Burkhard Gustorff

Prevalence of self-reported neuropathic pain and impact on quality of life: a prospective representative survey

Background: Data on the incidence of neuropathic pain (NeP) in Austria, its general characteristics and consequences for the quality of life (QOL) are still lacking. The prevalence in the United Kingdom is 8%.

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.

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 drugs 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 °C, P<0.0001 and P=0.0333), HPTT (1.74 and 1.58 °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.

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.

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

Summary Ultraviolet B irradiation induces generalized hyperalgesia to all pain modalities primarily on the basis of multiple mechanisms of peripheral sensitization, but also involves central sensitization (secondary hyperalgesia and dynamic mechanical allodynia). Abstract 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 24 h 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 cm2) 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.

Dose response of tramadol and its combination with paracetamol in UVB induced hyperalgesia

Combining tramadol with paracetamol is an established analgesic treatment strategy. However, dosing and differential effects on peripheral and central hyperalgesia are still to be determined. After Ethics Committee approval, 32 volunteers have been included in this 2 phased, double blinded, placebo controlled, cross‐over study. A defined small skin area was irradiated with a UVB source inducing hyperalgesia. Twenty‐four hours after irradiation, heat pain‐, cold pain threshold (HPPT, CPPT), mechanical pain sensitivity to pin prick (MPS) in the area of pin prick hyperalgesia (AsH) and MPS in the sunburn were determined. In phase I, measurements have been repeated 30 min after receiving cumulative 0.3, 0.6 and 1 mg/kg of intravenous (i.v.) tramadol or active placebo. Only at 1 mg/kg tramadol and solely for MPS in the sunburn a reduction to placebo could be demonstrated (p = 0.024). Accordingly in phase II, the trial has been repeated using 1 mg/kg tramadol and paracetamol or placebo in a cumulative i.v. dose of 330, 660 and 990 mg. Now the addition of 330 mg paracetamol to tramadol reduced thermal hyperalgesia by 1.15 °C (CI 0.55; 1.76). This effect, however, did not increase with higher doses. Tramadol showed week anti‐hyperalgesia reducing CPPT, MPS and AsH compared to baseline measurements (p < 0.05). Paracetamol also reduced secondary hyperalgesia, but no combination effect with tramadol could be shown. We conclude, in inflammatory hyperalgesia tramadol alone exerts only weak anti‐hyperalgesia. Even adding a small dose paracetamol enhances thermal anti‐hyperalgesia.

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

Abstract 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.

On the ropivacaine‐reducing effect of low‐dose sufentanil in intrathecal labor analgesia

Background: Combining ropivacaine with sufentanil for intrathecal (i.t.) analgesia in labor is well recognized, but information on dosing is limited. This study aimed to determine the ED 50 of i.t. ropivacaine and to assess the effect of adding defined low doses of sufentanil.

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.

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

Abstract 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.