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Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain

2011; Wiley; Volume: 33; Issue: 10 Linguagem: Inglês

10.1111/j.1365-2036.2011.04629.x

1365-2036

Anne Lund Krarup, Lars Ny, Magnus Åstrand, Antal Bajor, Frederik Hvid‐Jensen, Mark Berner Hansen, Magnus Simrén, Peter Funch–Jensen, Asbjørn Mohr Drewes,

Respiratory and Cough-Related Research

Alimentary Pharmacology & TherapeuticsVolume 33, Issue 10 p. 1113-1122 Free Access Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain A. L. Krarup, A. L. Krarup Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.Search for more papers by this authorL. Ny, L. Ny AstraZeneca R&D, Mölndal, Sweden.Search for more papers by this authorM. Åstrand, M. Åstrand AstraZeneca R&D, Mölndal, Sweden.Search for more papers by this authorA. Bajor, A. Bajor Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.Search for more papers by this authorF. Hvid-Jensen, F. Hvid-Jensen Department of Surgery L, Aarhus University Hospital, Aarhus, Denmark.Search for more papers by this authorM. B. Hansen, M. B. Hansen AstraZeneca R&D, Mölndal, Sweden.Search for more papers by this authorM. Simrén, M. Simrén Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.Search for more papers by this authorP. Funch-Jensen, P. Funch-Jensen Department of Surgery L, Aarhus University Hospital, Aarhus, Denmark.Search for more papers by this authorA. M. Drewes, A. M. Drewes Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.Search for more papers by this author A. L. Krarup, A. L. Krarup Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.Search for more papers by this authorL. Ny, L. Ny AstraZeneca R&D, Mölndal, Sweden.Search for more papers by this authorM. Åstrand, M. Åstrand AstraZeneca R&D, Mölndal, Sweden.Search for more papers by this authorA. Bajor, A. Bajor Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.Search for more papers by this authorF. Hvid-Jensen, F. Hvid-Jensen Department of Surgery L, Aarhus University Hospital, Aarhus, Denmark.Search for more papers by this authorM. B. Hansen, M. B. Hansen AstraZeneca R&D, Mölndal, Sweden.Search for more papers by this authorM. Simrén, M. Simrén Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.Search for more papers by this authorP. Funch-Jensen, P. Funch-Jensen Department of Surgery L, Aarhus University Hospital, Aarhus, Denmark.Search for more papers by this authorA. M. Drewes, A. M. Drewes Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.Search for more papers by this author First published: 16 March 2011 https://doi.org/10.1111/j.1365-2036.2011.04629.xCitations: 109 Professor A. M. Drewes, Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Mølleparkvej 4, DK-9000 Aalborg, Denmark.E-mail: amd@rn.dk AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Aliment Pharmacol Ther 2011; 33: 1113–1122 Summary Background Many patients with gastro-oesophageal reflux disease (GERD) are hypersensitive to heat and acid and may respond insufficiently to standard treatment. Antagonists of the heat and acid receptor ‘transient receptor potential vanilloid 1’(TRPV1) are a potential drug class for GERD treatment. Aim To investigate the effect of a TRPV1 antagonist (AZD1386) on experimentally induced oesophageal pain. Methods Twenty-two healthy men (20–31 years) participated in this randomised, placebo-controlled, double-blinded, crossover study examining the effects of a single-dose oral AZD1386 (30 and 95 mg). Subjects were block-randomised. On treatment days, participants were stimulated with painful heat, distension, electrical current and acid in the oesophagus. Heat and pressure pain on the forearm were somatic control stimuli. Data analysis: intention-to-treat. Results A total of 21 participants completed the protocol and 1 voluntarily discontinued. In the oesophagus, both 30 and 95 mg of AZD1386 increased pain thresholds to heat stimuli 23% [95% confidence interval (CI): 10–38%] and 28%, respectively (CI: 14–43%). The skin heat tolerance was increased 2.1 °C (CI: 1.1–3.2 °C) after 30 mg AZD1386 and 4.0 °C (CI: 3.0–5.0 °C) after 95 mg. Heat analgesia persisted for 2.5 h. Pain thresholds to the other stimuli were unaffected by AZD1386. 50% reported ‘feeling cold’ and body temperature increased in all subjects exposed to 30 and 95 mg AZD1386 (mean increase 0.4 ± 0.3 °C and 0.7 ± 0.3 °C, respectively, P < 0.05). Conclusions AZD1386 increased oesophageal and skin heat pain thresholds and had a safe adverse-event profile. This drug class may have a potential for treatment of GERD (ClinicalTrials.gov identifier: NCT00711048). Introduction The insufficient response to medical treatment with proton pump inhibitors (PPI) in approximately 25% of patients with gastro-oesophageal reflux disease (GERD) is a major challenge to the health system.1 Hence, new and better treatments are highly warranted. Many patients with GERD are hypersensitive to heat and acid.2-4 Therefore, an interesting target for drug research is the transient receptor potential vanilloid 1 (TRPV1) channel, responsive to e.g., noxious heat and acid.5, 6 Several TRPV1 antagonists are currently under investigation and have been effective in animal models of GERD, heat pain and inflammatory pain.7 However, in humans only two TRPV1 antagonists have been investigated in pain models of the skin and no data of analgesic efficacy on visceral pain are available.8, 9 A TRPV1 antagonist under development, AZD1386, has shown effect in attenuating human dental pain and is under evaluation for treatment of pain in GERD patients (Quiding et al. presentation PH 373, IASP 2010). However, when examining pain in patients, the analgesic effects are difficult to evaluate due to a number of factors including variable baseline pain assessment and psychosocial aspects of the illness.10 Hence, any change in these factors will invariably also confound the assessment of analgesics in clinical trials. To avoid these disease-related confounders, experimental pain models are often advantageous.10 Furthermore, experimental pain models in healthy volunteers can provide a link between results from animal studies and results from patients.10, 11 To further evaluate AZD1386, we chose to examine healthy volunteers in an experimental multimodal pain model (mechanical, heat and electrical stimuli) of the oesophagus. Furthermore, by perfusing the oesophagus with 0.1 N hydrochloric acid (pH = 1.0), a short lasting hyperalgesia is induced, mimicking the sensory findings in GERD patients.2, 4, 12, 13 This model has previously proved reliable in assessment of drug effects on oesophageal pain.14, 15 We hypothesised that AZD1386 would have an analgesic effect on oesophageal pain in both the normal and hyperalgesic state. Using the multimodal pain model in healthy male volunteers, the aims were to investigate whether treatment with AZD1386 compared with placebo: (i) had an analgesic effect on the response to oesophageal heat pain before and after acid-induced hyperalgesia and (ii) affected oesophageal pain to acid, distension and electrical current, before and after acid-induced hyperalgesia. Material and methods The study was conducted according to the Declaration of Helsinki and carried out in research laboratories at Aarhus University Hospital, Denmark and Sahlgrenska University Hospital, Sweden. The national medical agencies and local Ethical Committees approved the study protocol (ClinicalTrials.gov: NCT00711048; study code: D9127C00001) and Good Clinical Practice was followed. The design was a double-blind, randomised, crossover study comparing the effect of 30 and 95 mg AZD1386 vs. placebo. No medication potentially interfering with pain assessments was allowed for 24-h prior to experimental testing. Oral and written informed consents were obtained from all participants. Drug abuse screen and alcohol breath tests were performed at the screening visit and predose at each study visit. For safety reasons, subjects were required to fast for at least 4 h prior to the examination. Participants Healthy male volunteers aged 20–45 years were invited via newspaper advertisements and interviewed about symptoms and medical history. Inclusion criteria were male gender (Phase I trials are not allowed on fertile women in Sweden), weight 50–100 kg, and BMI 19–30 kg/m2. Furthermore, only subjects who could be sensitised with acid were included. To ensure this, a screening of oesophageal sensitisation potential was performed prior to randomisation, including multimodal pain measurements before and after an oesophageal acid perfusion (see below) –Figure 1. In this study, ‘sensitised after acid perfusion of the oesophagus’ was defined as at least a 20% reduction in oesophageal pain thresholds in two of three determinations (mechanical, thermal and electrical). Exclusion criteria included: gastrointestinal symptoms, previous long lasting pain, significant clinical illness, drug abuse, need of medication, smoking or excessive use of caffeine. Figure 1Open in figure viewerPowerPoint The stimulation protocol on visits with experimental pain tests. Multimodal stimulation consisted of mechanical, heat and electrical stimulation, until moderate pain was evoked. Somatic stimuli were heat and pressure at the forearm until the pain tolerance threshold was reached. Acid stimulation was terminated after 200 mL 0.1 N HCl was perfused or before if subjects reported moderate pain. Drug doses were 30 mg, 95 mg AZD1386 or placebo. Sensory assessment Before the experimental assessment, all subjects were instructed in the use of a 0–10 visual analogue scale. This scale has been shown to be reliable in discriminating sensations in the oesophagus.12, 16 On the visual analogue scale, 5 equals the pain detection threshold (PDT) and 7 the moderate pain threshold (MPT). The pain tolerance threshold (PTT) was used in somatic tests. Probe design The probe has been described in details previously. Briefly, a custom made oesophageal probe was fitted with a bag near the tip (Ditens A/S, Aalborg, Denmark).16 A hole for acid perfusion was situated 1 cm proximal to the bag and stainless steel electrodes for electrical stimuli were mounted 10 cm proximal to it. Protocol A treatment allocation list was generated by AstraZeneca R&D Mölndal, Sweden using a validated computer program. Twenty-two subjects fulfilling all inclusion criteria and none of the exclusion criteria was block-randomised to the study. The laboratory staff enrolled the participants and the hospital pharmacy assigned the patients using the randomisation list provided. On the next three visits, they received either an oral dose of 30 mg, 95 mg AZD1386 or matching placebo using a double dummy technique and the hospital pharmacy, investigators and participants were blinded to the treatment. Dose was determined by experience from a previous phase II study where 95 mg AZD1386 were the highest dose without significant adverse events and 30 mg a low, but still effective dose in relieving dental pain (data on file). Two doses were chosen to explore a dose-effect relationship. Visits were separated with a wash out period of at least 10 days –Figure 2. Figure 2Open in figure viewerPowerPoint Flow chart of study design. Treatment was a single oral dose of AZD1386 or matching placebo. R, randomisation. At each visit, a probe was inserted through the mouth and the centre of the bag was placed 8 cm above the oesophago-gastric junction. The validated multimodal oesophageal pain model was used for oesophageal stimulation and has proven reliable over visits.13, 17-19 Validated methods were also used for somatic stimuli of cutaneous and deep pressure pain.18 Figure 1 shows the stimulation protocol on each treatment visit. Multimodal stimulation consisted of distension, heat and electrical stimulation until the moderate pain threshold was perceived. The participants outlined the area of referred pain on transparent paper after each oesophageal stimulation type. The size of the referred pain area was later digitised (Trust, 1200 wireless tablet, Trust International BV, Dordrecht, The Netherlands). Somatic tests on the forearm consisted of cutaneous heat stimulations and of deep pressure pain stimulation to the PTT.18 Experimental stimulation of the oesophagus Stimulation using the multimodal oesophageal pain model has been described in detail previously and is only briefly explained here.16 Heat stimulation. The temperature in the bag was raised linearly at 0.2 °C/s while the volume in the bag was kept constant as described by Olesen et al.13 In the first eight subjects heat stimulation was terminated at the PDT. Thereafter, an advance in technical development offered the possibility to increase stimulation intensity to evoke the moderate pain threshold. Hence, a stimulus response curve for the heat pain response could be determined. Stimulation time until PDT (n = 22) and MPT (n = 14) was measured. Mechanical stimulation. Mechanical distension was performed by inflating the bag with water (37 °C) at a rate of 10 mL/min as described previously.19 The infused volume was measured when subjects reached the moderate pain threshold. Electrical stimulation. Stimulations were performed with the stimulation system previously described and the current evoking the moderate pain threshold was measured.19-21 Acid stimulation. About 0.1 N HCl, pH = 1.0 (Bie & Berntsen, Rødovre, Denmark) was administered at a rate of 7 mL/min until the subject perceived moderate pain or a maximum volume of 200 mL was reached.19‘Volume acid tolerated’ was measured. Experimental somatic stimulation Deep pressure stimulation. Pressure stimulation was performed on the lateral site of the extensor digitor muscle with a handheld algometer (Somedic AB, Hörby, Sweden) and the pressure was increased by 50 kPa/s. The pressure corresponding to the pain tolerance threshold was compared between groups.18 Cutaneous heat stimulation. Thermal stimulation was performed 10 cm proximal from the wrist on the right volar forearm three times, as previously described, and the average temperature evoking the pain tolerance threshold was compared between groups.18 Outcomes Primary outcome. Primary out included the effect of AZD1386 on oesophageal heat pain thresholds before and after acid-induced hyperalgesia of the oesophagus (1.5 h and 2.5 h after drug administration respectively) and the change in referred pain area to heat stimulation after the acid perfusion. Secondary outcome. (i) The effect of AZD1386 on oesophageal sensation to acid, mechanical distension and electrical stimulation before and after acid-induced hyperalgesia (1.5 h and 2.5 h after drug administration respectively) and (ii) the effect on the referred pain areas to distension and current after the acid perfusion were the secondary outcomes. Safety and tolerability assessments Adverse events were recorded and the severity rated during each treatment period (i.e. during the first 24 h after dose) and during the washout/follow-up periods. Physical examination, measurements of vital signs, 12-lead electrocardiography and assessment of laboratory parameters were performed at regular intervals during the study. During each treatment visit subjects were continuously monitored for safety reasons for 8 h after dose administration using telemetry and body temperature measurements (1, 2, 3, 4, 6 and 8 h after dosing). Pharmacokinetic assessments AZD1386 concentrations were measured in blood samples at 20, 40, 60, 80, 100 min and 2, 2.5, 3, 4.25, 5, 6, 8 and 24 h after dosing. Plasma concentrations were determined by reversed-phase liquid chromatography and liquid chromatography in combination with mass spectrometry detection after protein precipitation. Sample size calculation Based on an expected within subject standard deviation of the difference in logged time to VAS 5 after thermal stimuli of 0.08 and an increase 7% in time to VAS = 5 (AZD1386/Placebo), a sample size of 17 subjects was required to have 90% power when using a paired t-test at 5% significance level. Data analysis Logarithmic transformation was used for analysis of absolute pain thresholds and presented as arithmetic means ± standard deviations (s.d.). The ratios of pain thresholds during treatment with AZD1386/placebo are given with 95% confidence intervals. Pain threshold decreases after acid-induced hyperalgesia were compared between active and placebo treatment. The differences in these pain threshold decreases were presented as geometric means from the anova analysis with 95% confidence intervals. The levels of the stimulus intensity at the MPT or PDT were analysed using an anova model with predose measurement, centre, study period, treatment sequence and interaction between treatment and measurement (I and II) as fixed factors and subject as random factor. All results are presented unadjusted for multiplicity. The statistical software R (http://www.r-project.org) was used. Results Figure 3 shows the flow of subjects through the study. The first subject was enrolled June 2008 and the last follow-up visit was completed July 2009. The age of the 22 healthy men ranged from 20 to 31 years. Figure 3Open in figure viewerPowerPoint Flow chart of enrolment and randomisation. Other reasons for discontinuing were: four not meeting the inclusion criteria, six could not comply with study procedure and one discontinued due to technical errors. None of the randomised subjects was lost to follow-up. Pharmacokinetics Plasma levels of AZD1386 were characterised by rapid absorption and decline in concentration. The mean maximum plasma concentration of AZD1386 for 30 mg was 838 ± 466 nmol/L and for 95 mg 1943 ± 630 nmol/L, and was reached after a median of 46 min (20–100) and 68 min (40–150) respectively. The mean area under the plasma curve was for 30 mg 4197 ± 2062 h*nmol/L and for 95 mg 11 004 ± 4410 h*nmol/L. The mean half-life (T½) was 5.6 h for the 30 mg dose and 5.5 for the 95 mg dose. Primary outcome – oesophageal sensitivity to heat As shown in Figure 4 both 30 mg and 95 mg AZD1386 had an analgesic effect on the oesophageal heat pain detection threshold (n = 22, P < 0.01 and n = 22, P < 0.01 respectively) –Table 1. At moderate pain the effect of 30 mg was significant, whereas the effect of 95 mg was borderline significant (n = 22, P < 0.01, and n = 14, P = 0.08 respectively) –Table 1. Figure 4Open in figure viewerPowerPoint The effect of AZD1386 and placebo on the heat pain detection threshold (PDT) in the oesophagus. Both 30 and 95 mg of AZD1386 induced oesophageal heat analgesia with the effect lasting 2.5 h. Treatment with AZD1386 did not prevent acid-induced hyperalgesia. Arithmetic mean values are presented with S.E.M. error bars. *P < 0.05 compared with placebo. Table 1. Treatment with AZD1386 induced analgesia to heat in the oesophagus but not to mechanical distension or electrical current 1.5 h after drug administration Absolute thresholds and relative thresholds compared with placebo Mechanical MPT, n = 22 (mL) Heat MPT, n = 14 (s) Heat PDT, n = 22 (s) Electrical MPT, n = 22 (mA) Placebo 24.8 ± 11 121 ± 24 98 ± 26 14.5 ± 7.3 30 mg AZD1386 23.2 ± 10 136 ± 31* 118 ± 35* 14.2 ± 7.7 30 mg/placebo (95% CI) 0.97 (0.86–1.09) 1.20 (1.04–1.38)* 1.23 (1.10–1.38)* 0.97 (0.86–1.09) 95 mg AZD1386 22.7 ± 9 141 ± 33 127 ± 31* 15.8 ± 10.2 95 mg/placebo (95% CI) 0.95 (0.84–1.07) 1.13 (0.98–1.30) 1.28 (1.14–1.43)* 1.00 (0.89–1.11) CI, confidence interval; PDT, pain detection threshold; MPT, moderate pain threshold. Arithmetic mean ± s.d. are given and the ratios of AZD1386/placebo are presented with 95% confidence intervals. *P < 0.05 compared with placebo. The acid perfusion resulted in a significant pain detection threshold decrease to heat (acid-induced hyperalgesia) 2.5 h after drug administration and this decrease was comparable for treatment with placebo and AZD1386 –Table 2. Thus acid induced hyperalgesia was not prevented by the drug, but due to a prolonged analgesic effect, the heat pain thresholds were still higher in the 30 and 95 mg groups after acid compared with placebo [n = 22, 30 mg: 15% higher (91 ± 32 s to 103 ± 40 s, P = 0.02) and 95 mg: 28% higher (91 ± 32 s to 114 ± 31 s, P < 0.01)] –Figure 4. No effect of the treatment was seen in the referred pain areas after acid perfusion (n = 14 all P > 0.05). Table 2. AZD1386 had no effect on the decrease in oesophageal pain thresholds due to the acid-induced hyperalgesia 2.5 h after drug administration. Furthermore, no effect was measured on the change in referred pain area Absolute changes in pain thresholds after acid Mechanical MPT, n = 22 (mL) Heat MPT, n = 14 (mL) Heat PDT, n = 22 (s) Electrical MPT, n = 22 (mA) Placebo −2.2 ± 5.5 −15 ± 16* −7.5 ± 16* −0.8 ± 3.8 30 mg AZD1386 −3.9 ± 4.4 −10 ± 24 −18 ± 19 0.2 ± 4.2 Placebo – 30 mg (95% CI) −1.6 (−9.1–5.8) 4.8 (−16.0–25.5) −8.9 (−26.1–8.3) 1.9 (−4.7–8.5) 95 mg AZD1386 −3.7 ± 3.6 −12 ± 29 −13 ± 23 −0.3 ± 2.3 Placebo – 95 mg (95% CI) −1.5 (−9.0–6.1) 2.8 (−17.7–23.6) −4.5 (−21.6–12.5) 0.7 (−5.8–7.1) PDT, pain detection threshold; MPT, moderate pain threshold; CI, confidence interval. Data are given as change in mean pain thresholds after the acid perfusion ± s.d., and the differences in mean threshold changes after acid-induced hyperalgeisa between treatment and placebo groups are presented with 95% confidence intervals. *P < 0.05 compared with before the acid perfusion (1.5 h after placebo administration). Secondary outcome – oesophageal sensitivity to acid, mechanical and electrical stimulation AZD1386 had no effect on the tolerated volume of acid (mean acid volume tolerated; placebo: 150 ± 46 mL, 30 mg: 150 ± 50 mL and 95 mg: 156 ± 53 mL, P values all >0.05). One subject had very large variation in tolerated acid volume (placebo visit; 150 mL, 30 mg visit; 120 mL and 95 mg visit; 60 mL) and in an ad hoc analysis, data from this subject were removed. After removal, the variation in tolerated acid of the remaining subjects was similar between visits and there was a borderline significant effect of 95 mg AZD1386 with a 7% increase in tolerated acid volume (P = 0.09). Acid induced hyperalgesia to mechanical induced pain during the placebo treatment (volume inducing moderate pain, n = 22: 24.8 ± 10.7 mL decreased to 22.6 ± 12.0 mL, P = 0.03), but not to electrical pain (current inducing moderate pain, n = 22: 14.5 ± 7.3 mA decreased to 13.7 ± 6.6 mA, P = 0.4). AZD1386 had no effect on pain thresholds to mechanical and electrical stimulation, before or after the acid perfusion –Tables 1 and 2. Furthermore, no effect was seen on referred pain areas after these stimuli (P-values all >0.05). Somatic control stimulations AZD1386 had an analgesic effect on cutaneous heat pain but showed no effect on deep pressure pain –Table 3. Table 3. AZD1386 had an analgesic effect on cutaneous heat pain but no effect on muscle pain Somatic stimulation on the forearm Placebo 30 mg AZD1386 95 mg AZD1386 Cutaneous temp at PTT (°C) Preacid, n = 14 45.0 ± 1.4 48.3 ± 2.0 49.8 ± 3.0 AZD1386-placebo 3.4 (2.4–4.5)* 4.7 (3.7–5.8)* Postacid, n = 14 45.0 ± 1.5 47.0 ± 2.4 48.7 ± 3.0 AZD1386-placebo 2.1 (1.1–3.2)* 4.0 (3.0–5.0)* Pressure on forearm at PTT (kPa) Preacid 695 ± 241 627 ± 212 670 ± 195 AZD1386-placebo −47 (−143–49) −11 (−107–83) Postacid 658 ± 245 631 ± 204 627 ± 197 AZD1386-placebo −7 (−103–90) −17 (−113–77) PTT, pain tolerance threshold; CI, confidence interval. Data are given as arithmetic means ± s.d. and the differences in mean threshold change after acid-induced hyperalgeisa between treatment and placebo groups are presented with 95% confidence intervals. *P < 0.05 compared with placebo. Safety and tolerability The number of subjects reporting adverse events during treatment visits was 17, 14 and 5 for the treatments with 95 mg, 30 mg and placebo respectively. No patient discontinued the study early because of an adverse event and no serious adverse events were observed. The most commonly reported adverse event during active treatment was ‘feeling cold’– this was observed in 11 subjects for both doses of AZD1386 and none during placebo treatment. The intensity of ‘feeling cold’ was rated by all subjects as ‘mild’. No relation between temperature and clinical symptoms, such as ‘feeling cold’ was found. AZD1386 increased body temperature in all subjects by a mean increase of 0.4 ± 0.3 °C following the 30 mg dose, and by 0.7 ± 0.3 °C following the 95 mg dose. Maximum temperature observed was 37.9 °C and temperature was normalised within 24 h. A decrease in QTcF was observed following administration of AZD1386 with a maximum QTcF shortening of 20 ms from a predose value of 375 ms, 1 h after 95 mg AZD1386. No clinically significant changes in laboratory haematology or clinical chemistry values were observed during the study. Other adverse effects showed similar incidence during placebo and active treatment. Discussion In this double blind, placebo-controlled, crossover study the effect of the new TRPV1 antagonist, AZD1386 was studied in a human experimental pain model. Treatment with the TRPV1 antagonist AZD1386 demonstrated (i) an oesophageal heat specific analgesic effect lasting 2.5 h, (ii) no prevention of acid-induced hyperalgesia in the oesophagus, (iii) no effect on oesophageal pain following stimulation with acid, distension, or electrical current, (iv) a heat specific analgesic effect in response to skin pain and (v) an acceptable safety and tolerability profile. Methodological aspects Model. This is the first study to test a TRPV1 antagonist in an experimental visceral pain model in man. The choice of the multimodal oesophageal pain model enabled examination of the differentiated effects of AZD1386 on different types of oesophageal pain.13, 17, 18 During placebo treatment in this study, results after the acid perfusion resembled the heat hyperalgesia observed in patients with erosive and non-erosive reflux disease.2, 4 Thus, this pain model bridges results from healthy volunteers to clinical pain which is desirable from an ethical, scientific and medical point of view.10-12 However, findings using short lasting experimental stimuli as in this study cannot be translated directly to the clinical situation. Therefore, results from the current study require to be validated in GERD patients. In this study at the placebo visit, only three subjects fulfilled the inclusion criteria used at the screening visit regarding sensitisation. These criteria were a 20% reduction in oesophageal pain thresholds in two of three determinations (mechanical, thermal and electrical). Despite this, the acid perfusion still caused a significant heat hyperalgesia, although less pronounced. Protocol. We included only subjects in whom sensitisation with acid resulted in pain threshold decreases of a certain magnitude. Only roughly half of the screened subjects fulfilled these criteria and it can be argued that this compromised the external validity. However, we have previously shown that this sensitised state of the oesophageal sensory system mimics the abnormalities developed in GERD.2, 4, 22 Thus, the selection in this study may be beneficial when the effect of a possible new GERD treatment is evaluated. The dose chosen seemed appropriate as the plasma concentrations measured were in the range measured in previous studies of AZD1386, where analgesia was demonstrated on pain following tooth extraction. Primary outcome AZD1386 induced analgesia to heat pain in the oesophagus, as expected, since TRPV1 is activated by noxious heat.23, 24 The lack of effect on pain thresholds to electrical stimulation supports the assumption that AZD1386 had a receptor-specific and not a generalised analgesic effect in the oesophagus. This was further substantiated by an analgesic effect only in somatic cutaneous heat pain, but not deep pressure pain. The TRPV1 antagonist SB-705498 has shown a comparable effect in a human cutaneous model of heat pain.8 A dose response relationship was indicated at the PDT, as the 95 mg increased the heat PDT more than the 30 mg dose. At moderate pain, however, the effect was only borderline significant for the 95 mg dose, most probably reflecting a type II error, as only 14 of 22 subjects were stimulated to moderate pain. It has been shown in animal studies that the TRPV1 receptor is important to heat sensation in the inflammatory state.25-27 Regarding acid sensation, some classes of TRPV1 antagonists can attenuat