Combining Electrodermal Activity With the Peak-Pain Time to Quantify Three Temporal Regions of Pain Experience.

Background: Self-reported pain levels, while easily measured, are often not reliable for quantifying pain. More objective methods are needed that supplement self-report without adding undue burden or cost to a study. Methods that integrate multiple measures, such as combining self-report with physiology in a structured and specific-to-pain protocol may improve measures. Method: We propose and study a novel measure that combines the timing of the peak pain measured by an electronic visual-analog-scale (eVAS) with continuously-measured changes in electrodermal activity (EDA), a physiological measure quantifying sympathetic nervous system activity that is easily recorded with a skin-surface sensor. The new pain measure isolates and specifically quantifies three temporal regions of dynamic pain experience: I. Anticipation preceding the onset of a pain stimulus, II. Response rising to the level of peak pain, and III. Recovery from the peak pain level. We evaluate the measure across two pain models (cold pressor, capsaicin), and four types of treatments (none, A=pregabalin, B=oxycodone, C=placebo). Each of 24 patients made four visits within 8 weeks, for 96 visits total: A training visit (TV), followed by three visits double-blind presenting A, B, or C (randomized order). Within each visit, a participant experienced the cold pressor, followed by an hour of rest during which one of the four treatments was provided, followed by a repeat of the cold pressor, followed by capsaicin. Results: The novel method successfully discriminates the pain reduction effects of the four treatments across both pain models, confirming maximal pain for no-treatment, mild pain reduction for placebo, and the most pain reduction with analgesics. The new measure maintains significant discrimination across the test conditions both within a single-day's visit (for relative pain relief within a visit) and across repeated visits spanning weeks, reducing different-day-physiology affects, and providing better discriminability than using self-reported eVAS. Conclusion: The new method combines the subjectively-identified time of peak pain with capturing continuous physiological data to quantify the sympathetic nervous system response during a dynamic pain experience. The method accurately discriminates, for both pain models, the reduction of pain with clinically effective analgesics.

Multivariate analysis of single-sweep evoked brain potentials for pharmaco-electroencephalography.

BACKGROUND AND AIMS: Current findings on altered evoked potentials (EPs) caused by morphine are based on common alterations for a group of subjects after drug administration. However, this ignores the analysis of individual responses, which may explain the clinical differences in efficacy. Therefore, we explored the individual responses to morphine in terms of the altered single-sweep characteristics in a placebo-controlled crossover study. To account for multifactorial mechanisms, several characteristics were assessed simultaneously by multivariate pattern analysis (MVPA). METHODS: EPs were recorded from 62 channels and obtained before and after morphine and placebo administration during repeated electrical stimulations of the oesophagus in 12 healthy males. Additionally, the pain detection threshold was recorded to reflect the subjective analgesic effect in each subject. The characteristics of the sweeps were extracted by a multivariate matching pursuit algorithm with Gabor atoms implemented with a variable amplitude and constant phase across the sweeps. The single-sweep amplitudes were used as input to an MVPA algorithm to discriminate individual responses. The accuracy of the MVPA for each individual subject was used for correlation analysis of the analgesic effect. RESULTS: The mean classification accuracy when discriminating pre- and posttreatment morphine responses was 72% (p = 0.01). The individual classification accuracy was positively correlated to the analgesic effect of morphine (p = 0.03). Furthermore, the 2 posttreatment responses were classified and validated by the classification of the 2 pretreatment responses (p = 0.001). CONCLUSIONS: The alterations in the single-sweep EPs after morphine reflect the analgesic effect. The MVPA approach is a novel methodology for monitoring the individual efficacy of analgesics.

The genetic influences on oxycodone response characteristics in human experimental pain.

Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms (SNPs) rs589046 (P < 0.0001) and rs563649 (P < 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone.

Altered frequency distribution in the electroencephalogram is correlated to the analgesic effect of remifentanil.

Opioids alter resting state brain oscillations by multiple and complex factors, which are still to be elucidated. To increase our knowledge, multi-channel electroencephalography (EEG) was subjected to multivariate pattern analysis (MVPA), to identify the most descriptive frequency bands and scalp locations altered by remifentanil in healthy volunteers. Sixty-two channels of resting EEG followed by independent measures of pain scores to heat and bone pain were recorded in 21 healthy males before and during remifentanil infusion in a placebo-controlled, double-blind crossover study. EEG frequency distributions were extracted by a continuous wavelet transform and normalized into delta, theta, alpha, beta and gamma bands. Alterations relative to pre-treatment responses were calculated for all channels and used as input to the MVPA. Compared to placebo, remifentanil increased the delta band and decreased the theta and alpha band oscillations as a mean over all channels (all p ≤ 0.007). The most discriminative channels in these frequency bands were F1 in delta (83.33%, p = 0.0023) and theta bands (95.24%, p < 0.0001), and C6 in the alpha band (80.95%, p = 0.0054). These alterations were correlated to individual changes in heat pain in the delta (p = 0.045), theta (p = 0.038) and alpha (p = 0.039) bands and to bone pain in the alpha band (p = 0.0092). Hence, MVPA of multi-channel EEG was able to identify frequency bands and corresponding channels most sensitive to altered brain activity during remifentanil treatment. As the EEG alterations were correlated to the analgesic effect, the approach may prove to be a novel methodology for monitoring individual efficacy to opioids.

Electroencephalography and analgesics.

To assess centrally mediated analgesic mechanisms in clinical trials with pain patients, objective standardized methods such as electroencephalography (EEG) has many advantages. The aim of this review is to provide the reader with an overview of present findings in analgesics assessed with spontaneous EEG and evoked brain potentials (EPs) in humans. Furthermore, EEG methodologies will be discussed with respect to translation from animals to humans and future perspectives in predicting analgesic efficacy. We searched PubMed with MeSH terms 'analgesics', 'electroencephalography' and 'evoked potentials' for relevant articles. Combined with a search in their reference lists 15 articles on spontaneous EEG and 55 papers on EPs were identified. Overall, opioids produced increased activity in the delta band in the spontaneous EEG, but increases in higher frequency bands were also seen. The EP amplitudes decreased in the majority of studies. Anticonvulsants used as analgesics showed inconsistent results. The N-methyl-D-aspartate receptor antagonist ketamine showed an increase in the theta band in spontaneous EEG and decreases in EP amplitudes. Tricyclic antidepressants increased the activity in the delta, theta and beta bands in the spontaneous EEG while EPs were inconsistently affected. Weak analgesics were mainly investigated with EPs and a decrease in amplitudes was generally observed. This review reveals that both spontaneous EEG and EPs are widely used as biomarkers for analgesic drug effects. Methodological differences are common and a more uniform approach will further enhance the value of such biomarkers for drug development and prediction of treatment response in individual patients.

Gender, variation in opioid receptor genes and sensitivity to experimental pain.

BACKGROUND: Pain tolerance is subject to considerable inter-individual variation, which may be influenced by a number of genetic and non-genetic factors. The mu, delta and kappa opioid receptors play a role in pain perception and are thought to mediate different pain modalities. The aim of this study was to explore associations between pain thresholds and gender and genetic variants in the three opioid receptor genes (OPRM, OPRD and OPRK). Experimental multi-modal pain data from previously published studies carried out in healthy Caucasian volunteers were used in order to limit the number of confounders to the study outcome. Data on thermal skin pain (n=36), muscle pressure pain (n=31) and mechanical visceral pain (n=50)) tolerance thresholds were included. RESULTS: Nineteen genetic polymorphisms were included in linear regression modeling. Males were found to tolerate higher thermal and muscle pressure pain than females (p=0.003 and 0.02). Thirty four percent of variability in thermal skin pain was accounted for by a model consisting of OPRK rs6473799 and gender. This finding was just outside significance when correction for multiple testing was applied. Variability in muscle pressure pain tolerance was associated with OPRK rs7016778 and rs7824175. These SNPs accounted for 43% of variability in muscle pressure pain sensitivity and these findings remained significant after adjustment for multiple testing. No association was found with mechanical visceral pain. CONCLUSION: This is a preliminary and hypothesis generating study due to the relatively small study size. However, significant association between the opioid receptor genes and experimental pain sensitivity supports the influence of genetic variability in pain perception. These findings may be used to generate hypotheses for testing in larger clinical trials of patients with painful conditions.

A population pharmacokinetic and pharmacodynamic study of a peripheral κ-opioid receptor agonist CR665 and oxycodone.

BACKGROUND: Peripherally acting opioids, particularly peripheral κ-opioid agonists, may be effective for treating visceral pain by activating receptors expressed on afferent nerves within the gut. OBJECTIVE: The objective of this study was to investigate the pharmacokinetic/pharmacodynamic profile of a novel peripherally selective κ-opioid agonist, CR665 (JNJ-38488502), and compare it to that of oxycodone, a non-selective brain-penetrant opioid. METHODS: In a randomized, placebo-controlled, double-blind, three-way crossover study, healthy male volunteers were administered CR665 (0.36 mg/kg, intravenous), oxycodone (15 mg, oral) or placebo (intravenous and oral), followed by assessment of visceral pain tolerance thresholds (VPTT) measured as volume of water (mL) in the bag placed on an oesophageal probe. Plasma drug concentration data were used to generate pharmacokinetic models, which were then used to fit the VPTT data using NONMEM(®) VI to generate population pharmacokinetic/pharmacodynamic models. RESULTS: CR665 kinetics were optimally fitted with a two-compartment model, while oxycodone kinetics were best described by a one-compartment model with transit compartment absorption feeding directly into the central compartment. For both drugs, the plasma concentration effects on VPTT were best fit by a direct linear model, i.e. without the concentration-analgesia delay characteristic of brain-penetrant opioids. The slope of oxycodone (0.089 mL per ng/mL) was steeper than that of CR665 (0.0035 mL per ng/mL) for the plasma drug concentration acting on the VPTT. CONCLUSION: The results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.

Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs.

Pain models in animals have shown low predictivity for analgesic efficacy in humans, and clinical studies are often very confounded, blurring the evaluation. Human experimental pain models may therefore help to evaluate mechanisms and effect of analgesics and bridge findings from basic studies to the clinic. The present review outlines the concept and limitations of human experimental pain models and addresses analgesic efficacy in healthy volunteers and patients. Experimental models to evoke pain and hyperalgesia are available for most tissues. In healthy volunteers, the effect of acetaminophen is difficult to detect unless neurophysiological methods are used, whereas the effect of nonsteroidal anti-inflammatory drugs could be detected in most models. Anticonvulsants and antidepressants are sensitive in several models, particularly in models inducing hyperalgesia. For opioids, tonic pain with high intensity is attenuated more than short-lasting pain and nonpainful sensations. Fewer studies were performed in patients. In general, the sensitivity to analgesics is better in patients than in healthy volunteers, but the lower number of studies may bias the results. Experimental models have variable reliability, and validity shall be interpreted with caution. Models including deep, tonic pain and hyperalgesia are better to predict the effects of analgesics. Assessment with neurophysiologic methods and imaging is valuable as a supplement to psychophysical methods and can increase sensitivity. The models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. Knowledge obtained from this review can help design experimental pain studies for new compounds entering phase I and II clinical trials.

Advanced pharmaco-EEG reveals morphine induced changes in the brain's pain network.

INTRODUCTION: By using a novel brain source modeling approach, where the evoked potential (EP) signal was decomposed with multichannel matching pursuit (MMP) before source localization, we investigated brain generators of EPs after a pain stimulus in the esophagus before and after administration of placebo/morphine. We showed that this new approach of pharmaco-electroencephalogram (EEG) analysis can shed light on subtle changes, which cannot be foreseen from conventional analysis (amplitude/latency/topography). METHODS: In this placebo-controlled crossover study, the effects of orally administered morphine (30 mg) on esophageal pain elicited by electrical stimulation were investigated in 9 healthy volunteers. Using new methods (decomposition of the EPs with MMP and clustering) in combination with inverse modeling, we investigated brain sources of the EPs and their time-frequency properties. RESULTS: Morphine treatment resulted in a shift of the brain sources in the low-frequency range (2-4 Hz) toward the frontal cortex during the first 300 milliseconds after stimulus, whereas active brain sources after placebo treatment remained stable. CONCLUSIONS: Decomposing the EPs into the original brain generators showed that morphine mainly changes the low frequency electrical activity in the frontal brain area. This method can be used to increase the basic understanding of the opioid effect on the brain's processing of pain and eventually identify biomarkers of analgesia in experimental pain models.

The absorption profile of pregabalin in chronic pancreatitis.

It was recently shown that pregabalin decreased pain associated with chronic pancreatitis. It is well known that pancreatitis patients suffer from fat malabsorption with accompanying diarrhoea because of loss of exocrine pancreatic enzyme production. This may lead to changes in the mucosal surface in the small intestine and possibly affect the absorption of pregabalin. The pharmacokinetics of pregabalin has never been investigated in patients suffering from chronic pancreatitis. The aim of this study was to develop a population pharmacokinetic model of pregabalin administered to patients with chronic pancreatitis. The pregabalin population pharmacokinetic analysis was conducted on data from fifteen patients with chronic pancreatitis. Each patient received 75 mg of pregabalin (oral capsule). Pregabalin concentrations were measured using a validated liquid chromatographic method. Data analysis was performed using non-linear mixed effects modelling methodology as implemented by NONMEM. A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. Time to maximum observed plasma concentration (T(max) ) was 1.53 (95% CI 1.09-2.05). The maximum plasma concentration (C(max) ) was 1.98 µg/ml (95% CI 1.69-2.34), and area under the plasma concentration-time profile (area under the curve) was 18.2 µg*hr/ml (95% CI 14.7-26.3). Pregabalin is well absorbed in patients with chronic pancreatitis, and the pharmacokinetic profile of pregabalin is not extensively affected by chronic pancreatitis.

A translational study of the effects of ketamine and pregabalin on temporal summation of experimental pain.

BACKGROUND AND OBJECTIVES: Central sensitization is often seen in chronic pain. A relevant and potent mechanism of central sensitization is the central integration of nociceptive impulses. Temporal summation in humans and the wind-up process in animals share common features of central integration. This preclinical and clinical translational study investigated the effect of ketamine and pregabalin on temporal summation (TS) and wind-up of wide dynamic range (WDR) neurons of nociceptive electrical stimuli in healthy volunteers and rats. METHODS: This 3-way crossover study included healthy male volunteers (n = 18) receiving 3 doses of 300 mg pregabalin (orally) over 2 days, ketamine (intravenous loading dose 0.5 mg/kg followed by 9 µg/kg per minute for 20 mins) on the first day, or placebo. The pain detection thresholds to repetitive electrical cutaneous and suprathreshold responses stimulation were assessed.In male Sprague-Dawley rats (n = 30), WDR neuron recordings after electrical stimulation were obtained before and after 15 minutes of intravenous infusion pregabalin (0.127, 0.42, and 1.27 mg/kg per minute) and ketamine (0.006, 0.02, 0.06, and 0.2 mg/kg per minute). RESULTS: In the human study, ketamine compared with placebo significantly increased the TS pain detection threshold (P < 0.001) and significantly reduced suprathreshold pain responses (P < 0.001). In rats, the highest dose of ketamine significantly inhibited the wind-up response of the WDR neurons (P = 0.014). Pregabalin affected neither of the parameters in TS and WDR responses. CONCLUSIONS: It was shown that TS shares common features with wind-up of WDR neurons and that pregabalin does not affect this component of central sensitization.

[Tapentadol is a new, strongly efficative analgeticum with dual effect mechanisms]. / Tapentadol er et nyt stærktvirkende analgetikum med to virkningsmekanismer.

Tapentadol exerts its analgesic effects through opioid receptor agonism and noradrenaline reuptake inhibition in the central nervous system. Clinical studies show that tapentadol effectively relieves moderate to severe pain in both post-operative and chronic pain. In these trials with equianalgesic doses of tapentadol and oxycodone, treatment with tapentadol was associated with significantly fewer gastrointestinal-related adverse events. Furthermore, in a placebo-controlled study, tapentadol has shown good efficacy in painful diabetic polyneuropathy.

Is electrical brain activity a reliable biomarker for opioid analgesia in the gut?

The effects of morphine on brain potentials after experimental gut pain have never been investigated. This study explored whether multi-channel-evoked brain potentials (EP) and corresponding dipole sources in the brain would reflect the effects of morphine on experimental oesophageal pain. In a crossover study, the effects of oral morphine (30 mg) or corresponding placebo on pain from electrical oesophageal stimulation were tested in 12 healthy male volunteers. The electroencephalographic (EEG) activity was monitored with 64 surface recordings. Pain was assessed by subjective scores on a visual analogue scale, amplitude and latency of the vertex-EP as well as on multi-channel recordings of EPs. Finally, electrical brain sources after pain stimuli were modelled from the EEG data. Morphine attenuated subjective pain scores (p = 0.008). The amplitude of the P2 peak (230 msec. post-stimulus) in the vertex EPs was unaltered after treatment with morphine, whereas after placebo treatment, it decreased (p = 0.03). However, the overall topography changed and the source of P1 (100 msec. post-stimulus), possibly originating from areas near the cingulate gyrus, changed localization in an upward, posterior direction (p = 0.04). The length of the vector describing this shift correlated inversely with the magnitude of the subjective pain relief (r = -0.7; p = 0.02). With the potential of becoming a useful biomarker in analgesic trials, the localization of the dipole sources reflected the analgesic action of morphine after pain stimuli of the gut. Even though further evaluation of the method is necessary, it has the potential to be a valid objective biomarker for opioid analgesia.

A pharmacokinetic and pharmacodynamic study of oral oxycodone in a human experimental pain model of hyperalgesia.

BACKGROUND AND OBJECTIVE: Oxycodone is not as well characterized, with respect to its pharmacokinetic/pharmacodynamic properties, as other opioids. Moreover, the pharmacodynamic profile of oxycodone can be affected by changes in the pain system, e.g. hyperalgesia. Therefore, the aim of this study was to investigate the pharmacokinetic/pharmacodynamic profiles of oxycodone in a human experimental pain model of hyperalgesia. METHODS: Twenty-four healthy subjects received oral oxycodone (15 mg) or placebo. Pharmacodynamics were assessed utilizing a multimodal, multi-tissue paradigm where pain was assessed from skin (heat), muscle (pressure) and viscera (heat and electricity) before and 30, 60 and 90 minutes after induction of generalized hyperalgesia evoked by perfusion of acid and capsaicin in the oesophagus. Venous blood samples were obtained for quantification of oxycodone plasma concentrations before and 5, 10, 15, 30, 45, 60, 90 and 120 minutes after drug administration. RESULTS: Oxycodone blood concentrations could be described by a one-compartment model but, given the necessarily short timescale of the study, the concentrations were represented by linear interpolation for subsequent pharmacodynamic models. Time-dependent changes in the pain measures in the placebo arm of the study were represented by linear or quadratic functions. The time course of the pain measures in the oxycodone arm was taken to be the time course for the placebo arm plus a concentration-effect relationship that was either zero (no drug effect), linear or a maximum effect (E(max)) model. For three of the four pain measures, there was a time-dependent change after administration of placebo (e.g. due to the development of generalized hyperalgesia). CONCLUSION: There was a measurable effect of oxycodone, compared with placebo, on all pain measures, and a linear concentration-effect relationship without an effect delay was demonstrated. This could indicate an initial peripheral analgesic effect of oxycodone.

Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Previous studies using short-lasting experimental pain stimulations in healthy volunteers have shown differences in opioid effects regarding visceral pain stimulations. However, these differences can be more pronounced in patients due to a sensitized pain system. Therefore, the aim of the present study was to mimic the clinical situation by investigating opioid effects on experimental pain in healthy volunteers after experimentally evoked hyperalgesia. WHAT THIS STUDY ADDS? * We now know that morphine and oxycodone exerts different effects in the sensitized pain system as we found a greater analgesic effect of oxycodone in response to skin, muscle and oesophageal pain stimulation. This supports clinicians' experiences that oxycodone can be superior to morphine in the treatment of some pain conditions. The evoked hyperalgesia bridged findings from studies in healthy volunteers to patients, and new fundamental knowledge on different analgesic effects in hyperalgesia was found. AIM Similar analgesics may have different analgesic potencies especially in patients in whom the pain system is sensitized. The aim was to investigate different opioid effects on experimental pain after the sensitized pain system was mimicked evoking hyperalgesia in healthy volunteers. METHODS Twenty-four healthy volunteers were randomized to treatment with morphine (30 mg orally) and oxycodone (15 mg orally) or placebo in a double-blind crossover study. Hyperalgesia was induced by oesophageal perfusion with acid and capsaicin. Several exploratory endpoints were studied using skin heat, muscle pressure and oesophageal mechanical, heat and electrical stimulation. Effects on pain from deeper structures were considered most important. RESULTS Different analgesic potencies were found. Oxycodone had a greater analgesic effect than morphine attenuating pain from: (i) heat stimulation of skin (P= 0.016); difference between the means of 0.39 degrees C, 95% CI 0.22, 2.09. (ii) muscle pressure (P < 0.001); difference between the means of 11.93kPa, 95% CI 5.4, 18.5. (iii) oesophageal heat stimulation (P < 0.001); difference between the means of 38.54 cm(2), 95% CI 15.37, 61.71 and (iv) oesophageal electrical stimulation (P= 0.016); difference between the means of 6.69mA, 95% CI 1.23, 12.13. CONCLUSION After sensitization of the pain system different analgesic potencies of morphine and oxycodone were found in response to skin, muscle and oesophageal pain stimulation, in which oxycodone had a greater effect. As similar differential analgesic potencies of the two opioids have been found in patients with chronic pain, the experimental hyperalgesia model bridged findings from studies in healthy volunteers to patients.

Assessing efficacy of non-opioid analgesics in experimental pain models in healthy volunteers: an updated review.

AIM: Experimental pain models may help to evaluate the mechanisms of analgesics and target the clinical indications for their use. This review, the second in a series of two, addresses how the efficacy of non-opioid analgesics have been assessed in human volunteers using experimental pain models. METHODS: A literature search was completed for randomized controlled studies that included human experimental pain models, healthy volunteers and non-opioid analgesics. RESULTS: Nonsteroidal anti-inflammatory drugs worked against various types of acute pain as well as in hyperalgesia. Analgesia from paracetamol was difficult to detect in experimental pain and the pain needed to be assessed with very sensitive methods like evoked brain potentials. The N-methyl-D-aspartate antagonists exemplified by ketamine generally needed strong, long-lasting or repeated pain in the skin for detectable analgesia, whereas pain in muscle and viscera generally was more easily attenuated. Gabapentin worked well in several models, particularly those inducing hyperalgesia, whereas lamotrigine was weak in modulation of experimental pain. Imipramine attenuated pain in most experimental models, whereas amitriptyline had weaker effects. Delta-9-tetrahydrocannabinol attenuated pain in only a few models. CONCLUSIONS: Pain induction and assessment are very important for the sensitivity of the pain models. Generally, experimental pain models need to be designed with careful consideration of the pharmacological mechanisms and pharmacokinetics of analgesics. The drawback with the different study designs is also discussed. This knowledge can aid the decisions that need to be taken when designing experimental pain studies for compounds entering Phase I and II trials.

Assessing analgesic actions of opioids by experimental pain models in healthy volunteers - an updated review.

AIM: Experimental pain models may help to evaluate the mechanisms of action of analgesics and target the clinical indications for their use. This review addresses how the efficacy of opioids can be assessed in human volunteers using experimental pain models. The drawback with the different study designs is also discussed. METHOD: A literature search was completed for randomized controlled studies which included human experimental pain models, healthy volunteers and opioids. RESULTS: Opioids with a strong affinity for the micro-opioid receptor decreased the sensation in a variety of experimental pain modalities, but strong tonic pain was attenuated more than short lasting pain and non-painful sensations. The effects of opioids with weaker affinity for the micro-opioid receptor were detected by a more narrow range of pain models, and the assessment methods needed to be more sensitive. CONCLUSION: The way the pain is induced, assessed and summarized is very important for the sensitivity of the pain models. This review gives an overview of how different opioids perform in experimental pain models. Generally experimental pain models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. This knowledge can aid the decisions needed to be taken when designing experimental pain studies for compounds entering phase 1 clinical trials.

Analgesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human pain model: selective effect on visceral pain.

BACKGROUND: Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide kappa-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid). METHODS: The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order: (1) CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain detection and tolerance thresholds, (3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing. RESULTS: Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P < 0.001) and cuff pressure pain tolerance threshold (P < 0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P < 0.001) and thermal stimulation (P < 0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P < 0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007). CONCLUSION: CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.

Evoked human oesophageal hyperalgesia: a potential tool for analgesic evaluation?

Hypersensitivity is a common finding in visceral disorders. Therefore, in the development and testing of analgesics for the treatment of visceral pain, it is important to establish an experimental pain model of visceral hypersensitivity. Such a model will mimic the clinical situation to a higher degree than pain models where the receptors and peripheral afferents are briefly activated as with, for example, electrical, thermal, and mechanical stimulations. In this study, a model to evoke experimental hyperalgesia of the oesophagus with a combination of acid and capsaicin was introduced. The study was a randomised, double-blind, cross-over study. Fifteen healthy volunteers were included. Sensory assessments to mechanical, heat, and electrical stimulations were done in the distal oesophagus, before and after perfusion with a 200 ml solution of acid+capsaicin (180 ml HCL 0.1 M and 2 mg capsaicin in 20 ml solvent) or saline. Oesophageal pain assessment and referred pain areas were evaluated. There were reproducible pain assessments between repetitions within the same day and between days (all P > 0.05). Acid+capsaicin perfusion induced 56% reduction of the pain threshold to heat (P = 0.04), 19% reduction of the pain threshold to electrical stimuli (P < 0.001), 78% increase of the referred pain areas to mechanical stimulation (P < 0.001) and 52% increase of the referred pain areas to electrical stimulus (P = 0.045). All volunteers were sensitised to one or more modalities by acid+capsaicin. The model was able to evoke consistent hyperalgesia and may be useful in future pharmacological studies.

Applying concepts of generalizability theory on data from experimental pain studies to investigate reliability.

This work demonstrates how full modelling power in statistically mixed models can be used to study generalizability (reliability) coefficients of advanced data from human experimental pain studies utilizing placebo data from drug screening trials. This can be used to help optimizing outcome parameters from existing data sets.