A brief, high-dose remifentanil infusion partially reverses neuropathic pain in a subgroup of post herpetic neuralgia patients.

Mechanism-based therapy for chronic pain is desperately needed. Recent basic science research demonstrated that remifentanil can reverse long-term potentiation at C-fiber synapses in the dorsal horn of rats. In this exploratory, single group study, patients with chronic post-herpetic pain were treated with a single, one-hour, high-dose remifentanil infusion. The mean overall change of pain intensity seven days after treatment was -18 (-7.5; -28.5, 95%CI, p<0.001) points on the numeric rating scale (0-100) (-33 (±11) points amongst responders only). Eleven of 20 patients responded to treatment (≥30% reduction in pain), the mean relative reduction in pain from baseline amongst responders was 61.0%. These promising preliminary results suggest that a mechanism-based reversal of chronic pain may be impending.

Midazolam as an active placebo in 3 fentanyl-validated nociceptive pain models.

The use of inactive placebos in early translational trials of potentially analgesic compounds is discouraged because of the side-effect profiles of centrally acting analgesics. Therefore, benzodiazepines are used, although their use has not been validated in this context. Whether benzodiazepines confound the results of acute pain tests is unknown. Midazolam (0.06 mg/kg) as an active placebo was investigated in 3 nociceptive models that included contact heat, electrical pain, and pressure pain thresholds in 24 healthy volunteers. Fentanyl (1 µg/kg) served as an internal validator in this randomized, placebo (saline) controlled, 3-way cross-over trial. The primary outcome parameter (contact heat pain) was analyzed using a one-way, repeated measures analysis of variance and Tukey's post test. Midazolam did not reduce pain ([numeric rating scale], 0-100) in a statistically significant manner compared with placebo for the contact heat (mean difference -1.7, 95% confidence interval -10.6 to 7.3; P = 0.89) or electrical pain (4.3, -5.1 to 13.7; P = 0.51) test, nor did it raise the pressure pain thresholds (-28 kPa, -122; 64 kPa, P = 0.73). The width of the confidence intervals suggested that there were no clinically meaningful analgesic effects compared with the placebo. In contrast, the analgesic efficacy of fentanyl was effectively demonstrated in all 3 models (P < 0.01 vs midazolam and placebo). The findings of this study show that midazolam can be used as an active placebo in analgesic drug trials. Furthermore, the proposed models were simple to implement and very effective in detecting analgesia. The test battery can be used in translational trials for new compounds and comes with an active placebo and an optional active comparator.

Skin Matters: A Review of Topical Treatments for Chronic Pain. Part Two: Treatments and Applications.

In Part One of this two-part series, we discussed skin physiology and anatomy as well as generalities concerning topical analgesics. This modality of therapy has lesser side effects and drug-drug interactions, and patients tolerate this form of therapy better than many oral options. Unfortunately, this modality is not used as often as it could be in chronic pain states, such as that from neuropathic pain. Part Two discusses specific therapies, local anesthetics, and other drugs, as well as how a clinician might use specific aspects of a patient's neuropathic pain presentation to help guide them in the selection of a topical agent.

Skin Matters: A Review of Topical Treatments for Chronic Pain. Part One: Skin Physiology and Delivery Systems.

Chronic pain is a complex disorder with multiple etiologies for which the pathologic mechanisms are still largely unknown, making effective treatment a difficult clinical task. Achieving pain relief along with improved function and quality of life is the primary goal of pain clinicians; however, most patients and healthcare professionals consider 30% pain improvement to be clinically significant-a success level that would be unacceptable in other areas of medicine. Furthermore, patients with chronic pain frequently have multiple comorbidities, including depression and sleep apnea, and most have seen several physicians prior to being seen by a pain specialist, have more than three specific pain generators, and are taking multiple medications. The addition of further oral medications to control pain increases the risk of drug-drug interactions and side effects. However, topical analgesics have the advantage of local application with limited systemic levels of drug. Topical therapies benefit from reduced side effects, lower risk of drug-drug interactions, better patient acceptability/compliance, and improved tolerability. This two-part paper is a review of topical analgesics and their potential role in the treatment of chronic pain.

Multiregion thermal sensitivity mapping of the hand.

Previous neurophysiological studies of discrete hand regions have suggested the dorsum to be more sensitive to temperature changes than the palmar surface, but no multiple-region investigation of the corresponding dorsal and palmar regions has been performed. This study aimed to investigate whether the dorsum of the hand is more sensitive to temperature changes than the palm across multiple regions. In 15 healthy human volunteers, cold and warmth detection thresholds were measured in 10 defined areas of the hand using a thermode of 2.56 cm(2). The testing algorithm employed was the Method of Limits with a baseline temperature of 32 °C and a rate of change of 1°/s. In five subjects, cold-pain and heat-pain thresholds were also measured. All dorsal regions were significantly more sensitive to cold than equivalent palmar areas. Differences in warmth thresholds were not uniform but, overall, dorsal sensitivity was significantly higher. This study finds that the dorsal aspect of the hand was more sensitive to temperature changes than the palm, with higher sensitivity to painful thermal stimuli.

The pattern and time course of somatosensory changes in the human UVB sunburn model reveal the presence of peripheral and central sensitization.

The ultraviolet B (UVB) sunburn model was characterized with a comprehensive battery of quantitative sensory testing (QST). Primary hyperalgesia in UVB-irradiated skin and secondary hyperalgesia in adjacent nonirradiated skin were studied in 22 healthy subjects 24h after irradiation with UVB at 3-fold minimal erythema dose of a skin area 5 cm in diameter at the thigh and compared to mirror-image contralateral control areas. The time course of hyperalgesia over 96 h was studied in a subgroup of 12 subjects. Within the sunburn area, cold hyperesthesia (P=.01), profound generalized hyperalgesia to heat (P<.001), cold (P<.05), pinprick and pressure (P<.001), and mild dynamic mechanical allodynia (P<.001) were present. The finding of cold hyperalgesia and cold hyperesthesia is new in this model. The sunburn was surrounded by large areas of pinprick hyperalgesia (mean±SEM, 218±32 cm(2)) and a small rim of dynamic mechanical allodynia but no other sensory changes. Although of smaller magnitude, secondary hyperalgesia and dynamic mechanical allodynia adjacent to the UVB-irradiated area were statistically highly significant. Primary and secondary hyperalgesia developed in parallel within hours, peaked after 24-32 h, and lasted for more than 96 h. These data reveal that the UVB sunburn model activates a broad spectrum of peripheral and central sensitization mechanisms and hence is a useful human surrogate model to be used as a screening tool for target engagement in phases 1 and 2a of drug development.

Central origin of pinprick hyperalgesia adjacent to an UV-B induced inflammatory skin pain model in healthy volunteers.

Background and purpose The UV-B model is an established pain model of different types of hyperalgesia in animal and human pain research. Beside the skin region of the sunburn in human volunteers pinprick hyperalgesia has been described in a large zone of non-inflamed skin adjacent to the sunburn. However, there are opposing results on the existence of pinprick hyperalgesia and most notably a controversial discussion is still on-going whether this mechanical hyperalgesia in the undamaged tissue adjacent to and at some distance from the site of inflammation is of peripheral or central origin. We therefore addressed this in our study by hypothesising that pinprick hyperalgesia around a circular spot of UV-B inflamed skin is not reduced by a superficial local anaesthetic block and therefore underlies centrally mediated mechanisms. Methods This exploratory study was conducted in a prospective, controlled, randomised, single-blinded fashion in relation to the study hypothesis in 12 healthy volunteers. Before circular irradiation with UV-B light (3-times the individual minimal erythema dose at both thighs), a strip of continuous intradermal local anaesthetic block with lidocaine 2% was established via two single plasmaphoresis hollow fibres. These were positioned perpendicular to one thigh overlapping on the midline of the leg at the distal part of the planned irradiation site, and compared with the contralateral control side without anaesthetic block. The local anaesthetic block was established and then maintained via a syringe pump. The area of pinprick hyperalgesia was measured by pricking on a large skin surface including 360° around the circular irradiation site. This was done with a slightly painful pin (256 mN) until 8h after irradiation. Primary outcome was the area of pinprick hyperalgesia in the skin adjacent to the sunburn at 8h. Results Large areas of mechanical hyperalgesia to pinprick surrounding the adjacent skin of the sunburn developed on both sides after 8h without any significant difference between the side of the anaesthetic strip showing an area of 72.6±39.7 cm2 (mean±SD) and the control side (59.1±20.1 cm2); p = 0.24. Moreover, mechanical hyperalgesia to various pin stimuli of different strength was unchanged by the anaesthetic block. Conclusion This trial provides evidence that the development of mechanical hyperalgesia surrounding an experimental sunburn was not influenced by continuous peripheral afferent blockade with local anaesthetic at 8h after UV-B irradiation. Our data support the hypothesis that in the UV-B model peripheral nociceptive afferent input of inflamed skin may enhance central hypersensitivity of mechanosensitive nociceptors in a larger receptive field far beyond the inflamed skin. Furthermore, these findings are in line with other pain models demonstrating comparable central hypersensitivity around the site of injury. Implications As for other pain models this finding provides further evidence that the UV-B model offers secondary mechanical hyperalgesia in addition to its known primary hyperalgesia. Consequently, this is a further validation for the utilisation of the UV-B model in human pain research.

Treatment of neuropathic pain with the capsaicin 8% patch: Quantitative sensory testing (QST) in a prospective observational study identifies potential predictors of response to capsaicin 8% patch treatment.

Background and aims Peripheral neuropathic pain (PNeP) is a chronic and disabling condition for which no predictors of response to treatment have yet been identified. Clinical studies show that while many patients with PNeP respond positively to treatment with the capsaicin 8% patch, others do not. This study used quantitative sensory testing (QST) to determine whether any patient characteristics can predict response to treatment with the capsaicin 8% patch. Methods This was a prospective, non-placebo-controlled, observational study. Patients used the Visual Analogue Scale (VAS) to assess their pain at baseline and then on Days 1, 7-10 (from here referred to as Day 7/10), 28 and 84 following treatment with the capsaicin 8% patch. QST was undertaken at the same timepoints on the painful area at the region of maximum PNeP and on a contralateral, control area. In addition, the size of the painful area was assessed at baseline and Days 7/10, 28 and 84. Results A total of 57 patients were treated. Among 54 evaluable patients, 19 (35.2%) achieved a ≥30% reduction in VAS pain score at Day 7/10 post-treatment compared with baseline - these were defined as 'responders'. Analysis of the QST data showed that the PNeP area in responders, but not in non-responders, had a significantly lower pressure pain threshold compared with the control area at baseline (median 320 kPa vs. 480 kPa, respectively; p = .004). Furthermore, non-responders had approximately three times greater degree of allodynia at baseline compared with responders across tests using brush, cotton wool and Q-tip. These differences were significant for tests using brush and cotton wool (p = .024 and p = .046, respectively) and approached significance in the test using Q-tip (p = .066). Following treatment with the capsaicin 8% patch, responders showed a trend towards a reduction in warm perception and also appeared to show normalization of the pinprick hyperalgesia at some stimulus levels. Responders to therapy had significantly greater reductions than non-responders in the size of the painful area at Day 28 (p = .011) and Day 84 (p = .005) following treatment. However, both responders and non-responders had meaningful reductions in the size of the painful area compared with baseline values. Conclusions This study suggests that differences can be identified in the sensory profiles of patients with PNeP who respond to the capsaicin 8% patch and those who do not, specifically pressure pain threshold and degree of allodynia. Notably, both responders and non-responders experienced meaningful reductions in the size of the painful area following treatment. Implications The findings warrant further investigation in a larger number of patients and in prospective trials.

Antihyperalgesic efficacy of 5% lidocaine medicated plaster in capsaicin and sunburn pain models--two randomized, double-blinded, placebo-controlled crossover trials in healthy volunteers.

OBJECTIVE: The aim of this research is to analyze analgesic efficacy of the 5% lidocaine medicated plaster in two randomized, double-blinded, placebo-controlled, crossover studies in 16 healthy volunteers using capsaicin and sunburn pain models. METHODS: Lidocaine and placebo plasters were simultaneously applied to forearms and thighs at contralateral body sites for three alternating 12-h plaster-on/plaster-off periods. Between the second and third plaster-on period, 4.2-cm circular spots on both pretreated thighs were irradiated with three times the individual minimal erythema dose of UVB light. After the last plaster-on period, 20 µl of 0.1% capsaicin was injected intradermally into both forearms. The study was repeated using a single 12-h plaster application. RESULTS: The area of pinprick hyperalgesia was diminished by 53% (p < 0.003) in the capsaicin model and by 84% (p < 0.0001) in the sunburn model; the intensity of mechanical hyperalgesia to rigid filaments (8 - 512 mN) was reduced in both models. Cold pain perception threshold was reduced (19.7°C ± 8.0 vs 21.8°C ± 6.8 for placebo, p < 0.05, sunburn). Similar effects were observed in the 12-h exposure study. No effect was seen on capsaicin-induced spontaneous pain and flare size, or blood flow in the sunburn area, and heat hyperalgesia in either study. CONCLUSIONS: Lidocaine plaster effectively treats mechanical hyperalgesia and cold pain.

The impact of socio-economic status on pain and the perception of disability due to pain.

Pain is a major burden for society and a great challenge for public health. The aim of this study was to evaluate the association of socio-economic status (SES) with pain, and assess if there were socio-economic differences in the impairment due to pain, even when the same level of pain was reported. Data were sourced from the Austrian Health Interview Survey 2006-2007, a population based nation-wide survey with 15,474 respondents. SES, based on education, income and profession was inversely and gradually associated with the prevalence of severe pain, with the number of indicated painful body sites, the intensity of pain, and with the subjective level of feeling disabled through pain. In a stepwise logistic regression model, adjusted for age, gender, diseases, number of painful body sites and intensity of pain, people with lower SES gradually reported greater disability through pain. Even at the same intensity of pain and the same number of painful body sites, people in the lowest as compared to the highest socio-economic class were twice to three times more likely to feel disabled through pain. Adjusted odds ratios for the lowest group of SES was 2.80 (95% CI, 1.93-4.06) in terms of education, 1.83 (95% CI, 1.40-2.41) in terms of income and 2.05 (95% CI, 1.32-3.19) in terms of profession. This unexplained socio-economic gradient contributes to the confirmation of the social component in a bio-psycho-social model of pain.

The anxiolytic effect of pregabalin in outpatients undergoing minor orthopaedic surgery.

Preoperative anxiety can increase postoperative pain and is therefore important to avoid. Different approaches have already been tested for preoperative anxiolysis. Gabapentinoids might be a useful alternative to benzodiazepines. Pregabalin is used for treating generalized anxiety disorders and shows a favourable pharmacokinetic profile after oral administration; however, its anxiolytic effect preoperatively in healthy outpatients is still unclear. In this randomised, double-blind, placebo-controlled trial the anxiolytic effect of pregabalin in 40 outpatients undergoing standardised general anaesthesia and postoperative pain therapy for minor orthopaedic surgery was analysed. Patients received preoperatively either 300 mg pregabalin or placebo orally. The primary outcome was anxiety before anaesthesia induction, the secondary outcome the postoperative pain, both assessed using a visual analogue scale from 0 to 100. Without any side effects pregabalin reduced preoperative anxiety compared with the control group (23 ± 10 vs. 38 ± 17; p = 0.003). Pain scores did not differ between groups; however, need of piritramide in the postanaesthesia care unit was reduced to half by pregabalin compared with the control group. A single preoperative dose of 300 mg pregabalin reduces anxiety in patients undergoing minor orthopaedic surgery without any side effects like dizziness or persisting sedation resulting in a prolonged stay in the postanaesthesia care unit.

[Sedation and analgesia in intensive care: physiology and application]. / Sedierung und Analgesie auf der Intensivstation: Physiologie und Anwendung.

Many therapeutic and diagnostic procedures in intensive care medicine are perceived as painful by most patients. As a consequence analgesia and sedation represent two of the main pillars in the treatment of the critically ill. Adaptation to the individual needs of the patients poses one of the biggest challenges that we are confronted with. Both morbidity and mortality can be positively influenced by adequate treatment. In the first part of this review we will discuss the physiology of sleep patterns and pain. Furthermore modes of action and side effects of the most common anesthetics and analgetics will be presented. Finally, the last part of the manuscript deals with the practical application of these therapeutics and their monitoring in intensive care medicine.

Anaesthesia for brachytherapy.

PURPOSE OF REVIEW: The demand for anaesthesia in brachytherapy is increasing. Patients often present with high-risk factors and multiple comorbidities. To achieve a stable position of the implants, immobility is often mandatory. Duration of brachytherapy varies greatly and may exceed the duration of single-shot regional anaesthesia. Transportation of anaesthetized patients is a typical challenge. This review gives information about anaesthesia techniques in brachytherapy on the basis of the literature and the authors' experiences. RECENT FINDINGS: The choice of anaesthesia technique depends on the body region, the type of brachytherapy and the local infrastructure. Topical or local anaesthesia is used by radiotherapists. For brachytherapy of the lower body, regional anaesthesia provides effective and safe conditions. Catheter techniques are used for longer procedures and for high-risk patients, allowing excellent ongoing epidural patient-controlled analgesia. General anaesthesia is safely utilized for brachytherapy of the upper body or as an alternative to regional techniques. However, the effort under the typical conditions of the brachytherapy setting may be higher. Sedation is regarded as an alternative to general anaesthesia in less painful and short procedures. SUMMARY: In conclusion, anaesthesiologists play a key role in the ongoing challenge to provide safe and pain-free conditions for an optimum brachytherapy treatment effect.

Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers.

BACKGROUND: Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with Delta-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. METHODS: The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing Delta-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. RESULTS: Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. CONCLUSION: To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.

TENS relieves acute posttraumatic hip pain during emergency transport.

BACKGROUND: In Central Europe, ambulances for patients suffering from pain caused by nonlife-threatening trauma, such as hip fractures are staffed by medical personnel (medics) without physicians. Thus, there is an urgent need for nonpharmacological interventions that can be applied during the transport by basic life-support (BLS) medical personnel. METHODS: In all, 101 patients were screened for participation in this randomized placebo-controlled double-blind study, and randomly assigned to two groups (verum and sham transcutaneous electrical nerve stimulation [TENS]). First, medic A recorded all baseline parameters and measurements, then medic B performed TENS in absence of medic A. At the end of transportation, medic A performed data collection. Each patient was asked to grade his/her pain and anxiety level on visual analog scales (VAS, 0 to 100 mm). RESULTS: From 101 screened patients fulfilling the entry criteria, 29 declined consent and 9 had to be excluded from the analysis because of their final diagnosis. Therefore, the data from 30 patients (group 1, verum TENS) as well as from 33 patients (group 2 [control], sham TENS) were analyzed. No significant differences in potentially influencing factors were found before treatment. Pain scores upon arrival at the hospital differed significantly between group 1 and group 2 (p < 0.01). In group 1, pain reduction was observed between departure from the site of emergency and arrival at the hospital (VAS: 89 +/- 9 to 59 +/- 6 mm), whereas pain scores remained nearly unchanged in group 2 (VAS: 86 +/- 12 to 79 +/- 11 mm). CONCLUSION: Our findings show that TENS is a valuable and fast-acting pain treatment under the difficult circumstances of "out-of-hospital rescue". Because of its lack of side effects, it could also be a valuable tool in the hospital.

A lack of antinociceptive or antiinflammatory effect of botulinum toxin A in an inflammatory human pain model.

Several in vitro and in vivo investigations have shown that botulinum toxin A (BoNT/A) can inhibit the release of substance P and excitatory amino acids. Recently, a marked antinociceptive effect of BoNT/A and inhibition of glutamate release was observed in an animal pain model with inflammatory sensitization. In the present study, we tested the antiinflammatory and antihyperalgetic effect of BoNT/A in a well-characterized human inflammatory pain model. Using a randomized, double-blind, paired study design, we compared the effects of 100 mouse units of BoNT/A versus pure saline. Thermal and mechanical pain testings and superficial skin blood flow measurements were performed at baseline, at 48 h (in normal skin), and at 72 h (in inflamed skin) thereafter. Ultraviolet B irradiation resulted in a local inflammation with significant primary and secondary hyperalgesia. However, despite the evidence of efficacy on sudomotor function, BoNT/A had no effect on pain measures in either normal or inflamed skin. Signs of inflammation and primary and secondary hyperalgesia were found to be unaffected by BoNT. We have confirmed that BoNT/A has no direct effect on acute, noninflammatory pain. Furthermore, despite highly promising data from animal research, we have not observed antiinflammatory or antinociceptive effects of BoNT/A in human inflammatory pain.

Transcutaneous electrical nerve stimulation reduces acute low back pain during emergency transport.

BACKGROUND: Patients with acute low back pain may require emergency transport because of pain and immobilization. Transcutaneous electrical nerve stimulation (TENS) is a nonpharmaceutical therapy for patients with low back pain. OBJECTIVE: To evaluate the efficacy of paramedic-administered TENS in patients with acute low back pain during emergency transport. METHODS: This was a prospective, randomized study involving 74 patients transported to hospital. The patients were randomly assigned to two groups: group 1 (n = 36) was treated with true TENS, while group 2 (n = 36) was treated with sham TENS. The authors recorded pain and anxiety as the main outcome variables using a visual analog scale (VAS). RESULTS: The authors recorded a significant (p < 0.01) pain reduction (mean +/- standard deviation) during transport in group 1 (79.2 +/- 6.5 mm VAS to 48.9 +/- 8.2 mm VAS), whereas pain scores remained unchanged in group 2 (75.9 +/- 16.4 mm VAS and 77.1 +/- 11.2 mm VAS). Similarly, the scores for anxiety were significantly reduced (p < 0.01) in group 1 (81.7 +/- 7.9 mm VAS to 69.2 +/- 12.1 mm VAS) after treatment. No significant change was noted (84.5 +/- 5.8 mm VAS and 83.5 +/- 8.9 mm VAS, respectively) in group 2. CONCLUSIONS: TENS was found to be effective and rapid in reducing pain during emergency transport of patients with acute low back pain and should be considered due to its ease of use and lack of side effects in the study population.

Intravenous opioid testing in patients with chronic non-cancer pain.

The clinical use of an intravenous opioid testing can help to predict whether opioids will be beneficial. The determination of individual opioid responsiveness justifies subsequent long-term opioid treatment and is generally recommended. An overview over current testing procedures is given with particular regard to choice of opioid, maximum dose, determination of endpoints and duration of testing and recovery. Remifentanil testing is a new approch and is studied in a randomized placebo-controlled cross-over study in 24 patients suffering from severe non-cancer pain. An ascending infusion of remifentanil and placebo respectively was titrated against endpoints. The testing allowed a disctinction between 11 opioid-responders and 13 non-responders. Complete recovery after end of infusion was rapid with a reach of baseline conditions after 25 min in all patients. Thus the complete remifentanil testing procedure required at utmost 1 h. In conclusion, remifentanil testing offers a more rapid procedure allowing the routine use in an ambulatory setting.

Rofecoxib attenuates both primary and secondary inflammatory hyperalgesia: a randomized, double blinded, placebo controlled crossover trial in the UV-B pain model.

The analysis of drug's influence on peripheral and central sensitisation can give useful information about its mode of action and can lead to more efficacy in the treatment of pain. Peripheral inflammation is associated with peripheral expression and up-regulation of cyclooxygenase 2 (COX-2) in the CNS. The relative contribution of COX-2 mediated central sensitisation may be prominent under inflammatory conditions. In this randomized, double blinded, placebo controlled cross-over trial the effects of multidoses of the COX-2 selective inhibitor rofecoxib on primary and secondary hyperalgesia were evaluated in the UVB pain model. Twenty-four hours after local UVB irradiation at the upper leg of 42 healthy volunteers heat pain perception (HPPT) and heat pain tolerance thresholds (HPTT) were assessed within the inflammation. The area of secondary hyperalgesia was determined by pin prick test. Subjects received oral rofecoxib 50, 250, 500 mg or placebo. Pain testing was repeated after 3 and 6 h. Compared to placebo, rofecoxib significantly increased HPPT (1.55 and 1.08 degrees C, P<0.0001 and P=0.0333), HPTT (1.74 and 1.58 degrees C, P<0.0001 and P<0.0001), and reduced the mean area of secondary hyperalgesia by 15.6% (P=0.007) and 16.8% (P<0.001) after 3 and 6 h. No significant difference between the three dosage groups was observed. These data confirm peripheral effects of rofecoxib in a human inflammatory UV-B pain model and provide circumstantial evidence that even a standard clinical dose of rofecoxib reduces central hyperalgesia in inflammatory pain. We confirm that the effect of single oral dose of rofecoxib plateaus at 50 mg.