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Anesthesiology 2009; 111:616–24 Copyright © 2009, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Efficacy of Peripheral ␬- CR665 Compared to in a Multi-modal, Multi-tissue Experimental Pain Model Selective Effect on Visceral Pain Lars Arendt-Nielsen, Ph.D.,* Anne E. Olesen, M.Sc.Pharm.,† Camilla Staahl, Ph.D.,‡ Fre´de´ rique Menzaghi, Ph.D.,§ Sherron Kell, M.D., M.P.H.,͉͉ Gilbert Y. Wong, M.D.,͉͉ Asbjørn M. Drewes, Ph.D.# Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/3/616/247622/0000542-200909000-00031.pdf by guest on 30 September 2021 Background: Peripherally selective may be beneficial often used in the treatment of deep pain. However, in visceral pain management due to absence of centrally medi- inadequate analgesia, excessive adverse effects, or both ated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide ␬-opioid re- often limit the usage of opioids. Adverse effects like ceptor agonist, CR665, on experimental pain from multi-modal , sedation, respiratory , and nausea stimulation of skin, muscle, and viscera, and (2) contrast these are mainly mediated by ␮-receptors in the central ner- effects with those of oxycodone (centrally acting opioid). vous system, and this knowledge has stimulated new Methods: The study was designed as a single-center, single- approaches to improve opioid analgesia. In particular, dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Sub- there has been a focus on opioids with selective periph- jects received the following treatments in randomized order: (1) eral actions, as well as activity at receptor subtypes other CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxy- than the classic ␮-.2,3 For example, pe- codone (15 mg) administered orally, and (3) placebo administered ripherally restricted ␬- produced a substantial, intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain de- dose-dependent attenuation of visceral nociception, tection and tolerance thresholds, (3) cuff pressure pain tolerance whereas ␮- and ␦-opioid agonists were found to produce threshold, and (4) pain rating thresholds to distension and ther- only modest analgesia to colorectal distension.4,5 Periph- mal stimulation of the esophagus. Measurements were performed eral ␬-opioid receptors in the gut have been suggested as before dosing and at 30, 60, and 90 min after dosing. an important feature of the visceral pain system6 and a Results: Compared to placebo, oxycodone elevated cutane- 3,7 ous pinch pain tolerance (P < 0.001) and cuff pressure pain possible target for attenuating peripheral nociception. tolerance threshold (P < 0.001), as well as pain rating thresh- In addition, because of the absence of respiratory de- to esophageal distension (P < pression, constipation, and abuse liability, peripherally (7 ؍ olds (visual analogue scale 0.001) and thermal stimulation (P < 0.002). Compared to pla- selective ␬-opioid agonists should be safer and better cebo, CR665 significantly increased the pain rating threshold to ␮ 3,6 esophageal distension (P < 0.005) but reduced the pain toler- tolerated than classic -opioid agonists. The analgesic effects of novel compounds can be difficult .(0.007 ؍ ance threshold to skin pinching (P Conclusion: CR665 had a selective effect on visceral pain. to evaluate in patients due to a number of well-known and Oxycodone exhibited a generalized effect, elevating thresholds frequently encountered illness-related or iatrogenic con- for cutaneous, deep somatic, and visceral pain stimulation. founding factors. Human experimental pain models can therefore be advantageous in evaluation of analgesic ac- DEEP pain from muscle or viscera occurs frequently and tions in proof-of-concept studies in healthy volunteers.8 1 causes major challenges in pain management. Most external factors can be controlled, and the pain prov- and other centrally acting ␮-receptor opioid agonists are ocation can be standardized (including the modality, local- ization, intensity, frequency, and duration). The use of * Professor, Center for Sensory-Motor Interaction, Department of Health Science multi-modal, multi-tissue human pain testing may act as a and Technology, Aalborg University, Denmark; † Research Assistant, ‡ Assistant Professor, # Professor, Center for Sensory-Motor Interaction, Department of Health proxy for some of the mechanisms involved in clinical pain Science and Technology, Aalborg University, Denmark, and Department of Gastro- conditions.8,9 We recently, we used this approach to com- enterology, Aalborg Hospital, Denmark; § Vice President of Research Development, Cara Therapeutics Inc., Shelton, Connecticut; ͉͉ Impax Pharmaceuticals, Hayward, pare the efficacy profiles of oxycodone and morphine, and California, and ALZA Corporation, Mountain View, California. we found that oxycodone exhibited a superior, cross-mo- Received from Center for Sensory-Motor Interaction, Department of Health dality effect on visceral pain,10 consistent with the view Science and Technology, Aalborg University, Denmark. Submitted for publica- tion January 14, 2009. Accepted for publication March 17, 2009. Supported with that oxycodone may act through an additional population an unrestricted grant by Johnson and Johnson, Mountain View, California, by Det of opioid receptors (e.g., ␬-opioid, in addition to ␮-opioid Obelske Familie Fond, Aalborg, Denmark, and by the Spar Nord Foundation, 11 Aalborg, Denmark. receptors ). Address correspondence to Dr. Arendt-Nielsen: Center for Sensory-Motor The experimental compound under evaluation in the Interaction (SMI), Department of Health Science and Technology, Aalborg Uni- present study, CR665, is a tetrapeptide agonist at the ␬-opi- versity, Fredrik Bajers Vej 7, D3, DK-9220 Aalborg E, Denmark. [email protected]. Information on purchasing reprints may be found at www.anesthesiology.org or oid receptor, substantially excluded by the blood- bar- on the masthead page at the beginning of this issue. ANESTHESIOLOGY’s articles are rier, with essentially no activity at other opioid receptor made freely accessible to all readers, for personal use only, 6 months from the 12,13 cover date of the issue. subtypes. CR665 has been shown to relieve pain in a

Anesthesiology, V 111, No 3, Sep 2009 616 ␬ AGONIST AND EXPERIMENTAL VISCERAL PAIN 617 variety of rodent models, including jejunal distension-in- the first dose of study medication, the subject received a duced visceral pain.12,13 On the basis of this pharmacolog- concealed randomization assignment. ical profile, as well as other preclinical studies,3,6 it is Inclusion. The following inclusion criteria were ap- believed that CR665 could inhibit visceral pain in . plied: (1) semirecumbent blood pressure (after resting The aims of this proof-of-concept human experimental for 5 min) between the ranges of 90–139 mmHg systolic multi-modal, multi-tissue, placebo-controlled pain study (inclusive) and 50–89 mmHg diastolic (inclusive); (2) were: (1) to investigate, for the first time in man, partners must consent to use a medically acceptable whether CR665 had differential analgesic effects in tis- method of contraception throughout the entire study sues associated with somatic or visceral pain, (2) to period; (3) no known allergies to any of the compounds determine whether the actions of the drugs could be used in the study.

differentiated within tissues, according to the pain mo- Exclusion. The following exclusion criteria were ap- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/3/616/247622/0000542-200909000-00031.pdf by guest on 30 September 2021 dality, and (3) to compare these effects to oxycodone. plied: (1) any evidence of clinically significant hepatic, reproductive, gastrointestinal, renal, hematologic, pulmo- nary, neurologic, respiratory, endocrine, or cardiovascular Materials and Methods system abnormalities, psychiatric disorders, or acute infec- Subjects and Study Design tion; (2) any esophageal disease or disorders; (3) any ab- Eighteen healthy, nonsmoking, opioid-naı¨ve, white normality on the screening electrocardiogram; (4) con- male volunteers (age 19–43 yr, median age 25 yr, weight firmed screening of QTc ( rate-corrected QT interval 62.4–94.5 kg, median weight 80.0 kg, body mass index [Q and T peaks of the electrocardiogram]) greater than 450 20.5–27.4 kg/m2, median body mass index 23.6 kg/m2) ms or a history of additional risk factors for torsades de were recruited to participate in this single-center, single- pointes (e.g., heart failure, hypokalemia, family history of dose, randomized, double-blind, placebo- and active-con- long QT syndrome) or the use of concomitant medications trolled, double-dummy, three-way, crossover study. The that prolong the QT/QTc interval (Q and T peaks of the randomization ensured that six subjects had oxycodone, electrocardiogram/heart rate-corrected QT interval); (5) six had CR665, and six had placebo in each of the three resting heart rate at screening of less than 45 or greater study periods. This ensured a balanced design, and none than 85 beats per minute; (6) greater than 20-mmHg sys- of the persons involved in performing the study was tolic or greater than 10-mmHg diastolic drop in blood involved in the randomization. All subjects were in- pressure or greater than 30-beats per minute increase in formed about the risks of the study, gave their written heart rate within 3 min of standing or symptoms of light- informed consent before participating, and were paid for headedness or dizziness or fainting upon standing; (7) he- participating. Volunteers entering the study were in moglobin less than 12.5 g/dl (7.8 mmol/l) or donated blood good health and had no residual pain complaints from or plasma or blood loss of more than 400 ml within 4 any previous illness. The study was conducted in accor- weeks before dosing; (8) use or planned use of medication dance with the Declaration of Helsinki on biomedical during participation in the study. research involving human subjects. The study protocol was approved by the Regional Committee on Biomedical Medication Research Ethics, Aalborg, Denmark (registration no.VN- Equal numbers of subjects were randomly assigned to 20060021) and by the Danish Medicine Agency, Copen- one of three treatment sequences (ABC, BCA, or CAB), hagen, Denmark (reference number 2612-3145). and all subjects received the following three treatments. Treatment A: CR665 intravenous solution, 10 mg/ml, Screening, Inclusion, and Exclusion. Preadmission 1.1-ml vial, total dose of 0.36 mg/kg administered as an medical and concomitant medication history, physical intravenous infusion over1hatarate of 25 ml/h, and an examination including vital signs (orthostatic blood pres- oral placebo solution consisting of a colored, flavored sure and heart rate measurements taken after the subject beverage. This dose is selected on the basis of a safety had been semirecumbent for 5 min and then after the phase I trial. subject had been standing for 3 min, respiratory rate, Treatment B: Oxycodone, 15 mg oral liquid solution and body temperature), height, weight and body mass mixed with the colored, flavored beverage used for the index, 12-lead electrocardiogram, clinical laboratory oral placebo solution in Treatment A and a 1-h intrave- tests (hematology, chemistry, and urinalysis) and urine nous infusion of vehicle placebo solution. drug screening tests were performed. Treatment C: 1-h intravenous infusion of vehicle pla- Subjects meeting the preadmission criteria were then cebo solution and oral placebo solution as used in Treat- scheduled for a visit during which the different pain tests ments A and B. were administered to ensure that each subject could Subjects were admitted to the unit on the morning of tolerate the tests. Subjects underwent a urine drug dosing, and the multi-modal esophageal tube was placed screen and a test for at check-in before each before dosing. Subjects remained in a semirecumbent po- treatment period. Immediately before administration of sition for the first 12 h after the beginning of dosing. After

Anesthesiology, V 111, No 3, Sep 2009 618 ARENDT-NIELSEN ET AL. the 12-h period, subjects were allowed to sit up, stand, or (Somedic). A probe with a surface area of 0.28 cm2 was walk with assistance only if their sustained standing heart pressed onto the supinator muscle on the left forearm at rate was less than 100 beats per minute. The next morning, 10 cm distal to the elbow. The pressure was increased at 24 h after dosing initiation, the subject was released from a rate of 30 kPa/s until the pain detection or the pain the clinic if no symptoms were observed. Each treatment tolerance thresholds were reached. was followed by a 1- to 3-week washout period. The electronic cuff algometer (Aalborg University, Aal- To preclude possible physiologic effects from aquaretic borg, Denmark14,15) consisted of a pneumatic tourniquet activity, a known pharmacological effect of peripherally cuff, a computer-controlled air compressor, and an elec- selective as well as centrally acting ␬-opioid agonists, sub- tronic 10-cm visual analogue scale (VAS). The 0 and 10 jects were required to consume at least 1,500 ml of water cm extremes on the VAS were defined, respectively, as Ϫ Ϫ Ϫ Ϫ from 24 to 3 h, and at least 500 ml from 3to 2h no pain and as the worst pain imaginable. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/3/616/247622/0000542-200909000-00031.pdf by guest on 30 September 2021 before dosing. After dose initiation, subjects were required The compressor (Condor MDR2; JUN-AIR International to consume at least 250 ml of water at 1.5 h, and subjects A/S, Nørresundby, Denmark) was connected to an elec- received intravenous fluids (saline) for 1.5 to4hasneeded tric-pneumatic converter (ITV2030; SMC Corp., Tokyo, to fully replace urine loss. Japan) and controlled by a computer through a data acquisition card (PCI 6024E; National Instruments, Aus- Monitoring tin, TX). The subjects could immediately terminate com- During each treatment period, the following safety pression by means of a hand-held pressure release but- measurements were obtained: ton connected to the data acquisition card. The pain (1) Vital signs (semirecumbent and standing blood intensity was recorded continuously on the VAS and pressure and heart rate, respiratory rate, and body tem- sampled at 100-ms intervals. The computer continuously perature) were obtained at the screening visit and then controlled the compression rate to ensure a linear in- during the treatment period, as follows: predose, 30 min, crease in pressure. The pneumatic tourniquet cuff was and 1, 1.5, 2, 3, 4, 8, 12, 16, and 24 h (termination) after wrapped tightly around the gastrocnemius muscle. dose initiation. The cuff was automatically inflated (compression rate (2) Blood and urine laboratory evaluations, fluid bal- 0.50 kPa/s). The subject was instructed to rate the pain ance monitoring, and cardiac evaluation were obtained intensity continuously on the VAS from the first sensation before and throughout the treatment period. of pain, and the pressure continued to increase until the (3) Adverse events were recorded throughout the subject pressed the pressure release button again when the study. maximum pain tolerance threshold was reached. (4) Before treatments and at the end of the study, the following assessments were performed: physical exam, Viscera (Esophagus) including vital signs (semirecumbent and standing blood The multi-modal esophageal probe16 was inserted pressure, heart rate, respiratory rate, body temperature), through the mouth and passed into the stomach. The height (screening only), weight and body mass index probe was gradually retracted to identify the location of the (screening only); 12-lead electrocardiogram; clinical lab- lower esophageal sphincter as a zone of high resting pres- oratory tests (hematology, chemistry, urine analysis); sure that decreases with swallowing. The bag was placed 7 urine drug screen and alcohol test. cm proximal to the sphincter, and the probe was taped to the subject’s cheek. Subjects remained in a semirecumbent Pain Assessment position with the head tilted back 30 degrees. The different pain assessment parameters from skin, mus- The probe was 0.5 cm in diameter with a polyurethane cle, and visceral stimulation were measured before treat- bag attached to the distal end for mechanical and ther- ment and at 30, 60, and 90 min after drug administration. mal stimuli. The bag was 40 mm in length and could be inflated with fluid and then maintained at a constant Skin volume through a pair of infusion channels. The infusion The cutaneous pinching pain tolerance threshold was channels were connected to a precision infusion-with- determined by pinching a skin fold on the volar forearm drawal pump (type 111; Ole Dich Instrument Makers, at 20 cm distal from the elbow with an electronic pres- Hvidovre, Denmark) that was used to fill the bag at a sure algometer (Somedic AB, Ho¨rby, Sweden). The two volume rate of 10 ml/min. The bag completely enclosed probes each had a surface area of 0.28 cm2. The pressure a side hole, which was used for measurement of pres- was continuously increased at a rate of 30 kPa/s until the sure within the bag. A temperature probe (PR Electron- threshold was reached. ics, Rønde, Denmark) was used to continuously monitor the fluid temperature in the bag. Muscle For all visceral stimuli, a single 10-point electronic VAS The pressure pain detection and tolerance thresholds was used to assess nonpainful (VAS Ͻ 5) as well as were determined by an electronic pressure algometer painful sensations (VAS Ն 5) in response to the experi-

Anesthesiology, V 111, No 3, Sep 2009 ␬ AGONIST AND EXPERIMENTAL VISCERAL PAIN 619 mental visceral stimuli.17 The subjects rated the intensi- CR655, 3 of 18 for oxycodone, and 4 of 18 for placebo. ties of the nonpainful visceral sensations from 1–4. A The mean volume of urine collected during the entire rating of 5 was defined as the pain threshold. Thus, with session was 4,187 ml for CR655, 3,463 ml for oxyc- increasing stimulus intensity, the subjects rated the pain- odone, and 3,546 ml for placebo. No differences were ful visceral sensations from 5–10, where 7 was rated as found among groups (P Ͻ 0.148). moderate pain. For mechanical stimulation, the esophageal balloon Skin Stimulation was filled with 37°C water at a constant infusion rate of The average baseline pinching pain tolerance thresh- Ϯ 10 ml/min until the subjects reached the pain threshold old was 900 319 kPa. There was a significant differ- ϭ Ͻ (VAS ϭ 5) and moderate visceral pain intensity (VAS ϭ ence in the effect of drugs (F 26.3, P 0.001) (fig. 1). Further post hoc analysis showed that oxycodone in-

7) ratings. The total volumes (ml) required to reach these Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/3/616/247622/0000542-200909000-00031.pdf by guest on 30 September 2021 ratings were recorded. creased pinching pain tolerance threshold in compari- Ͻ The heat pain stimulus was generated by recirculating son with placebo and CR665 (P 0.001). CR665 de- temperature-controlled water (55°C) in the esophageal creased pinching pain tolerance threshold compared to ϭ Ͻ probe,16 and the volume of fluid in the bag was held placebo (P 0.007) and oxycodone (P 0.001). constant. Before recirculation, the bag was filled with a Muscle Stimulation volume of water corresponding to a mechanical VAS ϭ 3 The average baseline pressure pain detection and pres- rating (prepain) to ensure reliable mucosal contact. The sure pain tolerance thresholds were 475 Ϯ 182 kPa and perfusate temperature was increased gradually until a con- 716 Ϯ 330 kPa, respectively. No significant difference in stant temperature of 55°C was obtained. This temperature the effect of drug was found (F ϭ 0.154, P ϭ 0.858) was maintained for 90 s or until the pain detection thresh- and neither oxycodone nor CR665 was different from old (VAS ϭ 5) was reached. As a measure of the total placebo. thermal energy delivered to the tissue, the stimulus inten- The average cuff pressure-pain tolerance thresholds sity was calculated as the area under the curve (tempera- were 48.68 Ϯ 13.05 kPa. There was a significant differ- ture [°C] ϫ time [s]) from start to end of the stimulation.16 ence in the effect of drugs (F ϭ 12.3, P Ͻ 0.001). Further post hoc analysis showed that compared to placebo and Statistical Analysis CR665, oxycodone significantly increased the cuff pres- To correct for individual differences in baseline pain sure-pain tolerance thresholds (P Ͻ 0.001) (fig. 2). recordings, the change in stimulus intensity relative to baseline was calculated for each measure for each subject. Visceral Stimulation The results are expressed as mean Ϯ SD unless otherwise Repeated visceral stimuli are known also from previ- indicated. For overall statistical assessment of baseline-cor- ous studies10 to cause a reduction in threshold over time. rected stimulus intensities associated with the sensation The averaged baseline pain detection threshold (VAS ϭ and pain thresholds under investigation, two-way analysis 5) and a moderate pain threshold (VAS ϭ 7) to disten- of variance was used with the factors of drug and time. sion were 17.7 Ϯ 8.1 ml and 24.0 Ϯ 11.2 ml, respec- Tukey test was used for post hoc analysis. The difference in tively. For the VAS ϭ 5 threshold there was a significant urine level was analyzed by one-way analysis of variance difference in the effect of drugs (F ϭ 6.18, P ϭ 0.003). with drug as a factor. P Ͻ 0.05 was considered significant. Further post hoc analysis showed that oxycodone was The software package Sigma Stat 3.0 (Systat Software, Inc., better than placebo (P Ͻ 0.001). For the VAS ϭ 7 Point Richmond, CA) was used. threshold, there was a significant difference in the effect of drugs (F ϭ 9.15, P Ͻ 0.001). Further post hoc analysis showed that oxycodone was better than placebo (P Ͻ Results 0.001) and that CR665 was better than placebo (P ϭ 0.005) (fig. 3). All included 18 volunteers completed the study. Table The average baseline thermal energy (temperature 1 summarizes all adverse events, which were all mild in °C ϫ time [s]) was 205.8 Ϯ 141.3°C/s. There was a severity with the exception of one episode of moderate significant difference in the effect of drugs (F ϭ 7.96, increased heart rate in the CR655 treatment period. The P Ͻ 0.001). Further post hoc analysis showed that oxy- was characterized as mild, intermittent, and codone significantly increased the threshold compared to only possibly related to the study medication. No serious placebo and CR665 (P ϭ 0.002 and P Ͻ 0.001, respec- adverse events were reported. One subject used a con- tively). CR665 was not different from placebo (fig. 4). comitant medication (Zyrtec® [cetirizine hydrochlo- ride]; UCB Nordic, Denmark) (for allergy in the placebo period) during the study. Discussion The number of volunteers who urinated during the The present human proof-of-concept experimental first 2 h after drug administration was 13 of 18 for pain study showed significant analgesic effects of the

Anesthesiology, V 111, No 3, Sep 2009 620 ARENDT-NIELSEN ET AL.

Table 1. All Reported Adverse Events for Each Treatment Group

CR665 (n ϭ 18), n (%) Oxycodone (n ϭ 18), n (%) Placebo (n ϭ 18), n (%)

Subjects with no adverse events 3 (16.7%) 10 (55.6%) 15 (83.3%) Subjects with at least one adverse event 15 (83.3%) 8 (44.4%) 3 (16.7%) Cardiac disorders Bradycardia 1 (5.6%) 1 (5.6%) 0 Atrioventricular block first degree 1 (5.6%) 0 0 Sinus bradycardia 0 1 (5.6%) 0 Tachycardia 1 (5.6%) 0 0 Ear and labyrinth disorders Ear discomfort 1 (5.6%) 0 0

Gastrointestinal disorders Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/3/616/247622/0000542-200909000-00031.pdf by guest on 30 September 2021 0 1 (5.6%) 0 General disorders and administration site conditions Infusion site pruritus 6 (33.3%) 0 0 Infusion site erythema 1 (5.6%) 0 0 Pyrexia 0 0 1 (5.6%) Immune system disorders Hypersensitivity 0 0 1 (5.6%) Investigations Heart rate increased 1 (5.6%) 1 (5.6%) 0 Body temperature increased 1 (5.6%) 0 0 Electrocardiogram QT prolonged 0 1 (5.6%) 0 White blood cell count increased 0 0 1 (5.6%) Nervous system disorders Paraesthesia 11 (61.1%) 1 (5.6%) 0 Dizziness 1 (5.6%) 2 (11.1%) 0 Somnolence 1 (5.6%) 1 (5.6%) 0 Psychiatric disorders Dysphoria 1 (5.6%) 0 0 Skin and subcutaneous tissue disorders Cold sweat 0 1 (5.6%) 0 Erythema 1 (5.6%) 0 0 Hypoaesthesia facial 1 (5.6%) 0 0 Pruritus 0 1 (5.6%) 0 Vascular disorders Orthostatic hypotension 0 0 1 (5.6%)

Summary of all reported adverse events presented. All but one adverse event (hypersensitivity during placebo dosing) was considered related to study medication. The most frequently reported adverse events associated with the use of CR665 were infusion site pruritus and paraesthesia. All adverse events were mild in severity, with the exception of one episode of increased heart rate in the CR665 treatment period, which was moderate. No serious adverse events were reported during the study. QT ϭ Q and T peaks of the electrocardiogram.

peripherally acting ␬-opioid agonist CR665 on visceral In the current study, CR665 caused to skin pain and a paradoxical hyperalgesic action on skin pinching. The hyperalgesic effect of ␬-agonists on cuta- pinching pain. neous pain has not been reported previously in any Oxycodone showed pronounced effects on pain from preclinical or clinical studies on ␬-opioid agonist, but it is somatic as well as visceral structures supporting previ- known that central effects of A (endogenous 27 ous studies.10,18 The side effects after oxycodone were ␬-opioid agonist) possess pronociceptive properties. typical of ␮-opioid agonists.19,20 The side effects of CR665 were mainly limited to mild pruritus at the site of administration and to mild facial tingling (paraesthesia). Facial paraesthesia could be as- ␬ Peripherally Acting -Opioid Agonists sociated with ␬-receptor activation.28 In the clinic, visceral pain is often difficult to alleviate One example of dysphoria was observed after CR665, ␮ with morphine and other -agonists, and it has been which could be associated as a central effect; in general, 21,22,23,24 shown that ␬-opioid agonists can be effective. CR665 showed less centrally related effects as observed 25 ␬-Opioid agonists like and have with centrally acting ␬-opioid agonists (e.g., Pande et al.29). been tested for analgesic activity against pain from co- However, the dysphoria was characterized as mild, lonic distension in patients with irritable bowel syn- intermittent, and only possibly related to the study med- drome and functional dyspepsia21,22,23 with reported ication. However, other central nervous system side ef- clinical effectiveness. However, asimadoline caused fects were reported (paraesthesia, somnolence, and diz- slight hyperalgesia in nonvisceral postoperative pain.26 ziness), but it is not known whether the drug can cause

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Fig. 1. The mean ؎ SEM changes from baseline (30, 60, and 90 min after drug administration) in the skin pinching pain tolerance threshold (kPa). # Significant difference from placebo and CR665; * significant difference from placebo and oxycodone. Negative .CR665 ؍ oxycodone; hatched bar ؍ placebo; black bar ؍ values show sensitization compared with baseline. White bar central actions. Studies in humans with (CI- It is evident that peripherally located ␬-receptors are of 977),30 a highly selective and potent ␬-opioid agonist, importance, particularly for visceral pain.3,31 Clinical stud- have shown analgesic effects, although associated with ies have been performed with a number of peripherally neuropsychiatric side effects.29 acting (and usually also, to some degree, centrally ac-

Fig. 2. The mean ؎ SEM changes from baseline (30, 60, and 90 min after drug administration) in the cuff pressure pain tolerance threshold .CR665 ؍ oxycodone; hatched bar ؍ placebo; black bar ؍ kPa). # Significant difference from placebo and CR665. White bar)

Anesthesiology, V 111, No 3, Sep 2009 622 ARENDT-NIELSEN ET AL. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/3/616/247622/0000542-200909000-00031.pdf by guest on 30 September 2021

Fig. 3. The mean ؎ SEM changes from baseline (30, 60, and 90 min after drug administration) in the volume (ml) to esophageal Significant difference from placebo. There were no difference in drug effect of * .7 ؍ distension to elicit visual analogue scale .CR665 ؍ oxycodone; hatched bar ؍ placebo; black bar ؍ oxycodone and CR665. White bar ting) experimental ␬-opioids,32 including asimadoline These clinically tested ␬-opioids have all produced unac- (EMD61753),33 RP 60180,34 (RU 51,599),35 GR ceptable central side effects (e.g., Pfeiffer et al.41) at anal- 94839,36 ICI 204448,37 enadoline (CI-977),38 fedotozine,39 gesic doses or unreliable efficacy that may be related to (U62,066E),40 and ADL-10-0101.23 off-target activity (e.g., Machelska et al.26 and Coruzzi et

was 5 ؍ (Fig. 4. As a measure of the total thermal energy delivered to the tissue, the heat energy to elicit visual analogue scale (VAS calculated as the area under the curve (AUC) (temperature [°C] ؋ time [s]) from start to end of the stimulation. Bars indicate mean ؎ SEM changes from baseline (30, 60, and 90 min after drug administration) in AUC. # Significant difference from placebo and CR665. White .CR665 ؍ oxycodone; hatched bar ؍ placebo; black bar ؍ bar

Anesthesiology, V 111, No 3, Sep 2009 ␬ AGONIST AND EXPERIMENTAL VISCERAL PAIN 623 al.42) and/or low affinity for the ␬-opioid receptor (e.g., morphine-tolerant rats continue to exhibit analgesia Allescher et al.43). These clinical reports, together with with oxycodone, whereas oxycodone-tolerant rats fail to physiologic evidence for a role of ␬-opioid receptors in display analgesia with morphine.53 Recently, it has also modulating visceral pain,44,45 have lead to an intensified been shown that oxycodone and morphine have dis- search for high-affinity, peripherally selective ␬-opioids. tinctly different pharmacological profiles in rat models of Peptidic ␬-opioids, e.g., SK-9709,46 E-2078,47 FE200041 neuropathic pain.54 Nevertheless, it is difficult to at- (an earlier analog of CR66548), and FE200665 (CR665, tribute these findings to ␬-opioid receptor binding activ- 12,13 designated JNJ-38488502 ) have been developed with ity of oxycodone (receptor affinity greater than 1000 nM) the idea that a should be less likely than a nonpep- or its metabolites (Staahl et al.55). In human subjects, the tidic small molecule to cross the blood-brain barrier and only two metabolites with significant ␬-opioid receptor

cause centrally mediated side effects. This strategy is not binding activity are (receptor affinity 148 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/3/616/247622/0000542-200909000-00031.pdf by guest on 30 September 2021 invariably effective: E-2078, a synthetic, all-L-amino acid nM) and (receptor affinity 87 nM), but analog of ,1–8 was found to readily cross the these compounds are still 15-fold more potent at ␮-opi- blood-brain barrier and produce apparently nonopioid an- oid receptors.56 In addition, of these two metabolites, algesia in monkeys in doses overlapping with the sedative noroxymorphone reaches the higher maximum plasma dose range.49 However, preclinical studies with FE200041, concentration (7.8 ng/ml at about 1.5 h), which is still an all-D-amino acid tetrapeptide ␬-opioid agonist, demon- about five-fold lower than the concentration of oxyc- strated antinociception that was confirmed, with suitable odone itself, which is very potent at the ␮-opioid recep- antagonists to be peripherally mediated and selective via tor (receptor affinity 16 nM), but without activity at the 48 56 ␬-opioid receptors. Subsequent evaluation of an im- ␬-opioid receptor at 1,000 nM. Clearly, then, the ␮-opi- proved analog, FE200665 (CR665), confirmed this profile oid activity of oxycodone and its metabolites is collec- of peripheral ␬-opioid selectivity and demonstrated periph- tively much greater than ␬-opioid activity. However, this eral antinociceptive activity in a wide range of preclinical imbalance may not completely preclude some contribu- visceral pain models.12,13 The current experimental pain tion of ␬-opioid activity because interactions between study with CR665 substantiates these animal data in man. ␮-opioid and ␬-opioid receptors appear to play a signif- icant role in how nociception is mediated.57 Experimental Pain Models The need to improve the characterization of new com- Future Perspectives and Conclusion pounds for the treatment of pain has led to development In patients with severe pain originating from the gas- of a comprehensive battery of multi-modal, multi-tissue trointestinal tract, nonopioid are often insuf- 8,9 experimental pain models. Collectively, this experi- ficient to relieve pain to an acceptable level.58 Treatment mental concept has provided a valuable tool for differ- with traditional ␮-opioid agonists also often fails to re- entiating visceral pain from other forms of pain and lieve the pain sufficiently, and at the same time causes enables the profiling of new compounds such as CR665. constipation, which itself can be painful. To address This battery has recently been used to explore the dif- these problems, new therapeutic approaches have ferential analgesic effects of 15 mg of oxycodone and 30 emerged, and the development of new types of opioids 10 mg of morphine ; these opioids were found to be equi- that interact with different opioid receptors. CR665 and potent in somatic pain (skin and muscle), whereas oxy- oxycodone differ from traditional ␮-opioid agonists50 codone was clearly more effective than morphine in and have shown significant effects on visceral pain and 10 visceral pain. 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