European Journal of Pain - Articles in Press

The association between supra-physiological levels of estradiol and response patterns to experimental pain - Corrected Proof

Vicki Nisenblat, Batya Engel-Yeger, Gonen Ohel, Doron Aronson, Michal Granot — 2010-03-02

Abstract: The precise mechanism by which gonadal hormones influence pain perception is still obscure. However, no studies have examined experimental pain responses at supra-physiological hormone levels. This study explored the influence of pharmacological estradiol (E2) levels on the stability of pain perception obtained via quantitative sensory testing. A repeated measures design was used with 31 women, treated by a same In Vitro Fertilization (IVF) protocol. Patterns of experimental pain response were assessed in three different sessions (baseline, down regulation, maximal ovarian stimulation). Correlations between hormonal levels (E2, progesterone, luteinizing hormone (LH)) and pain perceptions were assessed at each session. While in the entire sample the pattern of response to pain stimulations remained unchanged regardless of hormonal manipulations, a greater pain sensitivity was associated with supra-physiological levels of E2 during the maximal ovarian stimulation session (for 47°C stimulation: r=.383, p=0.044). Mixed model repeated measures ANOVA indicated that participants who over-responded to the ovarian stimulation session (E2>10,500pmol/l) showed significant enhanced pain responses under this condition (p=0.004). No correlations between progesterone, LH and experimental pain perception were found in any of the study sessions. Although pain perceptions at different E2 levels remained constant, the enhancement of pain scoring at supra-physiological E2 levels, underscore the possible role of sex hormones in pain modulation and experience.

Pain-related fear predicts disability, but not pain severity: A path analytic approach of the fear-avoidance model - Corrected Proof

2010-03-02

Abstract: Two studies are reported that tested the fear-avoidance (FA) model using path analytic techniques. In study 1, 429 employees with back pain at baseline and back pain at 18months follow-up completed questionnaires assessing sociodemographic information, pain severity, negative affect, pain-related fear, and disability. Results indicated that pain severity at baseline predicted pain-related fear and disability at follow-up, and that pain-related fear is rather a consequence than an antecedent of pain severity. Results further revealed that the disposition to experience negative affect has a low impact upon pain severity and disability, and is best viewed as a precursor of pain-related fear. Study 2 included 238 employees without back pain at baseline, but who developed back pain at 1year follow-up. A similar model as in study 1 was tested. Overall, results are in line with those of study 1. Results are discussed in terms of theoretical relevance and clinical implications.

Parallel assessment of prolonged neonatal distress by empathy-based and item-based scales - Corrected Proof

Lars Garten, Philipp Deindl, Gerd Schmalisch, Boris Metze, Christoph Bührer — 2010-03-02

Abstract: Objective: To evaluate the association between the empathy-based Faces Pain Scale-Revised (FPS-R) and the item-based Neonatal Pain, Agitation and Sedation Scale (N-PASS) when used to assess prolonged distress in term and preterm infants.Method: Sequential prospective psychometric evaluations of distress, at 4-h intervals during a 48-h time period. FPS-R and N-PASS were employed in parallel by the nurses in charge in 44 term and preterm newborn infants.Results: During the overall 48-h observation period, median FPS-R declined from 6/10 to 2/10 (p<0.001) while N-PASS did not change significantly. FPS-R and N-PASS showed strong correlation during the first 12h of observation (Rs=0.786, p<0.001). During each of the following 12-h observation periods, the strength of this association decreased (12–24h: Rs=0.781; 24–36h: Rs=0.675; 36–48h: Rs=0.658) while remaining significant (p<0.001). However, when used to categorize infants as being in distress or not, the rate of agreement between FPS-R and N-PASS showed little variation (0–12h: 79.6%, 12–24h: 88.6%; 24–36h: 89.4%, 36–48h: 84.9%).Conclusions: In newborn infants serially assessed over 48 h, there is a progressive divergence between FPS-R and N-PASS. There is, however, reason to extend the use of the FPS-R also to the neonatal arena, as the rate of agreement between N-PASS and FPS-R to categorize an infant as being in distress or not remains stable. Preference of item- or empathy-based assessment may be a question of personal philosophy rather than medical science.

Adolescent chronic pain-related functioning: Concordance and discordance of mother-proxy and self-report ratings - Corrected Proof

Lindsey L. Cohen, Kevin E. Vowles, Christopher Eccleston — 2010-03-02

Abstract: Accurate assessment of adolescent chronic pain is critical to guiding treatment decisions. Given the multifaceted role of the parents in their children’s lives, parents, and patients often each provide reports of adolescents’ pain-related functioning. In order to make sense of these data, clinicians should be aware of patterns of discordance in perspectives. In this study, we aimed to examine concordance and discordance in adolescents’ self-report and mothers’ proxy-report of adolescents’ chronic pain-related functioning. Results suggested that although there were high correlations between the raters, there were also significant discordance with mothers rating their adolescents as having greater disability in social functioning, depression, and pain-specific anxiety. Analyses suggested that high pain and being older predicted greater concordance in ratings. Findings suggest that mothers and adolescents tended to have greater concordance for more observable and shared disability (e.g., physical disability, family functioning) and greater discordance for internal experiences (e.g., pain-specific anxiety, depression). Awareness of these patterns of concordance and discordance should help clinicians in interpreting mothers’ proxy-reports and adolescents’ self-reports of chronic pain-related functioning.

Is chronic pain associated with subsequent cancer? A cohort record linkage study - Corrected Proof

Alison M. Elliott, Nicola Torrance, Blair H. Smith, Amanda J. Lee — 2010-03-02

Abstract: A previous study has reported that chronic pain is associated with a higher incidence of overall and site-specific cancer in subsequent years. The aim of this study was to confirm or refute these findings. In 1996, a cohort of 6940 individuals was recruited, and information on chronic pain, general health and socio-demographic details collected. Ten years later, a record linkage study was conducted between these data and the routinely collected national dataset for cancer registration. Hazard ratios for the incidence of all cancers and eight cancer-specific sites by chronic pain status were calculated. Eighty-four percent of individuals from the original cohort were linked. After excluding those with a known previous cancer diagnosis, all non-melanoma skin cancers and cancers which were not first occurrences, a total of 646 cancers had occurred in 607 people since the baseline study. The overall cancer incidence in the cohort was 10.4% over the 10 years. There were no significant associations between chronic pain and all cancer, or any of the eight cancer-specific sites, after adjustment for age and sex. There was a significant increased risk of developing lymphoma/leukaemia amongst those with all chronic pain and various causes of chronic pain on univariate analysis. After adjustment, these trends remained, although most of the associations were no longer significant. There were no significant differences between those with severe chronic pain compared to those with mild chronic pain. The findings suggest that those with chronic pain are not at a significantly increased risk of developing cancer.

The impact of pain spread on the outcome of multidisciplinary therapy in patients with chronic musculoskeletal pain – A prospective clinical study in 389 patients - Corrected Proof

2010-03-02

Abstract: Background: Musculoskeletal pain represents a continuous process ranging from single-site to multiple-site pain, with an increase in pain sites accompanied by an increasing risk of chronification and the development of further comorbidities. Within this context, the impact of pain spread on therapy outcome is still unknown.Aims: This prospective clinical study aimed to evaluate whether and to what extent patients with pain at multiple sites would also benefit from multidisciplinary therapy or whether therapy success is limited by pain spread.Methods: Patients’ characteristics were assessed, including socio-demographic variables, occupational and workplace characteristics, pain intensity and dimensions of pain, psychological aspects and functional back capacity, as well as the generic health status. Data were prospectively collected at day 1 (baseline) and at 6-month follow-up from a sample of 389 patients undergoing multidisciplinary treatment. Patients were distributed into three groups based on the number of pain sites (single-site, dual-site and multiple-site) and the outcome parameters were compared.Results: All three groups improved significantly from baseline to the 6-month follow-up. Compared to patients with multiple-site pain, patients with single-site and dual-site pain displayed significantly better outcome on almost all measures. Only the subcategory mental health of the SF-36 did not show any statistically significant differences among the three groups.Conclusions: Our results display that patients with two or more pain sites also improve significantly in the outcome measures. Therefore, treatment should be offered independent of the extent of pain spread. However, therapy is significantly less successful in patients with pain at multiple sites.

Driving plasticity in the motor cortex in recurrent low back pain - Corrected Proof

Henry Tsao, Mary P. Galea, Paul W. Hodges — 2010-02-24

Abstract: The sensory and motor systems can reorganise following injury and learning of new motor skills. Recently we observed adaptive changes in motor cortical organisation in patients with recurrent low back pain (LBP), which are linked to altered motor coordination. Although changes in motor coordination can be trained and are associated with improved symptoms and function, it remains unclear whether these training-induced changes are related to reorganisation of the motor cortex. This was investigated using the model of a delay in postural activation of the deep abdominal muscle, transversus abdominis (TrA) in 20 individuals with recurrent LBP. Subjects were allocated to either motor skill training that involved isolated voluntary contractions of TrA, or a control intervention of self-paced walking exercise for 2 weeks. Electromyographic (EMG) activity was recorded from TrA bilaterally using intramuscular fine-wire electrodes. Motor cortical organisation using transcranial magnetic stimulation (TMS) and postural activation associated with single rapid arm movements were investigated before and after training. Motor skill training induced an anterior and medial shift in motor cortical representation of TrA, towards that observed in healthy individuals from our previous study. This shift was associated with earlier postural activation of TrA. Changes were not observed following unskilled walking exercise. This is the first observation that motor training can reverse reorganisation of neuronal networks of the motor cortex in people with recurrent pain. The observed relationship between cortical reorganisation and changes in motor coordination following motor training provides unique insight into potential mechanisms that underlie recovery.

Long-term facilitation of nociceptive withdrawal reflexes following low-frequency conditioning electrical stimulation: A new model for central sensitization in humans - Corrected Proof

José A. Biurrun Manresa, Carsten D. Mørch, Ole K. Andersen — 2010-01-28

Abstract: Central sensitization is believed to be one of the key mechanisms behind chronic pain conditions, and several models have been developed in order to characterize this phenomenon in humans. One of these models relies on conditioning electrical stimulation to elicit long-lasting effects on the nociceptive system. The aim of this study was to evaluate these effects using an objective electrophysiological measurement, the nociceptive withdrawal reflex (NWR). Long-term changes in spinal nociception after high- and low-frequency conditioning electrical stimulation were assessed in 13 healthy volunteers. Perceptual intensity ratings to mechanical stimuli and blood flow variations were assessed in the conditioned area (dorsum of the foot) and surroundings. To evaluate the excitability of the nociceptive system, the NWR was elicited within the same innervation area (superficial peroneal nerve) at graded stimulation intensities and recorded in the hamstrings. Following low-frequency stimulation, an intensity-independent long-lasting facilitation of the NWR was observed, with a significant increase in the reflex size (average of 31±4%, p<0.001) and in the number of reflexes (average increase of 22±10%, p<0.01), accompanied by a significant increase in the blood flow (average increase of 40±10%, p<0.001). These findings suggest that activity-dependent central sensitization can be elicited using conditioning electrical stimulation with a stimulation frequency that lies within the physiological firing range of primary afferents, and that it can be objectively assessed in humans using the NWR.

The Psychological Inflexibility in Pain Scale (PIPS) – Statistical properties and model fit of an instrument to assess change processes in pain related disability - Corrected Proof

Rikard K. Wicksell, Mats Lekander, Kimmo Sorjonen, Gunnar L. Olsson — 2010-01-27

Abstract: Recent developments within CBT have emphasized acceptance rather than control of pain and distress in treatments aimed at improving functioning and life quality, but there is still a lack of reliable and valid instruments to assess relevant processes in such interventions. The Psychological Inflexibility in Pain Scale (PIPS) was developed to assess target variables in exposure and acceptance oriented treatments. A preliminary validation study resulted in a two-factor solution with subscales for avoidance and cognitive fusion related to pain, showing satisfactory psychometric properties. This study sought to evaluate the instrument with 611 participants with whiplash associated disorders. Exploratory and confirmatory factor analyses supported a two-factor solution with 12 items which showed an acceptable model fit, adequate internal consistencies, and strong relations with criteria variables (e.g. disability and life satisfaction). The construct validity of the instrument was supported by high correlations with subscales from the Chronic Pain Acceptance Questionnaire (CPAQ) and the Tampa Scale of Kinesiophobia (TSK). Notably, hierarchical regression analyses illustrated that PIPS explained more variance than TSK in pain, disability, life satisfaction and depression. Furthermore, PIPS was found to mediate the relationship between e.g. pain and disability, suggesting the usefulness of PIPS as a process measure in treatments of people with chronic pain. Thus, it is argued that this 12-item version of PIPS may be used to explore the importance of psychological in/flexibility in chronic pain and to analyse processes of change in exposure based interventions, as well as for clinicians in tailoring interventions for patients with chronic debilitating pain.

St John’s wort greatly reduces the concentrations of oral oxycodone - Corrected Proof

2010-01-27

Abstract: Background: Chronic pain is associated with depression. Self-treatment of depression with herbal over-the-counter medicine St John’s wort makes pain patients prone to drug interactions.Aims: The aim of this study was to assess the potential of St John’s wort to alter the CYP3A-mediated metabolism of a μ-opioid receptor agonist, oxycodone.Methods: The study design was placebo-controlled, randomized, cross-over with two phases at intervals of 4weeks and was conducted with 12 healthy participants. St John’s wort (Jarsin®) or placebo was administered t.i.d. for 15days and oral oxycodone hydrochloride 15mg on day 14. Oxycodone pharmacokinetics and pharmacodynamics were compared after St John’s wort or placebo. Behavioural and analgesic effects were assessed with subjective visual analogue scales and cold pressor test. Plasma drug concentrations were measured from 0 to 48h, behavioural and analgesic effects from 0 to 12h.Results: Following St John’s wort administration the oxycodone AUC decreased 50% (p<0.001). Oxycodone elimination half-life shortened from a mean±SD 3.8±0.7 to 3.0±0.4h (p<0.001). The self-reported drug effect of oxycodone as measured by AUEC0–12 decreased significantly (p=0.004). Differences between St John’s wort and placebo phases in cold pain threshold and intensity AUEC0–12 were not observed.Conclusions: St John’s wort greatly reduced the plasma concentrations of oral oxycodone. The self-reported drug effect of oxycodone decreased significantly. This interaction may potentially be of some clinical significance when treating patients with chronic pain.

Cognitive and behavioral interventions for the management of chronic neuropathic pain in adults – A systematic review - Corrected Proof

2010-01-22

Abstract: Background: Chronic neuropathic pain is often associated with conditions such as depression and anxiety and strongly affects daily functioning and overall quality of life. It is argued, therefore, that psychosocial interventions should be added to traditional biomedical interventions. This systematic review evaluates the effectiveness of cognitive and behavioral interventions for the management of chronic neuropathic pain.Methods: Electronic databases were searched for all types of studies. Studies were selected by predefined inclusion criteria. Methodological quality was assessed with the Health Technology Assessment-Disease Management instrument. Furthermore, an explorative meta-analysis of four selected studies was performed.Results: Fourteen studies were assessed: three randomized controlled trials, three controlled before–after studies, seven uncontrolled before–after studies and one time series analysis. The findings of the meta-analysis were not consistent with a significant effect on pain intensity. Only one study had good methodological quality; it showed some significant effects of the interventions, but only in female participants. Other studies of limited methodological quality did report positive effects on pain and quality of life.Conclusions: This is the first systematic review that has evaluated the effectiveness of cognitive and behavioral techniques for the management of chronic neuropathic pain. Given the limited methodological quality, no informative conclusions can be drawn with respect to the study objective. However, this review does provide insight into the difficulties of this specific area, the need for a clear and widely accepted definition of neuropathic pain and the need for standardized multidimensional measurement instruments.

Development of a short version of the Neck Pain and Disability Scale - Corrected Proof

Eva Blozik, Michael M. Kochen, Christoph Herrmann-Lingen, Martin Scherer — 2010-01-22

Abstract: Previous evaluations of the 20-item Neck Pain and Disability Scale (NPAD) were indicative of excessive redundancy of the measure. The aim of this study was to develop a shortened version of the NPAD (sf-NPAD) based on results of item-to-total-score correlations and factor analysis as published by the developers of the original NPAD. Two items with the highest item-to-total score correlation were selected per factor subscale with the exception of one factor consisting of only one item. This resulted in the selection of 9 items for the sf-NPAD. The sf-NPAD was validated in a separate sample of 448 neck pain patients from 15 general practices in the area of Göttingen/Germany. Participants completed the 20-item NPAD German version and gave additional sociodemographic and clinical information. Psychometric properties of the sf-NPAD were evaluated using Cronbach’s alpha, item-to-total-score correlation, and unrestricted principal factor analysis. Construct validity was evaluated by Pearson’s r with clinical characteristics. Discriminative validity was examined by comparing differences between subgroups stratified by psychosocial characteristics using t-tests for mean scores. Cronbach’s alpha of the sf-NPAD was 0.88. Item-to-total-scale correlations ranged between 0.628 and 0.815, and sf-NPAD items homogeneously loaded on a single factor. Correlation analysis showed high correlations with criterion variables. The sf-NPAD scores of patient subgroups were significantly different showing good discriminative validity. In conclusion, the sf-NPAD demonstrated good validity and internal consistency in this general practice setting. The abbreviated version may facilitate applicability of the scale in clinical and research settings.

No relationship between the ins del polymorphism of the serotonin transporter promoter and pain perception in fibromyalgia patients and healthy controls - Corrected Proof

2010-01-18

Abstract: Background: In animals, decades of research have shown that serotonin (5-HT) is involved in endogenous pain inhibition systems, which are deficient in chronic pain disorders such as fibromyalgia (FM). In humans, there is preliminary evidence showing that 5-HT is involved in the FM pathophysiology. In the current endophenotyping study, we sought to investigate, for the first time in humans, the relationships between the serotonin transporter promoter region (5-HTTLPR) polymorphism and experimentally-induced pain perception/inhibition in healthy controls (HC) and FM patients.Methods: Participants were 58 FM patients and 60 HC, who did not differ in age, sex or menstrual cycle. Thermal stimuli were used to measure pain thresholds. Pain inhibition was elicited using a tonic thermal test (Peltier thermode) administered before and after activation of the diffuse noxious inhibitory controls (DNIC) by means of a cold-pressor test (CPT).Results: Thermal pain thresholds were higher in HC compared to FM patients. Pain ratings during the CPT were lower in HC, relative to FM patients. Also, DNIC efficacy was stronger in HC compared to FM patients. However, there was no relationship between 5-HTTLPR and experimentally-induced pain perception/inhibition.Discussion: Our results further confirm that FM is associated with thermal hyperalgesia and deficient DNIC. However, we found no evidence showing that the 5-HTTLPR polymorphism influences pain perception and DNIC. Potential reasons for this negative result will be discussed. Further endophenotyping studies of 5-HT-related gene polymorphisms are required to ascertain the potential relationships between 5-HT and human pain perception/inhibition.

The cartography of pain: The evolving contribution of pain maps - Corrected Proof

Geoffrey D. Schott — 2010-01-15

Abstract: Pain maps are nowadays widely used in clinical practice. This article aims to critically review the fundamental principles that underlie the mapping of pain, to analyse the evolving iconography of pain maps and their sometimes straightforward and sometimes contentious nature when used in the clinic, and to draw attention to some more recent developments in mapping pain. It is concluded that these maps are intriguing and evolving cartographic tools which can be used for depicting not only the spatial features but also the interpretative or perceptual components and accompaniments of pain.

Chronic pain following donor nephrectomy – A study of the incidence, nature and impact of chronic post-nephrectomy pain - Corrected Proof

Margaret Owen, Paula Lorgelly, Mick Serpell — 2010-01-11

Abstract: Chronic pain is a consequence of some types of surgery, but its incidence following open donor nephrectomy has never been investigated. We surveyed 123 patients who underwent open donor nephrectomy at our institution over a 10-year period, to determine the incidence, severity and nature of chronic pain and its effect on quality of life. Of the 81 (66%) responders, 27 (33%) had experienced prolonged pain, and 21 (26%) still had chronic pain related to their surgery. The overall incidence of severe, disabling pain (visual analogue score ⩾7) was 12% and of neuropathic pain was 14%. The average loss in quality adjusted life years (QALYs) was 1.053 for chronic pain sufferers, but was 1.851 for those who suffered specifically from neuropathic pain. Only one third of patients with chronic pain were receiving any treatment, and none were receiving neuropathic adjuvants or specialist pain management interventions. We conclude that the incidence of chronic pain following donor nephrectomy is underestimated and therefore under managed. Given the voluntary and altruistic nature of this procedure, and the enormous personal and social benefits which result from successful donor transplantation, those involved with the preparation and post-operative management should be more aware of, and actively question donors about chronic pain so that diagnosis and appropriate therapy can be commenced as early as possible.

Effects of soy diet on inflammation-induced primary and secondary hyperalgesia in rat - Corrected Proof

2010-01-11

Abstract: Soy consumption is said to prevent or treat atherosclerosis, cancer, pain, and memory deficits, but experimental and clinical evidence to support these claims are lacking. We used in vivo models of inflammation to determine whether a soy diet reduces primary or secondary hyperalgesia. In all three experiments, rats were fed either a soy- or casein-based diet for at least 2weeks before induction of inflammation and for the duration of experiments. Mechanical and heat paw withdrawal thresholds and edema were measured before and several times after induction of inflammation. Primary hyperalgesia was assessed in two models: unilateral intraplantar injection with 0.1ml of 25% complete Freund’s adjuvant (CFA) or 0.1ml of 1% carrageenan. Unilateral injection of the intra-articular knee space with 25% CFA (0.1ml) was used to determine the effects of soy in a model of secondary hyperalgesia. Following intraplantar injection of CFA, soy-fed animals exhibited significantly less paw edema, mechanical allodynia, and heat hyperalgesia compared to casein-fed animals. In the carrageenan model of paw inflammation, soy-fed animals were also less allodynic to mechanical stimuli, than were casein-fed animals, but showed no diet based differences in paw edema or heat hyperalgesia. Soy diet did not affect any of the outcome measures after the intra-articular injection of CFA. Our results suggest that a soy diet significantly decreases aspects of inflammation-induced primary, but not secondary, hyperalgesia in rats.

Acupuncture analgesia for temporal summation of experimental pain: A randomised controlled study - Corrected Proof

2010-01-04

Abstract: Background: Temporal summation of pain, a phenomenon of the central nervous system (CNS), represents enhanced painful sensation or reduced pain threshold upon repeated stimulation. This pain model has been used to evaluate the analgesic effect of various medications on the CNS.Aims: The present study aimed to evaluate the effects and characteristics of analgesia induced by electroacupuncture (EA), manual acupuncture (MA) and non-invasive sham-acupuncture (SA) in healthy humans on temporal summation of pain.Methods: Thirsty-six pain-free volunteers were randomised into one of the three groups EA (2/100Hz), MA or SA. Acupuncture intervention was on ST36 and ST40 on the dominant leg delivered by an acupuncturist blinded to the outcome assessment. Both subjects and the evaluator were blinded to the treatment allocation. Pain thresholds to a single pulse (single pain threshold, SPT) and repeated pulses electrical stimulation (temporal summation thresholds, TST) were measured before, 30min after and 24h after each treatment.Results: The baseline values of three groups were comparable. Compared to SA, EA significantly increased both SPT and TST immediately after the treatment on the treatment leg as well as 24h after on both the treatment and non-treatment legs (ANOVA, p<0.05). MA also increased SPT and TST, but the changes were not significantly different from those induced by SA.Conclusion: EA induces bilateral, segmentally distributed and prolong analgesia on both SPT and TST, indicating a non-centrally specific effect. This effect needs to be verified with heat or mechanical model and in pain patients.

Influence of risk of neurological impairment and procedure invasiveness on health professionals’ management of procedural pain in neonates - Corrected Proof

2010-01-04

Abstract: Objectives: To describe how (i) risk of neurological impairment (NI) and (ii) procedure invasiveness influence health professionals’ assessment and management of procedural pain in neonates in the Neonatal Intensive Care Unit (NICU).Design: Prospective observational study.Setting: Three tertiary level NICUs in Canada.Participants: 114 neonates, 25–40weeks gestational age (GA) undergoing painful procedures.Main Outcome Measures: Physical and behavioural pain indicators and pharmacological and nonpharmacological pain interventions.Results: 114 neonates at high (Cohort A, n=35), moderate (Cohort B, n=25) and low (Cohort C, n=54) risk of NI were observed during 254 painful procedures performed by 147 health professionals. Physical pain indicators were used more frequently by health professionals to assess pain with Cohorts A and B than C (p A, B>C, p<.05) and for increasingly invasive procedures (p<.05).Conclusions: Health professionals use multidimensional indicators to assess neonatal pain. Nonpharmacological interventions dominate pain management. NI risk status and procedure invasiveness are important contextual factors in neonatal pain assessment and management.

Effects of eccentric jaw exercise on temporal summation in jaw-closing muscles of healthy subjects - Corrected Proof

2010-01-04

Abstract: Eccentric jaw exercises has been known to cause muscle soreness but no studies have so far examined to what extent temporal summation mechanisms within the exercised muscles are changed. The purpose of the present study was to investigate the effects of an eccentric biting exercise on the temporal summation, mechanical pressure sensitivity and jaw muscle activity.A total of 15 healthy men participated in a two-session-experiment: In one session, they performed 30min controlled eccentric jaw exercise and the other session served as a no-exercise control. Soreness sensations at rest and during maximal biting, pressure pain thresholds (PPTs) and electromyographic (EMG) activity during maximal jaw biting were recorded before (baseline), immediately after (Post-task), and 1day after the exercise (1-day-after). The temporal summation ratio using intra-muscular electrical stimulation of the masseter was investigated at baseline and at 1-day-after. The eccentric jaw exercise was associated with significant increases in soreness sensation and decreased PPTs at Post-task and at 1-day-after. The EMG activity and biting force did not change. The summation ratio was significantly decreased at 1-day-after in both sessions. The present findings demonstrate that eccentric jaw exercise does not induce detectable changes in temporal summation. However, the summation ratio may have clinical utility to differentiate the location of sensitization.

Neuronal hyperactivity at the spinal cord and periaqueductal grey during painful diabetic neuropathy: Effects of gabapentin - Corrected Proof

Carla Morgado, Patrícia Pereira Terra, Isaura Tavares — 2009-12-28

Abstract: Painful diabetic neuropathy may be due to impairments in descending modulation of nociceptive transmission at the spinal cord. In the present study, streptozotocin diabetic rats (STZ rats) with neuropathic symptoms (mechanical hypersensitivity) were used to perform a time-course evaluation of neuronal activity at the spinal dorsal horn and at the periaqueductal grey matter (PAG), a major brainstem area of pain modulation. The expression of Fos protein, a marker of nociceptive activation, progressively increased at the spinal dorsal horn at 4 and 10weeks. At the PAG, increases in Fos expression were detected until the 4th week, with a reversal to baseline values at 10weeks in all areas except the ventrolateral PAG. Co-localisation of Fos with NeuN ascertained the neuronal nature of Fos-expressing cells at the spinal cord and PAG. Four weeks after diabetes induction, the effects of gabapentin (i.p. injection of 50mg/kg, daily during 3days) were assessed. Gabapentin decreased Fos expression at the spinal cord and PAG and reversed mechanical hypersensitivity. The present study shows that diabetic neuropathy is accompanied by a progressive increase of the spontaneous neuronal activity at the spinal cord. Changes in descending modulation of nociceptive transmission from the PAG are likely to occur during diabetic neuropathy, probably with exacerbation of facilitatory actions. The effects of gabapentin in reversing the behavioural signs of diabetic neuropathy and neuronal hyperactivity in the spinal cord and PAG reinforce the central causes of diabetic neuropathy and point to the central targets of the drug.

Mu-opioid receptors are not necessary for nortriptyline treatment of neuropathic allodynia - Corrected Proof

2009-12-28

Abstract: Tricyclic antidepressants (TCAs) are among the first line treatments clinically recommended against neuropathic pain. However, the mechanism by which they alleviate pain is still unclear. Pharmacological and genetic approaches evidenced a critical role of delta-opioid receptors (DORs) in the therapeutic action of chronic TCA treatment. It is however unclear whether mu-opioid receptors (MORs) are also necessary to the pain-relieving action of TCAs. The lack of highly selective MOR antagonists makes difficult to conclude based on pharmacological studies. In the present work, we thus used a genetic approach and compared mutant mice lacking MORs and their wild-type littermates. The neuropathy was induced by unilateral sciatic nerve cuffing. The threshold for mechanical response was evaluated using von Frey filaments. MOR-deficient mice displayed the same baseline for mechanical sensitivity as their wild-type littermates. After sciatic nerve cuffing, both wild-type and MOR-deficient mice displayed an ipsilateral mechanical allodynia. After about 10days of treatment, nortriptyline suppressed this allodynia in both wild-type and MOR-deficient mice. MORs are thus not critical for nortriptyline action against neuropathic pain. An acute injection of the DOR antagonist naltrindole induced a relapse of neuropathic allodynia in both wild-type and MOR-deficient mice, thus confirming the critical role of DORs in nortriptyline action. Moreover, morphine induced an acute analgesia in control and in neuropathic wild-type mice, but was without effect in MOR-deficient mice. While MORs are crucial for morphine action, they are not critical for nortriptyline action. Our results highlight the functional difference between DORs and MORs in mechanisms of pain relief.

Factors defining care-seeking in low back pain – A meta-analysis of population based surveys - Corrected Proof

2009-12-25

Abstract: Little is known about factors determining health care-seeking behavior in low back pain. While a number of studies have described general characteristics of health care utilization, only a few have aimed at appropriately assessing determinants of care-seeking in back pain, by comparing seekers and non-seekers. The objective of this systematic review was to identify determinants of health care-seeking in studies with well-defined groups of care-seekers and non-seekers with non-specific low back pain.A search was conducted in Medline, AMED, Cinahl, Web of Science, PsycINFO, National Research Register, Cochrane Library and LILACS looking for population- based surveys of non-specific low back pain patients older than 18years, published since 1966. To be included in the review, studies needed to report on characteristics of well-defined groups of care-seekers and non-seekers. Methodological quality was assessed using a criteria list based on sampling, response rate, data reproducibility, power calculation and external validity. Risk estimates were expressed as odd ratios (95% confidence intervals). When possible, meta-analyses were performed, using a random effects model.Eleven studies were included in the review. Pooled results show that women are slightly more likely to seek care for their back pain as are patients with a previous history of back pain. Pain intensity was only slightly associated with care-seeking, whereas patients with high levels of disability were nearly eight times more likely to seek care than patients with lower levels of disability.

Pain and clinical findings in the low back: A study of industrial employees with 5-, 10-, and 28-year follow-ups - Corrected Proof

Sanna-Mari Kääriä, Esko A. Mälkiä, Ritva A. Luukkonen, Päivi I. Leino-Arjas — 2009-12-25

Abstract: Little is known about the relationships of clinical findings in the low back with low back pain (LBP) in the normal working population. We studied whether physiotherapist’s findings in the low back were associated with local and radiating LBP among a cohort (n=902) of employees in the engineering industry. A systematic non-proportional sample was drawn in strata by age, gender, and occupational class. The non-proportionality aimed at increasing sample size in smaller strata. Physiotherapists performed the straight-leg raising test (SRL), and made assessments of the fingertip-to-floor distance and pain in palpation of the lumbar interspinous spaces. The variables on pain at the interspinous spaces and the SRL tests were entered in cluster analysis. Three clusters emerged: no, minor, and severe clinical findings. In logistic regression analysis at baseline, limited forward flexion and the clinical findings cluster variable were associated with local and, particularly, radiating LBP. Follow-ups of the occurrence of local and radiating LBP at 5, 10, and 28years from baseline were made. At the 5-year follow-up among subjects with no radiating LBP at baseline, the OR of radiating LBP for the clusters of minor and severe clinical findings compared to no findings were 2.7 (95% CI 1.4–5.1) and 3.8 (2.0–6.9), respectively, adjusted for age, gender, and occupational class. At the 10-year follow-up, the latter cluster predicted new reports of radiating LBP (1.9; 1.0–3.1) and of local LBP (4.1; 1.9–9.0, among subjects with no local LBP at baseline), similarly adjusted. No associations between limited forward flexion and new cases of LBP were observed. Thus, membership in clusters with different levels of findings in simple clinical measurements predicted new reports of radiating LBP, in particular, among employees. The generalizability of the results may be limited due to the characteristics of the sampling.

Self-discrepancies in work-related upper extremity pain: Relation to emotions and flexible-goal adjustment - Corrected Proof

2009-12-25

Abstract: Recurrent pain not only has an impact on disability, but on the long term it may become a threat to one’s sense of self. This paper presents a cross-sectional study of patients with work-related upper extremity pain and focuses on: (1) the role of self-discrepancies in this group, (2) the associations between self-discrepancies, pain, emotions and (3) the interaction between self-discrepancies and flexible-goal adjustment. Eighty-nine participants completed standardized self-report measures of pain intensity, pain duration, anxiety, depression and flexible-goal adjustment. A Selves Questionnaire was used to generate self-discrepancies. A series of hierarchical regression analyses showed relationships between actual–ought other, actual–ought self, actual–feared self-discrepancies and depression as well as a significant association between actual–ought other self-discrepancy and anxiety. Furthermore, significant interactions were found between actual–ought other self-discrepancies and flexibility, indicating that less flexible participants with large self-discrepancies score higher on depression.This study showed that self-discrepancies are related to negative emotions and that flexible-goal adjustment served as a moderator in this relationship. The view of self in pain and flexible-goal adjustment should be considered as important variables in the process of chronic pain.

Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome - Corrected Proof

2009-12-17

Abstract: Activated immune cells in the spinal cord may play an important role in the development and maintenance of neuropathic pain, such as occurs in response to peripheral inflammation or tissue injury. Immune activation may therefore serve as a therapeutic target for immune modulating drugs like corticosteroids. This double-blind randomized placebo-controlled parallel-group trial aimed to investigate the efficacy and safety of a single intrathecal administration of 60mg methylprednisolone (ITM) in chronic patients with complex regional pain syndrome (CRPS). The primary outcome measure was change in pain (pain intensity numeric rating scale; range 0–10) after 6weeks. With 21 subjects per group the study had a 90% power to detect a clinically relevant difference (⩾2 points). After 21 patients (10 on ITM) were included, the trial was stopped prematurely after the interim analysis had shown that ITM had no effect on pain (difference in mean pain intensity numeric rating scale at 6weeks 0.3, 95% confidence interval −0.7 to 1.3) or any other outcome measure. We did not find any difference in treatment-emergent adverse events between the ITM and placebo group. We conclude that a single bolus administration of ITM is not efficacious in chronic CRPS patients, which may indicate that spinal immune activation does not play an important role in this phase of the syndrome.

Effects of pain management on sleep in preterm infants - Corrected Proof

Anna Axelin, Jarkko Kirjavainen, Sanna Salanterä, Liisa Lehtonen — 2009-12-17

Abstract: Background: This study was conducted to gain better understanding of the prolonged effects of pain and pain management on preterm infants’ sleep.Aim: The hypothesis was that the sleep structure in very preterm infants is different after painful procedures with pain management (facilitated tucking by parents (FTP), oral glucose, and oxycodone) than without pain management (oral water as placebo).Methods: A prospective randomized placebo-controlled cross-over trial design was used. Thirteen-hour polysomnographic recordings were conducted when the study infants (n=18) were at a post-conceptional age of 28–32weeks. During the recordings, the standardized nursing care periods were carried out with different forms of pain management administered at 3-h intervals. Sleep structure was analyzed before and after the interventions. The main hypothesis was analyzed using mixed models.Results: During the first post-intervention hour, the amount of rapid eye movement (REM) sleep decreased after all interventions regardless of pain management (p<0.001). However, the oxycodone treatment further reduced the amount of REM sleep to 48.0% (SD 14.9) compared to other interventions: oral glucose to 64.4% (SD 12.8), (p<0.001); placebo to 62.9% (SD 16.1), (p<0.001); and FTP to 61.6% (SD 1.9), (p=0.004). In addition, sleep onset comprised non-rapid eye movement (NREM) sleep more frequently after oxycodone (50%) compared to placebo (6%, p=0.006), oral glucose (11%, p=0.019) or FTP (17%, p=0.056).Conclusion: Pain management with oxycodone markedly altered the structure of the subsequent sleep period. This reduced amount of REM sleep may have consequences for brain development in preterm infants.

Increased pain sensitivity in alcohol withdrawal syndrome - Corrected Proof

2009-12-17

Abstract: Withdrawal from analgesic and addictive substances such as opioids or ethanol is associated with increased sensitivity to sensory stimulation in animal models.Here, we investigated perception of innocuous and noxious thermal or electric stimuli applied to the left hand or sternum in 30 male patients undergoing withdrawal from alcohol, 30 male abstained alcoholics and matched controls. The alcohol withdrawal scale and the Banger score were obtained to estimate the severity of withdrawal. In addition, the Beck depression inventory was used to estimate the influence of depressive symptoms on pain perception.The data presented provide substantial evidence that subjects undergoing alcohol withdrawal show increased heat pain sensitivity. Interestingly, this effect was observed both on the left hand and sternum. Pain thresholds and tolerances of electric stimuli did not differ between groups. However, in a subgroup analysis, a higher sensitivity for electrical pain thresholds and tolerances was observed in those patients that were identified to require pharmacological treatment for withdrawal according to disease severity. Furthermore, the perceived painful thermal and electrical sensation was substantially influenced by the affective state of patients. No differences were found between patients of the abstained group and control subjects for any pain parameter.In conclusion, we demonstrate withdrawal-induced hyperalgesia upon thermal stimulation in patients. Since the influence of affective symptoms on pain perception during withdrawal is remarkable, we assume that peripheral and central mechanisms might account for this finding, which should be assessed in detail in future studies.

Subarachnoid transplantation of immortalized galanin-overexpressing astrocytes attenuates chronic neuropathic pain - Corrected Proof

Ke An, Ying Xu, Hui Yang, Hai-hua Shu, Hong-bing Xiang, Yu-ke Tian — 2009-12-10

Abstract: Treatment of chronic neuropathic pain resulted from peripheral nerve injury is one of the most difficult problems in modern clinical practice. The use of cell lines as biologic “minipumps” to chronically deliver anti-nociceptive molecules into the pain-processing centers of spinal cord is a newly developing technique for the treatment of pain. Moreover, spinal administration of exogenous galanin (GAL) is a useful target for the treatment of chronic pain after nerve injury. Because of better histocompatibility, lower immunogenicity and reproducibility, immortalized astrocytes (IAST) have been served as a promising cellular vehicle to deliver therapeutic molecules into CNS. In this study, the rat IAST was transfected with rat preprogalanin cDNA and the galanin-synthesizing and secreting cell line, IAST/GAL, was isolated. After cells were transplanted into the subarachnoid space of rats with chronic neuropathic pain induced by spared nerve injury (SNI) of sciatic nerve, their analgesic potential was evaluated by behavioral tests. The results showed that IAST/GAL transfected with preprogalanin gene could express and secrete significantly higher level of GAL protein in vitro and in vivo as compared with control cells. In addition, the pain-related behaviors, thermal hyperalgesia and mechanical allodynia were significantly alleviated during the 1–7weeks after grafts of IAST/GAL cells, which could be reversed by galanin receptor antagonist M35 temporarily. Taken together, these data suggest that subarachnoid transplant of immortalized galanin-overexpressing astrocytes near the pain-processing centers was able to reverse the development of chronic neuropathic pain, which offers an adjunct approach to currently used therapies for the pain management.

Modality of hyperalgesia tested, not type of nerve damage, predicts pharmacological sensitivity in rat models of neuropathic pain - Corrected Proof

Amynah Amir Ali Pradhan, Xiao Hong Yu, Jennifer M.A. Laird — 2009-12-07

Abstract: Although many types of nerve damage can cause neuropathic pain, there are substantial commonalities in neuropathic pain symptoms, and patients can be divided into sub-groups based on their symptom profile rather than etiology. Mechanism-based treatment suggests that pharmacotherapy should be chosen be based shared commonalities of symptoms rather than etiology. The aim of the present study was to determine whether type of injury (etiology) or behavioral endpoint (symptom) is a better predictor of pharmacological responsivity in the most commonly used rodent models of neuropathic pain. We used the chronic constriction injury (CCI) model to directly compare the temporal and pharmacological characteristics of four different types of evoked stimuli; heat, pressure, acetone cooling and punctate mechanical. We then compared heat hyperalgesia and mechanical allodynia endpoints across etiologies using the spinal nerve ligation (SNL) model. Evoked pain responses in both models had strikingly different temporal characteristics. We then tested three standard therapies for neuropathic pain from different drug classes, oxycodone, gabapentin, and amitriptyline. Notably, regardless of the model tested, or the time of onset, common endpoints showed near-identical pharmacological responses, and not all endpoints were equally sensitive to drug intervention within one model. Hypersensitivity to heat and pressure were highly responsive to oxycodone, gabapentin, and amitriptyline; whereas cold and mechanical allodynia were more difficult to reverse. Moreover, CCI- and SNL-induced mechanical allodynia was completely insensitive to amitriptyline treatment. We conclude that regardless of model and time course of presentation, different symptoms of peripheral neuropathy have unique pharmacological responses.

Relationships between coping strategies and lumbar muscle activity in subjects with chronic low back pain - Corrected Proof

2009-12-07

Abstract: Background: Concerning chronic low back pain (CLBP), different cognitive–behavioral models have hypothesized that coping strategies play a role in the chronification of pain by changes in physical activity. Strategies such as avoidance – or persistent coping may be related to changes in (lumbar) muscle activity.Aim: Investigate the different coping strategies present in CLBP and whether these are differentially related to lumbar muscle activity during walking.Methods: In a cross sectional study, 63 subjects with CLBP walked on a treadmill at 3.8km/h. Coping strategies were measured with the Dutch version of the Coping Strategies Questionnaire and three factors were identified with principal component analysis. Surface electromyography data of the erector spinae were obtained and smooth rectified electromyography (SRE) values were averaged per periods of swing and double support. The ratio of SRE values (swing/double support) was used as a measure of relaxation. The relation between SRE values and coping strategies was analyzed with random coefficient analysis.Results: Three coping strategies (i.e. “catastrophizing”, “distraction” and “persistence and control”) could be discerned. “Catastrophizing” was positively related to (natural logarithm) SRE values (β=0.06, 95% CI=0.01–0.10; R2=7.7%). “Distraction” was negatively associated with SRE ratios (β=−0.03, 95% CI=−0.05 to −0.01; R2=7.5%). No relation was found between “persistence and control” and SRE values or ratios.Conclusions: In CLBP, a maladaptive coping strategy like “catastrophizing” is related to increased lumbar muscle activity, and an adaptive strategy like “distraction” to increased lumbar muscle relaxation during walking.

Pain expression in children with an intellectual disability - Corrected Proof

Amandine Dubois, Xavier Capdevila, Sophie Bringuier, René Pry — 2009-12-07

Abstract: Background: Children with an intellectual disability (ID) are sometimes unable to verbalize and describe their painful experience; therefore family members and health carers can assess the intensity of the pain only from the behaviour exhibited by the children.Aim and method: The purpose of this descriptive and exploratory study was to examine the behavioural pain expression in 30 children with ID aged from 5 to 18years in a surgical context. Children were matched with 30 typically developing children of the same chronological age and 30 typically developing children of the same developmental age.Results: The results showed the influence of the level of expressive communication on the pain expression. Children who were able to verbalize their pain exhibited a normative pain expression with behavioural traits similar to those of typically developing children of the same developmental age. Children who were unable to verbalize their pain produced particular pain expressions with behavioural traits that were atypical and without a communicative goal.Conclusion: Pain expression modalities are extremely different between children able to verbalize their pain and those unable to do so. This study confirmed the necessity to take into account the particularities of each child with ID in order to individualize the pain management and avoid misdiagnosis and the under treating of pain in non verbal children.

The role of brain-derived neurotrophic factor in different animal models of neuropathic pain - Corrected Proof

2009-12-03

Abstract: Even in present day pain therapy, neuropathic pain remains a challenge for clinicians to treat and a challenge for researchers to investigate. Different animal models have been developed to mimic neuropathic pain. Neurotrophins such as nerve growth factor, brain-derived neurotrophic factor and neurotrophin 3 have been studied extensively in these models, yet few review articles concerning brain-derived neurotrophic factor have been published. This article reassesses the literature concerning brain-derived neurotrophic factor expression in the sciatic nerve chronic constriction injury model, the sciatic nerve transection model, the spinal nerve ligation model and the spinal nerve transection model and discusses differences in regulation of brain-derived neurotrophic factor between these models and their causality with neuropathic pain.

Interleukin-6 induces microglial CX3CR1 expression in the spinal cord after peripheral nerve injury through the activation of p38 MAPK - Corrected Proof

Kyung-Min Lee, Sang-Min Jeon, Hee-Jung Cho — 2009-12-03

Abstract: Peripheral nerve injury leading to neuropathic pain induces the upregulation of interleukin (IL)-6 and microglial CX3CR1 expression, and activation of p38 mitogen-activated protein kinase (MAPK) in the spinal cord. Here, we investigated whether IL-6 regulates CX3CR1 expression through p38 MAPK activation in the spinal cord in rats with chronic constriction injury (CCI) of the sciatic nerve. Similar temporal changes in the expression of IL-6, phosphorylated p38 MAPK and CX3CR1 were observed following CCI. The increases in CX3CR1 expression, p38 MAPK activation and pain behavior after CCI were suppressed by blocking IL-6 action with a neutralizing antibody, while they were enhanced by supplying exogenous recombinant rat IL-6 (rrIL-6). rrIL-6 also induced increases in spinal CX3CR1 expression, p38 MAPK activation and pain behavior in naı¨ve rats without nerve injury. Furthermore, treatment with the p38 MAPK-specific inhibitor, SB203580, suppressed the increase in CX3CR1 expression induced by CCI or rrIL-6 treatment. Finally, blocking CX3CR1 or p38 MAPK activation prevented the development of mechanical allodynia and thermal hyperalgesia induced by CCI or rrIL-6 treatment. These results suggest a new mechanism of neuropathic pain, in which IL-6 induces microglial CX3CR1 expression in the spinal cord through p38 MAPK activation, enhancing the responsiveness of microglia to fractalkine in the spinal cord, thus playing an important role in neuropathic pain after peripheral nerve injury.

A content analysis of ideal, ought, and feared selves in patients with chronic low back pain - Corrected Proof

2009-12-02

Abstract: Patients with chronic pain are not only faced with disabilities but are also challenged to maintain a valued sense of self. This sense of self is in part determined by the extent to which patients can accomplish their identity-related goals. The present study explores the content of three domains of the self, namely the ideal, ought and feared self and examines how the content relates to disability and depression.The ideal, ought and feared attributes of 80 chronic low back pain patients were analyzed and categorized in eight general goal-domains: interpersonal attributes, personal abilities, physical, emotional and psychological well-being, close interpersonal relationships, self-expression abilities, achievement-related attributes, physical appearance, and religion. Results showed that most of the attributes that patients generated involved interpersonal attributes. Comparisons between the self-guides revealed that ideal attributes were more intrapersonally focused while ought and feared attributes were interpersonally focused. The content appeared to be related to disability but not to depression. More specifically, the more disabled patients were, the more they listed well-being related attributes as part of their ought self. None of the other goal-domains was related to disability or depression.The present study provides additional insight into the goals of patients with chronic pain at the level of identity and has shown that these are, at least in part, related to the level of functional disability. These results might be useful for future studies incorporating the role of identity in chronic pain, such as psychological interventions.

Is physical functioning influenced by activity-related pain prediction and fear of movement in patients with subacute low back pain? - Corrected Proof

Ivan P.J. Huijnen, Jeanine A. Verbunt, Madelon L. Peters, Henk A.M. Seelen — 2009-11-30

Abstract: In patients with low back pain (LBP), physical functioning may be negatively influenced by both expectations on pain and pain-related fear. It is unclear whether these factors influence both physical functioning in the laboratory as well as in daily life. The aim of this study was to test if a combination of persistent overprediction of pain and fear of movement predicts lab-based performance and whether these factors are relevant for predicting daily-life functioning.One hundred and twenty four patients with subacute LBP performed a laboratory-based performance test twice. Maximum voluntary contraction, pre-test pain expectations, perceived pain during testing and fear of movement were measured. Patients were classified as correct or incorrect predictors, based on differences between expected and perceived pain on the second attempt. Next, physical activity in daily life was measured with an accelerometer.In explaining physical functioning in the laboratory and in daily life an interaction effect between fear and pain prediction was observed. In overpredictors, fear was negatively associated with lab-based performance (β=−0.48, p<0.01), and positively associated with daily-life functioning (β=0.50, p<0.05). No significant association between fear and performance or daily-life functioning were found in correct predictors.In contrast to correct predictors, in overpredictors lab-based performance and daily-life functioning was additionally explained by fear of movement. Thus it appears that fear of movement is only predictive of performance in patients with LBP who simultaneously overpredict the consequences of movements in terms of painfulness.

Estradiol and testosterone differently affect visceral pain-related behavioural responses in male and female rats - Corrected Proof

2009-11-30

Abstract: In the study of pain, the presence of sex differences is well known, with female subjects being more affected in a number of chronic painful conditions; however, the underlying mechanisms and the involvement of gonadal hormones, are still controversial. This study evaluated visceral pain in a validated rat model of artificial calculosis and the effects of estradiol and testosterone administration. Adult male and female rats were divided into groups and treated with one of the substances or Oil (vehicle) for 5 days, starting 2 days before surgery, with half receiving an artificial calculosis (Stone) and half only a sham (Sham) procedure. The animals’ behaviour (ureteral crises, frequency and duration) were recorded for 72h; estradiol and testosterone plasma levels were determined in all groups at the end of the observation period. After surgery, only Stone rats showed ureteral pain crises, with a significant sex difference in the Oil-treated groups in which the number and duration of crises were higher in females than in males. This difference was not present in the estradiol-treated groups in which ureteral crises were decreased only in females while testosterone treatment had no effect in either sex. Estradiol and testosterone plasma levels were affected by treatments in both sexes. These results confirm that, also in this model of visceral pain, females experience more pain than males; moreover, they show that supraphysiological levels of estradiol, but not of testosterone, are analgesic only in females. A dose and sex-dependent efficacy of gonadal hormones is suggested and discussed.

Pressure pain threshold mapping of the trapezius muscle reveals heterogeneity in the distribution of muscular hyperalgesia after eccentric exercise - Corrected Proof

Asbjørn T. Binderup, Lars Arendt-Nielsen, Pascal Madeleine — 2009-11-30

Abstract: This study aimed at investigating in details the spatial characteristics of muscular hyperalgesia after development of delayed onset muscle soreness (DOMS) in the trapezius muscle. High density pressure pain mapping consisting of 36 pain pressure threshold (PPT) recording points were assessed over the trapezius muscle from 20 subjects. PPT were recorded before, immediately after and 24h after eccentric exercise/rest for the exercise group (N=10) and the control group (N=10). A 36 points geometric grid was used on both the exercise and control groups. The eccentric exercise used to elicit DOMS consisted of 50 contractions against a downward pressing force at 100% maximum voluntary contraction in bouts of 10 contractions followed by 2min break. For the exercise group, PPT values decreased significantly over time for all points (P<0.001) but not for the control group. At baseline, both muscle belly sites and upper part of the trapezius were more sensitive than muscle belly sites and middle and lower parts (P<0.001 for both). The hyperalgesia was also mostly developed in the muscle belly sites (P<0.001), further enhancing its position as the most sensitive part of the muscle. The present results showed the topographical distribution of pressure pain sensitivity over the trapezius muscle and also that hyperalgesia developed in a heterogeneous manner over the trapezius muscle in response to eccentric exercise underlining sensory partitioning of the muscle. The technique of high density pressure pain topographical mappings can be helpful in characterizing muscle hyperalgesia and its heterogeneity.

Intact cutaneous C fibre afferent properties in mechanical and cold neuropathic allodynia - Corrected Proof

Richard Hulse, David Wynick, Lucy F. Donaldson — 2009-11-27

Abstract: Patients with neuropathy, report changes in sensory perception, particularly mechanical and thermal allodynia, and spontaneous pain. Similar sensory changes are seen in experimental neuropathies, in which alteration in primary afferent properties can also be determined. The neural correlate of spontaneous pain is ongoing activity in sensory afferents. Mechanical and heat allodynia are thought to result from lowered activation thresholds in primary afferent and/or central neurones, but the mechanisms underlying cold allodynia are very poorly understood.We investigated nociceptive behaviours and the properties of C and A fibre intact afferents running adjacent to damaged afferents following a partial ligation injury of the saphenous nerve (PSNI). Animals developed mechanical and cold allodynia by 3 days after PSNI. Intact mechanosensitive C fibre afferents developed ongoing activity, and had slower conduction velocities 3 and 7 days following nerve injury, with no change in mechanical threshold. There was a large increase (∼46-fold) in calculated afferent input 3 days after nerve injury, as a result of the ongoing activity in these fibres. Mechano-cooling-sensitive C fibre afferents showed both enhanced cooling-evoked firing, and increased ongoing activity. The afferent barrage associated with mechano-cooling-sensitive afferents was increased 26-fold 7 days after nerve injury. We observed no differences in the properties of intact A fibre mechanosensitive afferents.These studies demonstrate for the first time that the altered nociception seen after PSNI is associated with ongoing activity and enhanced cooling-evoked activity in intact C fibre afferents in the saphenous nerve, with no concurrent alteration in A fibre afferents.

Altered pain and thermal sensation in subjects with isolated parietal and insular cortical lesions - Corrected Proof

D.S. Veldhuijzen, J.D. Greenspan, J.H. Kim, F.A. Lenz — 2009-11-27

Abstract: Studies of sensory function following cortical lesions have often included lesions which multiple cortical, white matter, and thalamic structures. We now test the hypothesis that lesions anatomically constrained to particular insular and parietal structures and their subjacent white matter are associated with different patterns of sensory loss. Sensory loss was measured by quantitative sensory testing (QST), and evaluated statistically within patients relative to normal values.All seven subjects with insular and/or parietal lesions demonstrated thermal hypoesthesia, although the etiology of the lesions was heterogeneous. Cold and heat hypoalgesia were only found in the subject with the most extensive parietal and insular lesion, which occurred in utero. Cold allodynia occurred clinically and by thresholds in two subjects with isolated ischemic lesions of the posterior insular/retroinsular cortex, and by thresholds in two subjects with a lesion of parietal cortex with little or no insular involvement. Central pain occurred in the two subjects with clinical allodynia secondary to isolated lesions of the posterior insular/retroinsular cortex, which spared the anterior and posterior parietal cortex. These results suggest that nonpainful cold and heat sensations are jointly mediated by parietal and insular cortical structures so that lesions anywhere in this system may diminish sensitivity. In contrast, thermal pain is more robust requiring larger cortical lesions of these same structures to produce hypoalgesia. In addition, cold allodynia can result from restricted lesions that also produce thermal hypoesthesia, but not from all such lesions.

Self-management of persistent neck pain: A randomized controlled trial of a multi-component group intervention in primary health care - Corrected Proof

Catharina Gustavsson, Eva Denison, Lena von Koch — 2009-11-27

Abstract: Studies regarding self-management of persistent neck pain are infrequent. Objective: to compare treatment effects of (a) a multi-component pain and stress self-management group intervention (PASS) and (b) individually administered physical therapy (IAPT) for patients with persistent musculoskeletal tension-type neck pain. Methods: Persons seeking physical therapy treatment due to persistent tension-type neck pain at nine primary health care centers in Sweden were randomly assigned to either PASS or IAPT. Before treatment (baseline) and at 10- and 20-weeks the participants completed a self-assessment questionnaire comprising: the Self-Efficacy Scale, the Neck Disability Index, the Coping Strategies Questionnaire, the Hospital Anxiety and Depression Scale, the Fear-Avoidance Beliefs Questionnaire and questions regarding neck pain, analgesics and utilization of health care. Intention-to-treat analyses were performed using repeated measures analysis of variance between baseline, 10-week and 20-week follow-up. Results: One hundred and fifty six participants were included (PASS n=77, IAPT n=79). On average participants receiving PASS attended seven treatment sessions and participants receiving IAPT 11 sessions over the 20-week follow-up period. Repeated measures ANCOVA showed significant time×group interaction effects for ability to control pain , self-efficacy regarding pain-interfering activities , disability due to neck pain (p=0.001) and levels of catastrophic thinking in favour of PASS. Conclusion: PASS had a better effect than IAPT in the treatment of persistent musculoskeletal tension-type neck pain regarding coping with pain, in terms of patients’ self-reported pain control, self-efficacy, disability and catastrophizing, over the 20-week follow-up.

Discharge patterns of nociceptive primary afferent fibres in the rat coccygeal nerve after UVA-light exposure - Corrected Proof

Andreas Themistocleous, Peter Kamerman, Duncan Mitchell — 2009-11-26

Abstract: We have shown that administration of the local anaesthetic bupivacaine into the base of rats’ tails prevents the development of hyperalgesia induced by UVA-light to a noxious thermal challenge, but not to noxious mechanical challenges. The aim of this study was to determine whether exposure of rats’ tails to UVA-light altered the responses of Aδ- and C-fibres innervating the tail to noxious mechanical and noxious thermal challenges. We dissected the right ventral coccygeal nerve in Sprague–Dawley rats that had their tails exposed to, or shielded from, UVA-light 24-h earlier. Single afferent Aδ- and C-fibres receptive fields were located and the response of a fibre to noxious blunt (3.9Nbar algometer) and punctate (rat toothed forceps) mechanical challenges, as well as a noxious thermal (49°C) challenge was measured. In rats exposed to UVA-light, the peak firing rates and areas under the curve of post-challenge histograms of Aδ- and C-fibres evoked neural activity were increased when noxious blunt and punctate challenges were applied to the rats’ tails. However, the peak firing rate and areas under the curve of post-challenge histograms of C-fibre evoked neural activity, which were responsive to noxious thermal challenges, were not increased after UVA-light exposure. We have shown that the Aδ- and C-fibres that encode for noxious punctate and blunt challenges were sensitized after UVA-light exposure, but C-fibres responsible for encoding noxious thermal challenges were not sensitized by UVA-light exposure.

Roles of kinin B1 and B2 receptors in skin cancer pain produced by orthotopic melanoma inoculation in mice - Corrected Proof

2009-11-26

Abstract: Background: Although bradykinin is a potent algogenic peptide, the roles of this peptide and kinin receptors in cancer pain are unclear.Aims: The present study was conducted to clarify whether kinin B1 and B2 receptors would be involved in pain using a mouse model of skin cancer pain.Methods: B16-BL6 melanoma cells were inoculated into the hind paw of C57BL/6 mice. Licking, an index of spontaneous pain, allodynia and hyperalgesia were observed. Expression of kinin receptor mRNAs was analyzed with reverse transcription and polymerase chain reaction. The contents of kininogen and bradykinin-related peptides were assayed with Western blotting and enzyme immunoassay, respectively.Results: Melanoma inoculation induced spontaneous licking of the melanoma-bearing paw from day 18 post-inoculation, which was inhibited by local injections of B1 and B2 receptor antagonists. Allodynia was briefly attenuated by B2, but not B1 antagonist and hyperalgesia was not inhibited by either B1 or B2 antagonist. Local injections of B1 and B2 receptor agonists increased licking behavior in melanoma-bearing, but not healthy, paw. The expression of kinin B1, but not B2, receptor mRNA was markedly increased in the L4/5 dorsal root ganglia on the melanoma-bearing side. Melanoma cells expressed B1 and B2 receptors and kininogen. The content of bradykinin and related peptides was increased in the melanoma mass as compared with healthy skin.Conclusions: Bradykinin and related peptides released from melanoma cells may cause spontaneous pain and allodynia in the melanoma-bearing paw, in which B1 and B2 receptors on primary afferent and melanoma cells may have different roles.

The role of brain-derived neurotrophic factor in experimental inflammation of mouse gut - Corrected Proof

2009-11-23

Abstract: Previous studies suggested that brain-derived neurotrophic factor (BDNF) might act as an important modulator in chronic pain states. However, no systematic study has used knock-out mice to clarify its effect on visceral sensitivity. In the present study, 2,4,6-trinitrobenzene sulfonic acid (TNBS) was administered to heterozygous (BDNF+/−) knock-out and wild-type (BDNF+/+) mice to induce colitis. Visceral response to colorectal distension (CRD) and bladder reactivity were recorded. Results demonstrated that in normal state, BDNF+/− and BDNF+/+ mice did not differ in the visceral response to CRD at <60mmHg pressure and the bladder reactivity; however, with ⩾60mmHg pressure, BDNF+/− mice showed a weaker visceral response to CRD. In inflammatory state of colitis, TNBS induced upregulation of BDNF in dorsal root ganglia of both genotypes while BDNF+/− mice showing significantly lower sensitivity in the colon at ⩾30mmHg and lower sensitivity in bladder than BDNF+/+ mice. The two genotypes showed no significant difference in inflammatory severity. Thus, BDNF deficiency results in developmental changes in colonic nociception in both control and inflammatory states, which are more significant in inflammatory state. For bladder reactivity, BDNF deficiency leads to lower sensitization in inflammatory state but has no effect in control state.Perspective: This article highlights the role of BDNF in colonic and referred bladder hyperalgesia in mice. The findings might help in determining novel pharmaceutical interventions targeted at BDNF to relieve abdominal pain.

Factors affecting – And relationships between – Different modes of endogenous pain modulation in healthy volunteers - Corrected Proof

Roi Treister, Elon Eisenberg, Edith Gershon, May Haddad, Dorit Pud — 2009-11-11

Abstract: Endogenous analgesia (EA) can be reflected by diffuse noxious inhibitory control (DNIC), non-noxious inhibitory control (NNIC) and habituation to repeated painful stimuli. However, the coexistence of these phenomena in a given individual and the degree to which various factors predict their magnitudes have not been fully investigated. Using experimental paradigms of DNIC, NNIC and habituation, the present study explored the relationships between – and the contribution factors to – the magnitude of EA exhibited by healthy volunteers (n=191; 104F, 87M) exposed to these three experimental paradigms. Each subject was assigned to all three paradigms (DNIC-tested by co-administering repeated short painful heat stimuli and a conditioning tonic cold pain stimulation; NNIC – tested similarly with the exception of using a painless conditioning stimulation; habituation – tested by applying repeated painful heat stimuli only) in a random order. Pain intensities decreased from baseline in all three paradigms. However, DNIC produced significantly more pain reduction than the other two modes (RM-ANOVA). The magnitude of pain reduction of DNIC was found to be highly correlated with that of NNIC and habituation (r=0.56, p<0.001 for both correlations). A hierarchical regression analysis showed that baseline (p<0.001) and conditioning pain scores (p=0.043) predicted the magnitude of DNIC. A gender split analysis showed that conditioning pain scores served as a predictive factor for men only. Conclusions: Under these experimental conditions, different EA conditions seem to be related to each other. High initial pain intensities predict ‘effective’ DNIC and habituation, whereas intensity of the conditioning stimulus determines the magnitude of DNIC in men only.

Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine - Corrected Proof

2009-11-09

Abstract: Background: Oral ketamine is used as an adjuvant in the treatment of refractory neuropathic and cancer-related pain. Drug interactions may alter the analgesic or other effects of ketamine.Aim and methods: The aim of the study was to investigate the effect of cytochrome P450 3A enzyme inhibition with clarithromycin on the pharmacokinetics and pharmacodynamics of oral S-ketamine in a randomized controlled cross-over study with two phases. Ten healthy subjects were pre-treated with oral clarithromycin or placebo for 4days. On day 4, they ingested an oral dose of 0.2mg/kg of S-ketamine syrup. Plasma concentrations of ketamine and norketamine were measured for 24h. Analgesic effects were evaluated in a cold pressor test and psychomotor effects were followed for 12h.Results: Clarithromycin increased the mean Cmax of ketamine by 3.6-fold (p<0.001) and the mean AUC0–∞ of ketamine by 2.6-fold (p=0.001). The relative amount of the CYP3A dependent metabolite norketamine was decreased by 54% by clarithromycin (p=0.004). Self-rated drug effect of S-ketamine was enhanced by clarithromycin (p<0.05) but other behavioral effects or cold pain scores were not affected.Conclusions: Clarithromycin strongly increases plasma concentrations of oral S-ketamine probably by inhibiting its CYP3A-mediated N-demethylation. This increase is reflected as modest changes in behavioral effects of oral S-ketamine.

Long-term depression of pain-related cerebral activation in healthy man: An fMRI study - Corrected Proof

Silke Rottmann, Kerstin Jung, René Vohn, Jens Ellrich — 2009-11-09

Abstract: Electrical low-frequency stimulation (LFS) of cutaneous afferents reliably induces long-term depression (LTD) of nociception and pain in man. In this study LFS effects on cerebral activation were investigated by functional magnetic resonance imaging (fMRI).In 17 healthy volunteers, nociceptive fibers of right hand dorsum were electrically stimulated via a concentric electrode. Test stimulation sessions consisted of three alternating stimulation periods and rest periods. They were performed before (Pre) and after (Post) conditioning LFS (1200 stimuli, 1Hz) or 20min break (Control). Volunteers rated sensory and affective pain perception.Before LFS, test stimulation produced activation in bilateral primary and secondary somatosensory cortex (S1,S2), insula, anterior cingulate cortex (ACC), superior temporal cortex (STG), prefrontal cortex and right inferior parietal lobule (IPL). After LFS, exclusively right IPL was activated. Contrast between Pre and Post LFS indicated significant activity decrease in bilateral S1,S2, and ACC and right insula, IPL, and STG. Pre Control and Pre LFS were not different. Activity in Control experiments remained unchanged. Sensory and affective pain rating solely decreased after LFS. Subsequent regression analysis showed significant correlation between pain relief and increased activity after LFS in ACC, anterior insula, striatum, frontal and temporal cortex.The study revealed LTD of pain-related cerebral activation, involving sensory, affective, cognitive, and attentional processes. Positive correlation between pain relief and increased brain activation after LFS may indicate involvement of endogenous pain control mechanisms in LTD. These experiments may help to judge the potency of LTD for future chronic pain treatment.

Do illness perceptions predict pain-related disability and mood in chronic orofacial pain patients? A 6-month follow-up study - Corrected Proof

Ursula Galli, Dominik A. Ettlin, Sandro Palla, Ulrike Ehlert, Jens Gaab — 2009-10-30

Abstract: In our study, we investigated the predictive value of illness beliefs as measured by the revised illness perception questionnaire (IPQ-R) in the context of other clinical predictors in patients with chronic orofacial pain over a 6-month follow-up period. Consecutive patients (152) referred to the interdisciplinary orofacial pain service at the Centre for Dental and Oral Medicine and Cranio-Maxillofacial Surgery, University of Zurich received questionnaires to assess pain and pain-related disability, anxiety, depression as well as physical and mental quality of life at three time points: prior to treatment, 3 and 6months after beginning of treatment. Results: significant improvement was found over time for all outcome measures except mental quality of life. Results of the regression analysis indicated that believing pain could have serious consequences on one’s life (IPQ subscale consequences) is one of the most important predictors for treatment outcome. The belief in low personal control and in a chronic timeline is also shown to be predictive for outcome, though explaining a smaller proportion of variance. These results provided evidence that beliefs about pain are important predictors for treatment outcome even when controlled for pain and mood. They therefore need to be considered in the management of patients with chronic orofacial pain. Assessing patients’ illness beliefs can provide essential information on these important psychological determinants of adjustment to chronic pain and may be specific targets for individualised treatment approaches.

Use of oral ketamine in chronic pain management: A review - Corrected Proof

2009-10-30

Abstract: The analgesic effect of ketamine is primarily based on the antagonism of the N-methyl-D-aspartate (NMDA) receptor. Activation of NMDA receptors may play a crucial role in the pathogenesis of chronic pain. Little formal research has been performed on the efficacy and safety of ketamine in chronic pain, especially concerning long-term oral administration. This review provides an overview of the available clinical data on the use of oral ketamine in chronic pain management. A literature search was performed in MEDLINE, EMBASE and the Cochrane Library, resulting in 22 relevant articles. Because most retrieved articles were of a descriptive nature (e.g. case reports and case series) a quantitative analysis was not possible. There was no consistent dose–response relation. A recommended starting dosage in ketamine-naive patients is 0.5mg/kg racemic ketamine or 0.25mg/kg S-ketamine as a single oral dose. The dosage is increased by the same amount if required. For a continuous analgesic effect it is usually given 3–4 times daily. The injection fluid can be taken orally. When parenteral ketamine is switched to oral administration the daily dosage can be kept equal and, depending on clinical effect and/or adverse effects, is slowly increased. The pharmacologically active metabolite norketamine is believed to contribute to the analgesic effect of oral ketamine. Lack of evidence regarding efficacy, and the poor safety profile, do not support routine use of oral ketamine in chronic pain management. Oral ketamine may have a limited place as add-on therapy in complex chronic pain patients if other therapeutic options have failed.

Increased sensitivity to heat pain after sad mood induction in female patients with major depression - Corrected Proof

2009-10-19

Abstract: Patients suffering from major depressive disorder (MDD) have been shown to exhibit increased thresholds towards experimentally induced thermal pain applied to the skin. In contrast, the induction of sad mood can increase pain perception in healthy controls. Here, we aimed to test the hypothesis that heat pain thresholds are further increased after sad mood induction in depressed patients.Thermal pain thresholds were obtained from 25 female depressed patients and 25 controls before and after sad mood induction applying a modified Velten Mood Induction procedure (MIP). Valence and arousal ratings were obtained using the self-assessment manikin. The Montgomery Depression Rating Scale and the Beck Depression Inventory (BDI) were obtained at baseline from all participants.Pain thresholds at baseline did not significantly differ between groups. Pain thresholds and valence of mood significantly decreased both in patients and controls, while arousal showed an inverse time course between groups. Therefore, our hypothesis could not be confirmed. From these data, we propose that the depressed mood as seen in MDD patients influences pain experience differently as compared to the shorter-lasting mood change after MIP. A differential interaction of both affective states with brain areas of the pain matrix might be assumed. Eventually, the induction of sad mood might mirror the increased number of pain complaints in depressed patients and thus adds to the current concept of adjuvant antidepressant treatment both in depressed patients with pain complaints and in chronic pain patients.

Psychometric properties of Chronic Pain Acceptance Questionnaires: A systematic review - Corrected Proof

Michiel F. Reneman, Arie Dijkstra, Jan H.B. Geertzen, Pieter U. Dijkstra — 2009-10-12

Abstract: Background: Theoretically, acceptance of chronic pain (CP) is an important determinant in the functional status and well-being of patients with CP. Several questionnaires that aim to measure acceptance of CP have been developed. An overview of the psychometric properties of these questionnaires is unavailable.Methods: A systematic review of the literature of the psychometric properties of questionnaires that aim to measure acceptance of CP was performed. Psychometric properties including content construct and criterion validity, internal consistency. agreement, reliability, responsiveness, floor/ceiling effects and interpretability, were assessed using a standardized protocol. All studies were assessed by two observers independent from each other.Results: A total of 23 studies including 4 questionnaires or subscales were identified. The questionnaires/subscales included were the Chronic Pain Acceptance Questionnaire (CPAQ), Illness Cognitions Questionnaire (ICQ), Pain Solutions Questionnaire (PASOL) and Acceptance of Illness Scale (AIS) adapted to pain. When applying the criteria of the protocol, results indicate that none of the questionnaires are currently able to meet all 9 criteria for psychometric quality. Individual questionnaires met between 0 and 3 of the criteria.Conclusions: If strict psychometric quality criteria are applied, none of the questionnaires are currently able to meet all nine criteria for psychometric quality, but overlooking the cumulative results over all the studies conducted, especially for the CPAQ, it can be concluded that information on several important characteristics has been reported and a fairly clear picture emerges about the psychometric properties of the CPAQ.