European Journal of Pain

Editorial Board

2010-03-01

Impact of chronic inflammation on the pharmacokinetic–pharmacodynamic relationship of naproxen

2009-08-13

Abstract: Objectives: The use of biomarkers for predicting the clinical doses of analgesic drugs relies on the understanding of the relationship between drug exposure and response under disease conditions. In this study, we demonstrate the relevance of such a relationship for COX-inhibitors by modelling the effect of naproxen on prostaglandin E2 and thromboxane B2 in a chronic inflammation model in rats.Methods: Rats were treated with Freund’s complete adjuvant (FCA) by intraplantar injection. On post-inoculation days (PID) 7–21, animals received single or chronic (qd until day 21) doses of naproxen (10mg/kg). Blood samples were collected at various intervals after dosing to characterise naproxen pharmacokinetics and its effects on and production. PK-PD modelling was performed using nonlinear mixed effects in NONMEM.Results: The inhibition of and could be described by a sigmoid model. A decrease in the potency estimates of both biomarkers was observed under chronic inflammation, as compared to healthy animals. values for inhibition showed a shift from to , whilst values for inhibition increased from to in healthy and FCA-inoculated animals, respectively.Conclusions: Our results show that chronic inflammation causes a significant change in the potency estimates for COX-inhibition. These findings illustrate the implications of pathophysiological processes on pharmacodynamics and consequently on the required exposure levels for achieving response during chronic treatment.

Persistent deep mechanical hyperalgesia induced by repeated cold stress in rats

Teruaki Nasu, Toru Taguchi, Kazue Mizumura — 2009-06-29

Abstract: Chronic muscle pain of the neck, shoulder and low back is quite common and often related to a stressed condition. In this study we tried to make a model of long-lasting muscle mechanical hyperalgesia based on one type of stress, repeated cold stress (RCS) (Kita T, Hata T, Yoneda R, Okage T. Stress state caused by alternation of rhythm in environmental temperature, and the functional disorders in mice and rats. Folia Pharmacol Jpn 1975;71:195–210). We first validated a method of measuring the muscle mechanical nociceptive threshold through skin, with surface anesthesia of the skin covering the muscle. We found that a pressure test using a Randall–Selitto analgesiometer equipped with a larger probe (ϕ 2.6mm) can measure the deep mechanical withdrawal threshold even under the presence of cutaneous punctuate hyperalgesia. RCS was performed by changing the temperature from 22°C to either 4°C (RCS at 4°C) or −3°C (RCS at −3°C) every 30min, and then maintained at 4°C/−3°C from 17:30 to 10:00 the next day. RCS at 4°C for 5days induced bilateral deep mechanical hyperalgesia lasting 2–3weeks without cutaneous punctuate hyperalgesia. Deep mechanical hyperalgesia observed after RCS at −3°C lasted longer (∼6weeks) and was severer than RCS at 4°C. Bilateral cutaneous punctuate hyperalgesia was also observed with RCS at −3°C. Intramuscular injection of lidocaine confirmed that the muscle was hyperalgesic. RCS might serve as a useful model for study of the mechanism of chronic muscle pain and its treatment.

Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat

Åsa Amandusson, Anders Blomqvist — 2009-06-15

Abstract: Estrogens exert a substantial influence on the transmission of nociceptive stimuli and the susceptibility to pain disorders as made evident by studies in both animals and human subjects. The estrogen receptor (ER) seems to be of crucial importance to the cellular mechanisms underlying such an influence. However, it has not been clarified whether nociceptive neurons activated by pain express ERs. In this study, a noxious injection of formalin was given into the lower lip of female rats, thereby activating nociceptive neurons in the trigeminal subnucleus caudalis as demonstrated by immunohistochemical labeling of Fos. Using a dual-label immunohistochemistry protocol ERα-containing cells were visualized in the same sections. In the superficial layers of the medullary dorsal horn, 12% of ERα-labeled cells, mainly located in lamina II, also expressed noxious-induced Fos. These findings show that nociceptive-responsive neurons in the medullary dorsal horn express ERα, thus providing a possible morphological basis for the hypothesis that estrogens directly regulate pain transmission at this level.

The integrity of the anterior pretectal nucleus and dorsolateral funiculus is necessary for electroacupuncture-induced analgesia in the rat tail-flick test

Marcelo L. Silva, Josie R.T. Silva, Wiliam A. Prado — 2009-06-29

Abstract: Previous studies have indicated that the anterior pretectal nucleus (APtN) is implicated in pathways that descend through the dorsolateral funiculus (DLF) to modulate nociceptive inputs in the spinal dorsal horn. The activation of descending inhibitory mechanisms also seems to be involved in electroacupuncture (EA)-induced analgesia. This study utilized the tail-flick test to examine the changes produced by DLF lesion or injection of 2% lidocaine into the APtN in the analgesia induced by 2 or 100Hz EA applied to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints in lightly anesthetized rats. Tail-flick latency was significantly increased by EA, the effect of 2Hz EA lasting longer than that produced by 100Hz EA. The effect of either 2 or 100Hz EA did not occur in DLF lesion rats. The effect of 2Hz EA did not occur in rats with neural block of the whole or dorsal APtN. In contrast, the effect of 100Hz EA was reduced in rats with neural block of the whole APtN, but remained unchanged in rats with neural block of the dorsal APtN. We thus conclude that the integrity of the APtN and DLF is necessary for EA-induced analgesia in the rat tail-flick test. In addition, the integrity of the dorsal APtN is necessary for the analgesic effect of 2 but not 100Hz EA.

Spinal cord long-term potentiation (LTP) is associated with increased dorsal horn gene expression of IL-1β, GDNF and iNOS

Linda M. Pedersen, Line M. Jacobsen, Steen Mollerup, Johannes Gjerstad — 2009-07-14

Abstract: Previous data show that spinal cord long-term potentiation (LTP) can be induced by electrical high-frequency stimulation (HFS) conditioning applied to the sciatic nerve. It has been suggested that the cellular events leading to this form of plasticity may contribute to central hyperalgesia. In the present study, extracellular recordings from single dorsal horn neurons and quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) on rat dorsal horn tissue were used to examine whether maintenance of spinal LTP is associated with changes in gene expression of the proinflammatory interleukin-1β (IL-1β), glial cell-line derived neurotrophic factor (GDNF), inducible nitric oxide synthase (iNOS), p38 mitogen-activated protein kinase (p38 MAPK), cyclooxygenase 2 (COX2) and tumor necrosis factor α (TNFα). The data demonstrated that the HFS conditioning induced a robust increase in the dorsal horn C-fibre responses, which outlasted the duration of the experiments of 6h (p<0.05, HFS vs. control). Moreover, a significant increase in the expression of mRNA for IL-1β, GDNF and iNOS were observed 6h following the HFS conditioning (p<0.05, HFS vs. control). For the first time we show that spinal cord LTP is associated with an increased dorsal horn expression of the genes for IL-1β, GDNF and iNOS.

Using the intact hand for objective assessment of phantom hand-perception

2009-05-28

Abstract: After amputation, most patients experience a phenomenon known as a phantom limb (PL). A variety of PL experiences appear to be associated with neural plasticity within the CNS. However, due to the subjective nature of PL experiences, there was no definitive way to reliably assess PL experiences other than using patients’ direct reports. Here, we were able to obtain patients’ indirect responses to PL experiences, for a more objective evaluation. First, we conducted a study with normals and 17 non-PL patients experiencing pathological pain in one hand. We took digital photographs of their affected and unaffected hands, altered the sizes of the images digitally, and then asked each subject to choose the image that most closely matched the actual size of their own hands (from a series of images presented on a video screen). Subjective size perceptions of the hands were homologous, regardless of the pathological condition of one hand (p<0.0001, Spearman R2=0.82). Next, we used the same method for total 19 patients with a phantom hand. The intact hand-size perception was linearly correlated with phantom hand-size perception (weighted linear regression analysis: p<0.0001, R2=0.75, adjusted R2=0.73, F-value=50.1, degree of freedom=18). Thus, without requiring a subjective description about PL, the patients’ evaluation of the intact hand-size precisely but indirectly indicated whether the PL was perceived to be telescoped (shrunken), normal or enlarged. This more objective evaluation of PL phenomena could become a key tool for disentangling the neural mechanisms involved.

Differential physiological effects during tonic painful hand immersion tests using hot and ice water

Anouk Streff, Linn K. Kuehl, Gilles Michaux, Fernand Anton — 2009-06-22

Abstract: The cold pressor test (CPT) is an empirically validated test commonly used in research on stress, pain and cardiovascular reactivity. Surprisingly, the equivalent test with water heated to noxious temperatures (hot water immersion test, HIT) has not been thoroughly investigated. The aim of the present study was to characterize the physiological effects and psychophysics of both tests and to analyze whether the autonomic responses are mainly induced by baroreflexes or a consequence of the pain experience itself. The study consisted of a single session including one CPT (4±0.2°C) and one HIT (47±0.5°C; cut-off point 5min) trial performed on 30 healthy drug free volunteers aged 19–57 (median 24) yrs. The sequence of both trials was alternated and participants were randomly assigned to sequence order and parallelized with respect to gender. Physiological parameters (cardiovascular, respiratory and electrodermal activity) and subjective pain intensity were continuously monitored. In addition, pain detection and tolerance thresholds as well as pain unpleasantness were assessed. Both tests were comparable with regard to the time course and intensity of subjective pain. However, a significantly higher increase of blood pressure could be observed during the CPT when compared to the HIT. The HIT appears less confounded with thermoregulatory baroreflex activity and therefore seems to be a more appropriate model for tonic pain.

Central pain mechanisms following combined acid and capsaicin perfusion of the human oesophagus

2009-06-22

Abstract: Visceral afferents originating from different gut-segments converge at the spinal level. We hypothesized that chemically-induced hyperalgesia in the oesophagus could provoke widespread visceral hypersensitivity and also influence descending modulatory pain pathways. Fifteen healthy volunteers were studied at baseline, 30, 60 and 90min after randomized perfusion of the distal oesophagus with either saline or 180ml 0.1M HCl+2mg capsaicin. Electro-stimulation of the oesophagus, 8cm proximal to the perfusion site, rectosigmoid electrical stimulation and rectal mechanical and heat stimulations were used. Evoked brain potentials were recorded after electrical stimulations before and after oesophageal perfusion. After the perfusion, rectal hyperalgesia to heat (P<0.01, 37%) and mechanical (P=0.01, 11%) stimulations were demonstrated. In contrast, hypoalgesia to electro-stimulation was observed in both the oesophagus (P<0.03, 23%) and the sigmoid colon (P<0.001, 18%). Referred pain areas to electro-stimulation in oesophagus were reduced by 13% after perfusion (P=0.01). Evoked brain potentials to rectosigmoid stimulations showed decreased latencies and amplitudes of P1, N1 and P2 (P<0.05), whereas oesophagus-evoked brain potentials were unaffected after perfusion. In conclusion, modality-specific hyperalgesia was demonstrated in the lower gut following chemical sensitization of the oesophagus, reflecting widespread central hyperexcitability. Conversely, hypoalgesia to electrical stimulation, decreases in referred pain and latencies of evoked brain potentials was seen. This outcome may reflect a counterbalancing activation of descending inhibitory pathways. As these findings are also seen in the clinical setting, the model may be usable for future basic and pharmacological studies.

Attentional modulation fails to attenuate the subjective pain experience in chronic, unexplained pain

T.J. Snijders, N.F. Ramsey, F. Koerselman, J. van Gijn — 2009-07-21

Abstract: Background: Chronic, unexplained pain is a common, ill-understood clinical problem. Increased sensitivity for pain and other stimuli is often implied as an underlying mechanism. Attentional processes influence central pain processing and might mediate hypersensitivity at a cerebral level.Aims: To study patients with chronic, unexplained pain with respect to (a) subjective pain experience; (b) effects of attentional manipulation; (c) level at which alterations in pain processing occur: locally (symptomatic body region), or generalised.Methods: We compared 16 patients with chronic, unexplained limb pain with 16 matched healthy controls. Pain thresholds to electrical stimuli were recorded. Subjects then received individually thresholded painful and non-painful stimuli, with manipulation of attention towards or away from pain. The intensity of pain perception was recorded by means of visual analogue scales (VAS). Pain thresholds and effects of Attention and Laterality on VAS scores were compared between groups by means of general linear modelling (restricted to 12 patients with unilateral pain and 12 controls).Results: Distraction increased thresholds for pain in healthy volunteers, but this effect was significantly attenuated in patients. Significant interactions between attention-effects, stimulus laterality and stimulus intensity indicated that VAS scores for painful stimuli were attenuated during distraction in healthy controls, but not in pain patients.Conclusions: Results support the notion that pain processing is enhanced in chronic, unexplained pain, and that the influence of attentional modulation on pain processing is attenuated. Potential cerebral mechanisms are changes in either attentional allocation or attention-mediated descending pain modulation. The changes seem to occur at a generalised level.

Increasing use of opioids from 2004 to 2007 – Pharmacoepidemiological data from a complete national prescription database in Norway

2009-06-08

Abstract: Background: A high opioid consumption for cancer related and acute pain may indicate adequate pain treatment. Analysis of a national, compulsory and complete database of all dispensed prescription drugs in Norway (NorPD) may reveal important epidemiological data on prescription pattern of opioids. This study investigated the prevalence of opioid dispensions in 2004–2007 and explored patterns of use.Methods: All pharmacies in Norway submit data electronically to NorPD on all dispensed prescriptions. All prescriptions to any individual are identified by a unique pseudonym. All persons who were dispensed opioids from 2004 to 2007 are included in the study. Cancer patients are identified by a reimbursement code. Non-cancer pain indications are inferred from pattern of prescriptions.Results: 470,638 Norwegians were dispensed opioids in 2007, corresponding to 9.7% of the population (13.0% of adults). Only 13,220 persons (2.8% of all patients) received opioids for cancer pain, accounting for 10% of all dispensed opioids measured in defined daily doses (DDDs). Among persons with non-cancer pain 77% received only one dispension per year or less than 50 DDDs/year. Fifteen percent received from 50 to 200 DDDs/year. Only 13,846 (4%) received >400 DDDs/year and are likely to be daily users for chronic non-cancer pain. From 2004 to 2007 a 9 % increase was observed in the number of persons receiving opioids and the number of dispensions, whereas opioid types, doses, and indications appeared stable.Interpretation: From these prescription patterns it can be concluded that the majority of patients received opioids for acute, non-cancer pain.

Effect of chronic intra-peritoneally administered chimeric peptide of met-enkephalin and FMRFa-[d-Ala2]YFa-on antinociception and opioid receptor regulation

Ishwar Dutt Vats, Snehlata, Mahendra Nath, M.A. Qadar Pasha, Santosh Pasha — 2009-06-29

Abstract: The physiological role of NPFF/FMRFa family of peptides is complex and exact mechanism of action of these peptides is not yet completely understood. In same line of scrutiny, previously we reported an enzymatically stable chimeric analog of YGGFMKKKFMRFamide (YFa) i.e., [d-Ala2]YAGFMKKKFMRFamide ([d-Ala2]YFa) which have a role in antinociception and modulatory effect on opioid analgesia. In continuation, presently we investigated using tail-flick test whether [d-Ala2]YFa on systemic administration induced any antinociception in rats and if so then which specific opioid receptor(s) μ, δ or κ mediated it. Further, the antinociceptive effect of [d-Ala2]YFa on 6 days chronic intra-peritoneal (i.p.) treatment in rats was examined and finally, effect of this chronic treatment on the differential expression of opioid receptors was assessed.[d-Ala2]YFa on i.p. administration induced dose dependent antinociception which was mainly mediated by δ (DOR) and partially by μ (MOR) and κ (KOR) opioid receptors. Moreover, its antinociceptive effect remained comparable throughout the chronic treatment even during insufficient availability of DOR1. Importantly, during this treatment the mRNA expression of all three opioid receptors (MOR1, KOR1 and DOR1) was increased as assessed by real-time RTPCR though subsequent western blot analysis revealed a selective increase in the protein level of DOR1, only.Thus, pharmacological behavior of [d-Ala2]YFa suggests that competency of an opioid agonist to bind with multiple opioid receptors may enhance its potency to induce tolerance free analgesia.

An observational study on the effect of S(+)-ketamine on chronic pain versus experimental acute pain in Complex Regional Pain Syndrome type 1 patients

2009-06-19

Abstract: Aims: The aim of the study was to explore the analgesic effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex Regional Pain Syndrome type 1 (CRPS-1) patients.Methods: Ten patients suffering from chronic CRPS-1 and with a Visual Analogue pain Score (VAS) of >5 were recruited. Seven intravenous 5-min low-dose S(+)-ketamine infusions with increasing doses at 20-min intervals were applied. Spontaneous pain ratings and VAS responses to experimental heat stimuli were obtained during infusion and for 3-h following infusion.Results: CRPS pain: Ketamine produced potent analgesia with a significant VAS reduction from 6.2±0.2 to 0.4±0.3cm at the end of infusion. Analgesia persisted beyond the infusion period (VAS=2.8±1.0cm at 5-h), when measured plasma ketamine concentrations were low (<100ng/ml). Experimental pain: Ketamine had a dose-dependent antinociceptive effect on experimental pain that ended immediately upon the termination of infusion.Discussion: The data indicate that while ketamine’s effect on acute experimental pain is driven by pharmacokinetics, its effect on CRPS pain persisted beyond the infusion period when drug concentrations were below the analgesia threshold for acute pain. This indicates a disease modulatory role for ketamine in CRPS-1 pain, possibly via desensitization of NMDAR in the spinal cord or restoration of inhibitory sensory control in the brain.

Referral practices in patients suffering from non-malignant chronic pain

2009-07-01

Abstract: This paper presents the results of a prospective observational cohort study investigating referral practices to six specialized pain centres (SPCs) in 303 patients with headache (HD), low back pain (LBP), and neuropathic pain (NP). The study was divided into three parts. Part 1: The pain health care history (contacts with general practitioners and specialists, further referrals, time spans, therapies) before first contact with the SPC. Part 2: Reality of pain therapy and management in the SPC (patients’ attrition, interdisciplinarity of therapy and novel therapeutic strategies instigated). Part 3: Follow-up and assessment of pain levels (NRS, SES), disability scores (PDI), QoL scores (SF 12), and anxiety and depression scores (HADS) at 0, 6 and 12 months. Using an ordinal linear regression model, factors predicting a good treatment outcome were identified.On average it took 3 years of pain symptoms before first consultation with GP. The median time period from the first pain sensations until the appointment in the SPC was 12 years. Nearly half of the referrals to specialists or SPCs were initiated by a non-professional. In the SPC the medication was changed in 71% of cases. Care was interdisciplinary in only 32%. At 6 and 12 months after the first contact with the SPC, only 20% of the patients had improved with respect to levels of pain and psychometric data. A high degree of chronicity, a history of pain-associated surgeries and low social support were negative predictors for treatment outcome.

Acceptance of pain in adolescents with chronic pain: Validation of an adapted assessment instrument and preliminary correlation analyses

Lance M. McCracken, Jeremy Gauntlett-Gilbert, Christopher Eccleston — 2009-05-25

Abstract: It is important to understand the processes that contribute to disability and distress in adolescents with chronic pain. For example, research has identified that when adolescents can positively adapt to the consequences of health condition, rather than attempt to change the condition itself, they also function better and experience less distress. This pattern of behavior is similar to what is referred to as “acceptance” of pain in the adult literature. Although acceptance is consistently associated with positive outcomes in adult studies, there has been less investigation of acceptance in adolescents. This study aimed to examine the reliability and validity of an adolescent-adapted version of the Chronic Pain Acceptance Questionnaire (CPAQ-A), and, using this instrument, to carry out a preliminary investigation of acceptance in adolescents with chronic pain. A sample of 122 highly disabled adolescents with chronic pain attending a specialty service completed the adapted CPAQ-A. They also completed standardized measures of their pain and daily functioning. Results supported the reliability and validity of the CPAQ-A. Correlation analyses showed that higher levels of acceptance were associated with lower levels of distress and disability, but not with lower pain intensity. Regression analyses were carried out to assess the independent contribution of acceptance after pain intensity and demographic variables were taken into account. In these analyses acceptance accounted for significant variance in disability, psychological distress, and developmental and family functioning. We discuss developmental aspects of acceptance in adolescents and clinical implications of these findings.

Evoked potentials generated by noxious stimulation in the human infant brain

2009-05-29

Abstract: While human infants can display distinctive behavioural and physiological spinal cord and brainstem responses to noxious stimulation, it is not known whether cortical neurons are specifically activated by noxious stimuli in newborns. Here, using a novel approach to time-lock an EEG recording to a clinically required heel lance, we show the presence of a distinct nociceptive-specific potential in newborn infants (35–39weeks postmenstrual age). The potential can be observed in single trials in the central electrodes (Cz and CPz) and using principal component analysis is characterised by a positivity that occurs at approximately 560ms post-stimulus (N420–P560; P, positive; N, negative). The magnitude of the nociceptive-specific potential is not dependent on sleep state, whereas an earlier potential (N150–P260–N430), which is sleep-state dependent, is evoked by both noxious and non-noxious stimulation. These results provide the first direct evidence of specific noxious-evoked neural activity in the infant brain and suggest that newborn infants are capable of the sensory-discriminative aspects of pain experience.

Co-occurrence and associations of pain and fatigue in a community sample of Dutch adults

2009-06-19

Abstract: Widespread pain and chronic fatigue are common in the general population. Previous research has demonstrated co-occurrence of syndromes that are associated with pain and fatigue (fibromyalgia and chronic fatigue syndrome), but there is limited existing data on the co-occurrence of these symptoms in general. This study investigates the co-occurrence of pain and fatigue, and characterises people with these symptoms individually, and in combination. A postal questionnaire was sent to a random sample of 4741 community dwelling Dutch adults registered with five general practices. There were 2447 participants (adjusted response=53.5%). Persistent fatigue was reported by 60% of the 451 subjects with chronic widespread pain. Chronic widespread pain was reported by 33% of the 809 responders with persistent fatigue. Anxiety and depression were more common in subjects who reported both symptoms than those who reported either one or neither. Participants who had chronic disease, high body mass index, low activity levels or did not perceive ability to influence health had higher adjusted odds of reporting both symptoms (but not one alone) than subjects not having these characteristics. Pain and fatigue occur more often than would be expected by chance and there are a number of reasons for this. Clinicians should be aware that co-occurrence of the symptoms is common, especially in people who have high BMI or chronic disease, and that people with both symptoms are often anxious or depressed. Further work should address longitudinal associations of pain and fatigue.

Measuring musculoskeletal pain by questionnaires: The manikin versus written questions

Linda H.J. van den Hoven, Kees J. Gorter, H. Susan J. Picavet — 2009-08-21

Abstract: A picture of a human figure (manikin) on which pain can be indicated can be used to measure musculoskeletal pain in self administered or web-based questionnaires. In this paper we present an analysis of the agreement between pain reported on a manikin and pain reported using written questions as assessed in the follow-up questionnaire of the Dutch population-based Musculoskeletal Conditions and Consequences Cohort (DMC3-study). Both a manikin and extensive questions on pain were included and the agreement between the two measures was studied for nine pain locations. For a similar pain definition – pain lasting at least a week – the manikin gave slightly higher prevalences than the written questions. Around three quarter of those who reported pain on the written questionnaire also indicated pain on the manikin on the same anatomical location. There were no differences in the percentage of agreement by sex, age group or level of education, except for a lower percentage of agreement of the manikin among the elderly for pain in the lower extremities, neck and shoulder and among the lower level of education group for neck pain. Almost 6% of the participants reported pain according to the questions only and more than 10% (especially men) reported pain on the manikin only. We concluded that a manikin gives similar findings on prevalence of pain as written questions and could therefore be a good alternative for written questions only.