting velocities, arriving earlier at Cl (mean conduction velocities 0.27 and standard deviation ±0.06m/s) and then at PfCx (mean conduction velocities 0.20± 0.04 m/s). The presence of orthodromic responses suggests reciprocal connections. The paper also describes the suppression of spontaneous and nociceptive‐evoked activity in the PfCx and Cl following electrical stimulation in LC.

It is proposed that the LC innervation could be associated with an ascending noradrenergic system acting upon a C1‐PfCx pain‐modulation mechanism.
Systemic morphine in the prevention of allodynia in the rat spinal nerve ligation model of neuropathic pain
Authors: Kontinen V.K. , Paananen S. , Kalso E.
Published: February 2004

Peripheral nerve injury may lead to neuropathic pain that has been considered unresponsive to opioids. In animal models of neuropathic pain, there are previous data of both increased and decreased effect of opioids, but only limited information of the long‐term effects of opioid treatment on the development of the symptoms of neuropathy. The possibility of preventing the development of signs of neuropathy with either a single preinjury injection or chronic postinjury administration of morphine was studied in rats with unilateral peripheral neuropathy due to tight ligation of the L5 and L6 spinal nerves.

These rats developed both mechanical and cold allodynia, but no thermal hyperalgesia. Neither subcutaneous morphine given as single injection (10 mg/kg) before the nerve injury nor chronic administration starting immediately after surgery using slow‐release pellets (one, two or five pellets containing 75 mg of morphine, resulting in a total dose of 75, 150 or 375 mg) prevented the development of either mechanical or cold allodynia. No autotomy, signs of distress, altered social behaviour or morphine withdrawal was seen in any of the rats. The fact that neuropathic painlike symptoms were not attenuated by any of the treatments studied could indicate that neither premedication nor postoperative pain management with systemic morphine is effective in preventing postoperative neuropathic pain.
Influence of formalin concentration on the antinociceptive effects of anti‐inflammatory drugs in the formalin test in rats: Separate mechanisms underlying the nociceptive effects of low‐and high‐concentration formalin
Authors: Yashpal K. , Coderre T.J.
Published: February 2004

The present study has assessed the relationship between formalin‐induced nociception and formalin‐induced inflammation by comparing the dose‐related effects of anti‐inflammatory treatments on both nociceptive scores and plasma extravasation in the rat hind paw in response to high and low concentrations of formalin. The degree of plasma extravasation produced by 1% formalin did not differ significantly from that produced by the same volume of saline, and was not significantly affected by either of the anti‐inflammatory agents. The 5% formalin injection produced significant plasma extravasation that was dose‐dependently reduced by both dexamethasone and ibuprofen. The early‐phase nociceptive responses to either 1 or 5% formalin were not affected significantly by either of the anti‐inflammatory agents. In contrast, the late‐phase nociceptive responses to 5%, but not 1%, formalin were dose‐dependently reduced by both dexamethasone and ibuprofen. The present study suggests that there is a positive correlation between the nociceptive and inflammatory effects of formalin in the rat hind paw. However, only a high concentration of formalin, which produces significant plasma extravasation, is capable of demonstrating the antinociceptive effects of anti‐inflammatory agents, and the effects are restricted to the late phase of the formalin test.
Long‐term intrathecal (i.t.) infusion of bupivacaine relieved intractable pain and spasticity in a patient with multiple sclerosis
Authors: Dahm P.O. , Nitescu P.V. , Appelgren L.K. , Curelaru I.
Published: February 2004

There is no reliable method to relieve both ‘refractory'; pain and spasticity in patients with multiple sclerosis (MS). This paper reports on the long‐term use of continuous intrathecal bupivacaine infusion in such a patient.

The patient under study was a 56‐year‐old woman affected for 18 years by MS, unsuccessfully treated with analgesics, baclofen, opioids, peripheral neurolysis (obturator nerves, lumbar plexus) and six intrathecal neurolyses of the L4‐S3 nerve roots, each time with 1.5 ml of 50% phenol in glycerol. Intrathecal baclofen was not considered (MS with bulbar location and neurogenic pains). An intrathecal catheter was inserted via the L3‐L4 interspace and its tip was placed at the height of the T12‐L1 intervertebral disc. An intrathecal infusion of 0.5% bupivacaine at a rate of 3 ml (=15 mg)/day was started.

The infusion rate was gradually increased from 20 mg on the first day to 95 mg/day after 68 days. The pain intensity decreased from a mean visual analogue score (VAS/mean) of 7 before treatment to 1 (on a 0–10 scale) during the intrathecal treatment. The patient became free from pain and spasticity. No side‐effects or complications were recorded. The treatment was given for 712 days, at which point the patient died (unrelated to the treatment).

Intrathecal infusion of bupivacaine relieved ‘refractory'; spasticity and pain in a MS patient in whom administration of intrathecal baclofen was contraindicated and neurodestructive procedures had been inefficient.
Assessing surgical patients' expectations and subsequent perceptions of pain in the context of exploring the effects of preparatory information: raising issues of gender and status
Authors: Campbell Carol , Guy Alison , Banim Maura
Published: February 2004

The present study explored both patients' expectations and experiences of pain in the context of utilizing an established research procedure, which previously reported a significant effect of instructional information on post‐surgical recovery. No research to date has systematically attempted to identify pre‐operative expectations of post‐operative pain, nor has it compared pre‐ and post‐operative ratings. A further variable scrutinized during the study was patient gender.

Thirty‐two males and 31 females undergoing two types of elective surgery were randomly allocated into experimental and control conditions by a third party. Patients in the experimental group received additional instruction information pre‐operatively from the anaesthetist and the control group received the routine preoperative visit. Using a numerical pain scale, all participants provided ratings of expected pain levels and subsequently rated their pain following surgery.

Results obtained were contrary to expectations with respect to the effects observed by the established study as instructional information had no significant effect on recovery variables. However, the study did suggest that pre‐ and post‐operative pain ratings were broadly equivalent. A significant gender difference was also found with male patients expecting less pain than they perceived and an opposite pattern for females. Measuring both pain expectations and perceptions is considered a useful technique to inform pain management and is worthy of further investigation. The inconsistent effect of instructional information and the gendered rating patterns are considered in relation to gender and status differentials between health providers and have important implications for future research.
Pain and inflammatory hyperalgesia induced by intradermal injections of human platelets and leukocytes
Authors: Blunk J. , Osiander G. , Nischik M. , Schmelz M.
Published: February 2004

Acute and prolonged inflammatory processes, induced by intradermal injections of autologous platelet preparations, leukocytes, platelet‐leukocyte mixtures and vehicle solutions, were monitored in 20 human subjects for up to 48 h. Psychophysical methods were employed to assess the time course of pain response, and the development of hyperalgesia. Time course of the axon reflex erythema was analysed by computer based videography. Injections of functionally intact platelets [4.4 × 107 ± 0.6 × 107 in 50 μl (mean ± SEM)] caused distinct pain sensations [median pain rating 7.25 (25–75%: 6.5–7.5) on a scale form 0–10]. Both platelets injected through a microfilter (0.2 gm) and heat‐inactivated platelets induced similar initial pain response; however, pain duration was significantly shorter than for intact platelets. Control injections of leukocytes (5.4 × 106 ± 3.7 × 106 in 50 μl) and of vehicle solutions only caused minute pain sensations.

Although platelet concentration in the mixture was only 50%, platelet/leukocyte mixtures produced axon reflex erythema that were significantly larger than those seen with naive platelets alone (11.1 ± 2.3 vs 8.3 ± 0.8 cm2), Intact platelets and heat‐inactivated platelets both induced mechanical hyperalgesia and skin indurations at the injection site. Both reactions peaked between 6 and 24 h after the injection and disappeared within 48 h. Neither hyperalgesia, nor the development of indurations was noted at the injection sites of filtered platelets and vehicle solutions. Leukocyte injections induced hyperalgesia and indurations only in samples with a platelet contamination of more than 50 000 cells/μl. We conclude that platelets induce acute pain responses due to a soluble factor, whereas the development of hyperalgesia and the formation of indurations depends on a membrane‐bound factor. Moreover, platelets and leukocytes act synergistically in nociceptor activation.