[Show abstract][Hide abstract] ABSTRACT: Background:
Inability to predict the therapeutic effect of a drug in individual pain patients prolongs the process of drug and dose finding until satisfactory pharmacotherapy can be achieved. Many chronic pain conditions are associated with hypersensitivity of the nervous system or impaired endogenous pain modulation. Pharmacotherapy often aims at influencing these disturbed nociceptive processes. Its effect might therefore depend on the extent to which they are altered. Quantitative sensory testing (QST) can evaluate various aspects of pain processing and might therefore be able to predict the analgesic efficacy of a given drug. In the present study three drugs commonly used in the pharmacological management of chronic low back pain are investigated. The primary objective is to examine the ability of QST to predict pain reduction. As a secondary objective, the analgesic effects of these drugs and their effect on QST are evaluated.
In this randomized, double blinded, placebo controlled cross-over study, patients with chronic low back pain are randomly assigned to imipramine, oxycodone or clobazam versus active placebo. QST is assessed at baseline, 1 and 2 h after drug administration. Pain intensity, side effects and patients' global impression of change are assessed in intervals of 30 min up to two hours after drug intake. Baseline QST is used as explanatory variable to predict drug effect. The change in QST over time is analyzed to describe the pharmacodynamic effects of each drug on experimental pain modalities. Genetic polymorphisms are analyzed as co-variables.
Pharmacotherapy is a mainstay in chronic pain treatment. Antidepressants, anticonvulsants and opioids are frequently prescribed in a "trial and error" fashion, without knowledge however, which drug suits best which patient. The present study addresses the important need to translate recent advances in pain research to clinical practice. Assessing the predictive value of central hypersensitivity and endogenous pain modulation could allow for the implementation of a mechanism-based treatment strategy in individual patients.
[Show abstract][Hide abstract] ABSTRACT: Reliability is an essential condition for using quantitative sensory tests (QSTs) in research and clinical practice, but information on reliability in patients with chronic pain is sparse. The aim of this study was to evaluate the reliability of different QST in patients with chronic low back pain.
Eighty-nine patients with chronic low back pain participated in 2 identical experimental sessions, separated by at least 7 days. The following parameters were recorded: pressure pain detection and tolerance thresholds at the toe, electrical pain thresholds to single and repeated stimulation, heat pain detection and tolerance thresholds at the arm and leg, cold pain detection threshold at the arm and leg, and conditioned pain modulation using the cold pressor test.Reliability was analyzed using the coefficient of variation, the coefficient of repeatability, and the intraclass correlation coefficient. It was judged as acceptable or not based primarily on the analysis of the coefficient of repeatability.
The reliability of most tests was acceptable. Exceptions were cold pain detection thresholds at the leg and arm.
Most QST measurements have acceptable reliability in patients with chronic low back pain.
Regional anesthesia and pain medicine 07/2015; DOI:10.1097/AAP.0000000000000289 · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypersensitivity of pain pathways is considered a relevant determinant of symptoms in chronic pain patients, but data on its prevalence are very limited. To our knowledge, no data on the prevalence of spinal nociceptive hypersensitivity are available. We studied the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity in 961 consecutive patients with various chronic pain conditions. Pain threshold and nociceptive withdrawal reflex threshold to electrical stimulation were used to assess pain hypersensitivity and spinal nociceptive hypersensitivity, respectively. Using 10 percentile cut-off of previously determined reference values, the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity (95% CI) was 71.2 (68.3-74.0) and 80.0 (77.0-82.6), respectively. As secondary aim, we analyzed demographic, psychosocial and clinical characteristics as factors potentially associated with pain hypersensitivity and spinal nociceptive hypersensitivity using logistic regression models. Both hypersensitivity parameters were unaffected by most factors analyzed. Depression, catastrophizing, pain-related sleep interference and average pain intensity were significantly associated with hypersensitivity. However, none of them was significant for both unadjusted and adjusted analyses. Furthermore, the odds ratios were very low, indicating modest quantitative impact. To our knowledge, this is the largest prevalence study on central hypersensitivity and the first one on the prevalence of spinal nociceptive hypersensitivity in chronic pain patients. The results revealed an impressively high prevalence, supporting a high clinical relevance of this phenomenon. Electrical pain thresholds and nociceptive withdrawal reflex explore aspects of pain processing that are mostly independent of socio-demographic, psychological and clinical pain-related characteristics.
[Show abstract][Hide abstract] ABSTRACT: Objectives: Disturbed endogenous pain modulation is likely one of the mechanisms underlying central hypersensitivity and might be a contributing factor for the development and maintenance of chronic pain. To our knowledge, no study has investigated endogenous pain modulation in both acute and chronic low back pain. We tested the hypothesis that endogenous pain inhibition is impaired in patients with acute and chronic low back pain. Methods: We evaluated 40 patients with acute low back pain, 34 patients with chronic low back pain and 30 pain-free controls for their conditioned pain modulation (CPM), with pressure pain tolerance and cold pressor as test and conditioning stimulus, respectively. Measurements were repeated up to 10 minutes after cold pressor test. Results: There was no difference in CPM among the groups immediately after cold pressor test. However, the decline in CPM effect was significantly faster in chronic and acute low back pain patients than in controls, with no evidence for differences between pain groups. Discussion: The present study provides evidence for some alterations of endogenous modulation in both acute and chronic low back pain. CPM was still detected in both patient groups, indicating that endogenous modulation, although effective for a shorter duration, is partially functioning in patients with low back pain.
Clinical Journal of Pain 04/2015; Publish Ahead of Print. DOI:10.1097/AJP.0000000000000238 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine the reliability of the conditioned pain modulation (CPM) paradigm assessed by an objective electrophysiological method, the nociceptive withdrawal reflex (NWR), and psychophysical measures, using hypothetical sample sizes for future studies as analytical goals. Thirty-four healthy volunteers participated in two identical experimental sessions, separated by 1 to 3 weeks. In each session, the cold pressor test (CPT) was used to induce CPM, and the NWR thresholds, electrical pain detection thresholds and pain intensity ratings after suprathreshold electrical stimulation were assessed before and during CPT. CPM was consistently detected by all methods, and the electrophysiological measures did not introduce additional variation to the assessment. In particular, 99% of the trials resulted in higher NWR thresholds during CPT, with an average increase of 3.4 mA (p<0.001). Similarly, 96% of the trials resulted in higher electrical pain detection thresholds during CPT, with an average increase of 2.2 mA (p<0.001). Pain intensity ratings after suprathreshold electrical stimulation were reduced during CPT in 84% of the trials, displaying an average decrease of 1.5 points in a numeric rating scale (p<0.001). Under these experimental conditions, CPM reliability was acceptable for all assessment methods in terms of sample sizes for potential experiments. The presented results are encouraging with regards to the use of the CPM as an assessment tool in experimental and clinical pain.
Clinical Trials.gov NCT01636440
PLoS ONE 06/2014; 9(6):e100241. DOI:10.1371/journal.pone.0100241 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Translational research has not yet elucidated whether alterations in central pain processes are related to peripheral inflammatory processes in chronic pain patients. We tested the hypothesis that the concentration of cytokines in the peritoneal fluid of endometriosis patients with chronic pain correlate with parameters of hyperexcitability of the nociceptive system. The concentrations of 15 peritoneal fluid cytokines were measured in 11 patients with chronic pelvic pain and a diagnosis of endometriosis. Six parameters assessing central pain processes were recorded. Positive correlations between concentration of some cytokines in the peritoneal fluid and amplification of central pain processing were found. The results suggest that inflammatory mechanisms may be important in the pathophysiology of altered central pain processes and that cytokines produced in the environment of endometriosis could act as mediators between the peripheral lesion and changes in central nociceptive processes.
Regional anesthesia and pain medicine 04/2014; 39(3). DOI:10.1097/AAP.0000000000000068 · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The nociceptive withdrawal reflex (NWR) has been proven to be a valuable tool in the objective assessment of central hyperexcitability in the nociceptive system at spinal level that is present in some chronic pain disorders, particularly chronic low back and neck pain. However, most of the studies on objective assessment of central hyperexcitability focus on population differences between patients and healthy individuals and do not provide tools for individual assessment. In this study, a prediction model was developed to objectively assess central hyperexcitability in individuals. The method is based on statistical properties of the EMG signals associated with the nociceptive withdrawal reflex. The model also supports individualized assessment of patients, including an estimation of the confidence of the predicted result.
up to 80% classification rates were achieved when differentiating between healthy volunteers and chronic low back and neck pain patients. EMG signals recorded after stimulation of the anterolateral and heel regions and of the sole of the foot presented the best prediction rates.
A prediction model was proposed and successfully tested as a new approach for objective assessment of central hyperexcitability in the nociceptive system, based on statistical properties of EMG signals recorded after eliciting the NWR. Therefore, the present statistical prediction model constitutes a first step towards potential applications in clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Background
Mechanistic, translational, human experimental pain assessment technologies (pain biomarkers) can be used for: (1) profiling the responsiveness of various pain mechanisms and pathways in healthy volunteers and pain patients, and (2) profiling the effect of new or existing analgesic drugs or pain management procedures. Translational models, which may link mechanisms in animals to humans, are important to understand pain mechanisms involved in pain patients and as tools for drug development. This is urgently needed as many drugs which are effective in animal models fail to be efficient in patients as neither the mechanisms involved in patients nor the drugs’ mechanistic actions are known.
The aim of the present topical review is to provide the basis for how to use mechanistic human experimental pain assessment tools (pain biomarkers) in the development of new analgesics and to characterise and diagnose pain patients. The future aim will be to develop such approaches into individualised pain management regimes.
Experimental pain biomarkers can tease out mechanistically which pain pathways and mechanisms are modulated in a given patient, and how a given compound modulates them. In addition, pain biomarkers may be used to assess pain from different structures (skin, muscle and viscera) and provoke semi-pathophysiological conditions (e.g. hyperalgesia, allodynia and after-sensation) in healthy volunteers using surrogate pain models.
With this multi-modal, multi-tissue, multi-mechanism pain assessment regime approach, new opportunities have emerged for profiling pain patients and optimising drug development. In this context these technologies may help to validate targets (proof-of-concept), provide dose–response relationships, predicting which patient population/characteristics will respond to a given treatment (individualised pain management), and hence provide better understanding of the underlying cause for responders versus non-responders to a given treatment.
In recent years, pain biomarkers have been substantially developed to have now a role to play in early drug development, providing valuable mechanistic understanding of the drug action and used to characterise/profile pain patients. In drug development phase I safety volunteer studies, pain biomarkers can provide indication of efficacy and later if feasible be included in clinical phase II, III, and IV studies to substantiate mode-of-action.
Refining and optimising the drug development process ensures a higher success rate, i.e. not discarding drugs that may be efficient and not push non-efficient drugs too far in the costly development process. Mechanism-based pain bio-markers can help to qualify the development programmes and at the same time help qualifying them by pain profiling (phenotyping) and recognising the right patients for specific trials. The success rate from preclinical data to clinical outcome may be further facilitated by using specific translational pain bio-markers. As human pain biomarkers are getting more and more advanced it could be expected that FDA and EMA in the future will pay more attention to such mechanism-related measures in the approval phase as proof-of-action.
Scandinavian Journal of Pain 10/2013; 4(4):226–230. DOI:10.1016/j.sjpain.2013.07.026
[Show abstract][Hide abstract] ABSTRACT: Background and objectives:
Quantitative sensory testing (QST) is widely used to investigate peripheral and central sensitization. However, the comparative performance of different QST for diagnostic or prognostic purposes is unclear. We explored the discriminative ability of different quantitative sensory tests in distinguishing between patients with chronic neck pain and pain-free control subjects and ranked these tests according to the extent of their association with pain hypersensitivity.
We performed a case-control study in 40 patients and 300 control subjects. Twenty-six tests, including different modalities of pressure, heat, cold, and electrical stimulation, were used. As measures of discrimination, we estimated receiver operating characteristic curves and likelihood ratios.
The following quantitative sensory tests displayed the best discriminative value: (1) pressure pain threshold at the site of the most severe neck pain (fitted area under the receiver operating characteristic curve, 0.92), (2) reflex threshold to single electrical stimulation (0.90), (3) pain threshold to single electrical stimulation (0.89), (4) pain threshold to repeated electrical stimulation (0.87), and (5) pressure pain tolerance threshold at the site of the most severe neck pain (0.86). Only the first 3 could be used for both ruling in and out pain hypersensitivity.
Pressure stimulation at the site of the most severe pain and parameters of electrical stimulation were the most appropriate QST to distinguish between patients with chronic neck pain and asymptomatic control subjects. These findings may be used to select the tests in future diagnostic and longitudinal prognostic studies on patients with neck pain and to optimize the assessment of localized and spreading sensitization in chronic pain patients.
Regional anesthesia and pain medicine 06/2013; 38(4). DOI:10.1097/AAP.0b013e318295a3ea · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Chronic pain is associated with generalized hypersensitivity and impaired endogenous pain modulation (conditioned pain modulation; CPM). Despite extensive research, their prevalence in chronic pain patients is unknown. This study investigated the prevalence and potential determinants of widespread central hypersensitivity and described the distribution of CPM in chronic pain patients.
We examined 464 consecutive chronic pain patients for generalized hypersensitivity and CPM using pressure algometry at the second toe and cold pressor test. Potential determinants of generalized central hypersensitivity were studied using uni- and multivariate regression analyses. Prevalence of generalized central hypersensitivity was calculated for the 5th, 10th and 25th percentile of normative values for pressure algometry obtained by a previous large study on healthy volunteers. CPM was addressed on a descriptive basis, since normative values are not available.
Depending on the percentile of normative values considered, generalized central hypersensitivity affected 17.5-35.3% of patients. 23.7% of patients showed no increase in pressure pain threshold after cold pressor test. Generalized central hypersensitivity was more frequent and CPM less effective in women than in men. Unclearly classifiable pain syndromes showed higher frequencies of generalized central hypersensitivity than other pain syndromes.
Although prevalent in chronic pain, generalized central hypersensitivity is not present in every patient. An individual assessment is therefore required in order to detect altered pain processing. The broad basic knowledge about central hypersensitivity now needs to be translated into concrete clinical consequences, so that patients can be offered an individually tailored mechanism-based treatment.
European journal of pain (London, England) 06/2013; 17(10):1-20. DOI:10.1002/j.1532-2149.2013.00332.x · 2.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pain hypersensitivity has been consistently detected in chronic pain conditions, but the underlying mechanisms are difficult to investigate in humans and thus poorly understood. Patients with endometriosis pain display enlarged reflex receptive fields (RRF), providing a new perspective in the identification of possible mechanisms behind hypersensitivity states in humans. The primary hypothesis of this study was that RRF are enlarged in patients with musculoskeletal pain. Secondary study end points were subjective pain thresholds and nociceptive withdrawal reflex (NWR) thresholds after single and repeated (temporal summation) electrical stimulation. Forty chronic neck pain patients, 40 chronic low back pain patients, and 24 acute low back pain patients were tested. Electrical stimuli were applied to 10 sites on the sole of the foot to quantify the RRF, defined as the area of the foot from where a reflex was evoked. For the secondary end points, electrical stimuli were applied to the cutaneous innervation area of the sural nerve. All patient groups presented enlarged RRF areas compared to pain-free volunteers (P<.001). Moreover, they also displayed lower NWR and pain thresholds to single and repeated electrical stimulation (P<.001). These results demonstrate that musculoskeletal pain conditions are characterized by enlarged RRF, lowered NWR and pain thresholds, and facilitated temporal summation, most likely caused by widespread spinal hyperexcitability. This study contributes to a better understanding of the mechanisms underlying these pain conditions, and it supports the use of the RRF and NWR as objective biomarkers for pain hypersensitivity in clinical and experimental pain research.
[Show abstract][Hide abstract] ABSTRACT: Central hypersensitivity, defined as an increased excitability of the central nervous system, is considered as the main factor behind facilitation of central pain processes and is probably a very important factor in the induction and maintenance of chronic pain. Widespread hyposensitivity is less studied than hypersensitivity states, but recent work indicates that hypoesthesia may be present in chronic non-neuropathic pain conditions and could have negative prognostic value. Electrical pain and reflex thresholds are well established measures of central pain sensitivity in human pain research. One potential application of these assessments in clinical practice is the detection of central hyper- or hyposensitivity in individual patients. In order to identify these disturbances in the central pain processing of individual patients, knowledge of reference values is essential. We computed percentile normative values of nociceptive withdrawal reflex (NWR) and pain thresholds to different electrical stimulation paradigms. The aim was to provide reference values for the assessment of widespread central hyper- and hyposensitivity in individual patients.
Scandinavian Journal of Pain 04/2013; 4(2):120-124. DOI:10.1016/j.sjpain.2012.09.002
[Show abstract][Hide abstract] ABSTRACT: Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain.
In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry.
For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed.
Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds.
PLoS ONE 03/2013; 8(3):e43896. DOI:10.1371/journal.pone.0043896 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Ilioinguinal (IL) and iliohypogastric (IH) nerve blocks are used in patients with chronic postherniorrhaphy pain. The present study tested the hypothesis that our method, previously developed in cadavers, blocks the nerves separately and selectively in human volunteers.
We blocked the IL and the IH nerves in 16 volunteers in a single-blinded randomized cross-over setting under direct ultrasound visualization, by injecting two times the ED95 volume of 1% mepivacaine needed to block a peripheral nerve. The anaesthetized skin areas were tested by pinprick and marked on the skin. A digital photo was taken. For further analysis, the parameterized picture data were transformed into a standardized and unified coordinate system to compare and calculate the overlap of the anaesthetized skin areas of the two nerves on each side. An overlap <25% was defined as selective block.
Fifty nerve blocks could be analysed. The mean volume injected to block a single nerve was 0.9 ml. Using ultrasound, we observed spread from one nerve to the other in 12% of cases. The overlap of the anaesthetized skin areas of the nerves was 60.3% and did not differ after exclusion of the cases with visible spread of local anaesthetic from one nerve to the other.
The IL and IH nerves cannot be selectively blocked even if volumes below 1 ml are used. The most likely explanation is the spread of local anaesthetic from one nerve to the other, although this could not be directly observed in most cases.
BJA British Journal of Anaesthesia 03/2013; 111(2). DOI:10.1093/bja/aet028 · 4.85 Impact Factor