Effects of asimadoline, a κ-opioid agonist, on satiation and postprandial symptoms in health


Prof. M. Camilleri, Mayo Clinic, Charlton 8–110, 200 First Street S.W., Rochester, MN 55905, USA.
E-mail: camilleri.michael@mayo.edu


Aim:  To evaluate the effect of single administrations of asimadoline, a κ-opioid agonist, on satiation volume, postprandial symptoms and gastric volumes.

Methods:  Healthy subjects received oral placebo, or 0.5 or 1.5 mg asimadoline in a randomized, double-blind fashion 1 h prior to testing. We assessed effects on the volume of Ensure to achieve full satiation and postprandial symptoms 30 min after meal, and on gastric volume (fasting and postprandial) measured by 99mTc-single photon emission tomography (SPECT) imaging.

Results:  Thirteen healthy subjects were studied in each treatment arm. Compared to placebo, asimadoline 0.5 mg decreased postprandial fullness (P = 0.027) without affecting the volume ingested at full satiation (P = 0.6). Asimadoline 1.5 mg decreased satiation during meal, allowing increased satiation volumes (P = 0.008) and tended to decrease postprandial fullness (P = 0.067), despite higher volumes ingested. There was a significant treatment–gender interaction in the effect of asimadoline on gastric volumes (P < 0.05). Asimadoline 0.5 mg (not 1.5 mg) increased fasting (P = 0.047) and postprandial (P = 0.009) gastric volumes in females but decreased fasting volumes in males (P = 0.008). The effect of asimadoline on gastric volume did not explain the effect observed on satiation volume (P = 0.371) or postprandial fullness (P = 0.399).

Conclusion:  A single oral administration of asimadoline decreases satiation and postprandial fullness in humans independently of its effects on gastric volume.


The neurophysiology of visceral sensation is still incompletely understood, and approaches to treat visceral hypersensitivity are generally ineffective.1 The κ-opioid receptors participate in the inhibition of perception of noxious stimuli from the gastrointestinal tract, as shown in well validated models of visceral sensation.2–5 Studies with the κ-receptor agonist fedotozine in patients with functional gastrointestinal symptoms have shown some promising results.5–7

Asimadoline (EMD61 753) is a new selective agonist of the κ-opioid receptor8 which does not cross the blood–brain barrier.9, 10 Asimadoline has been shown to reduce sensation responses to gastric and colonic distention in animal models.11–13 In a previous human phase I study, we showed that asimadoline has a good safety profile and does not have any deleterious effects on gastrointestinal or colonic motor functions after repeated oral doses.14 Asimadoline decreased perception of gas in response to colonic distention after a single dose. In the same study, we showed that after 6 days of treatment with asimadoline, healthy subjects were able to ingest greater volumes of Ensure to reach complete satiation. We did not observe any effect of asimadoline on gastric emptying, small intestine or colonic transit of solids.14

In our previous study, asimadoline decreased colonic tone (increased colonic volume) and gas perception to colonic distention.14 We also observed decreased satiation with asimadoline treatment; however, the mechanism of this effect on sensation was unclear, as gastric emptying was not affected by asimadoline and we did not measure gastric volume. In the present study, our hypothesis was that asimadoline increases gastric volume, allowing increased nutrient intake and reducing postprandial symptoms.

The specific aims of this study were to evaluate, in healthy subjects, the effect of a single oral administration of two different doses of asimadoline (1) on the volume of a nutrient liquid necessary to induce satiation, (2) on postprandial symptoms and gastric volume during fasting, and (3) in response to feeding.

Materials and methods

Study population

The study was conducted between May and October 2002. Healthy volunteers between 18 and 60 years of age were recruited from the local community by public advertisement. Exclusion criteria included: pregnant or breast-feeding females; females with childbearing potential who were not using reliable methods of contraception; known hypersensitivity to asimadoline or opioid agonists; known substance abuse; significant affective or anxiety disorder [with the Hospital Anxiety and Depression Scale (HADSS) used for screening purposes]; systemic disease; prior abdominal surgery other than appendectomy, laparoscopic cholecystectomy or tubal ligation; present or previous chronic gastrointestinal illness, including functional gastrointestinal disorders (with the Bowel Disease Questionnaire used for this purpose); use of medications that may alter gastrointestinal motility or induce cytochrome P450 (CYP) 3A4 and 2D6, or of analgesic drugs including opioids, nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors. The protocol was approved by the Mayo Institutional Review Board, and written informed consent was obtained from all participants prior to enrolment in the study.

Study design

This was a randomized, double-blind, placebo-controlled study. Eligible volunteers were randomized (using random permuted blocks stratified on age and gender) to receive treatment with either 0.5 or 1.5 mg of asimadoline (EMD 61,753, provided by Merck KGaA, Darmstadt, Germany) or identical-appearing placebo, orally, 1 h prior testing on two different days.

Study protocol

Satiation and postprandial symptoms were assessed at baseline (day 0) before starting the treatment period and one week later 1 h after receiving the assigned treatment (day 1). On a different day (at least 48 h after day 1) gastric volumes during fasting and in response to feeding were assessed 1 h after receiving the assigned treatment (day 2). (Figure 1). Medication was administered at the study site.

Figure 1.

Study protocol. Satiation, postprandial symptoms and gastric emptying of a liquid nutrient were assessed at baseline before the treatment period (day 0). One week later, satiation, postprandial symptoms and gastric emptying of a liquid nutrient were again assessed 1 h after receiving the assigned treatment (day 1). On a third day (day 2), 1 h after receiving the assigned treatment, participants underwent measurement of gastric using the SPECT technique.

Measurements of satiation and postprandial symptoms performed at baseline (day 0) were used in the final analysis to account for the intraindividual variability in these parameters.15

Safety monitoring

Adverse effects were monitored at the study site daily from day 0 to day 2, and patients were given a telephone number to contact study investigators to report any side-effects. A follow-up visit was scheduled within one week of the end of active treatment to follow any abnormality observed in the previous visit.

Assessment of satiation and postprandial symptoms by a nutrient drink test

We used a standard nutrient drink test16, 17 to measure satiation (defined as the final sensation during ingestion that leads to meal termination18), postprandial fullness, and symptoms of nausea, bloating and pain.

Satiation was assessed by measuring the amount of Ensure ingested, at a constant rate, to reach maximum satiation.19 After an overnight fast participants drank a nutrient liquid meal (Ensure: 1 kcal/mL, 11% fat, 73% carbohydrate and 16% protein) at a constant rate (30 mL/min). Every 5 min participants scored their level of fullness or satiation using a horizontal scale that combines verbal descriptors and numbers (0 = no symptoms; 5 = maximum or unbearable fullness/satiation). Meal intake was stopped when they reached the score of 5, and the satiation volume was recorded.

Thirty minutes after reaching the point of maximum satiation, participants scored their levels of fullness and symptoms of nausea, bloating and pain, using 100 mm horizontal visual analogue scales (VAS), with the words ‘none’ and ‘worst ever’ anchored at the left and right ends of the lines.

Participants were allowed to choose among three different Ensure flavors (chocolate, vanilla and strawberry) and were excluded from enrolment if they expressed a dislike for the taste of the test meal during the consent process.

Assessment of gastric volume by99mTc-single photon emission tomography (SPECT) imaging

We used a noninvasive method to measure gastric volumes during fasting and during 32 min after 300 mL of Ensure (316 kcal, 7.6 g fat, 50.6 g carbohydrate and 11.4 g protein) using single photon emission computed tomography (SPECT).20 The method has been described and validated in detail elsewhere.20–22 Intravenous injection of 99mTc-sodium pertechnetate, which is taken up by the parietal and nonparietal cells of the gastric mucosa, allows visualization of the stomach wall using SPECT scanning. Briefly, tomographic images of the gastric wall are obtained throughout the long axis of the stomach using a dual-head gamma camera (SMV SPECT Systemä, SMV America, Twinsburg, Ohio, USA) that rotates around the body. This allows assessment of the radiolabelled circumference of the gastric wall rather than the intragastric content. Using the AVW 3.0 (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN) image processing libraries, a three-dimensional rendering of the stomach is obtained and its volume calculated (Figure 2).

Figure 2.

SPECT assessment of gastric volume. Images of the stomach from a healthy subject acquired by SPECT. Panel a shows the transaxial images of the stomach during fasting (left) and 10 min after ingestion of 300 mL of Ensure (right). Note how the gastric wall is visualized rather than intragastric content, and how the gastric walls separate in response to feeding. Panel b shows the reconstructed stomach and its volume during fasting (left) and postprandially (right) using AVW 3.0 image processing libraries. Note that the volumes and shape do not reflect the intragastric content but rather the volume and shape of the viscus.

We used 10 mCi of 99mTc-sodium pertechnetate. The radiation-effective dose to the body (HE) and organ dose exposures have been published previously21 and are shown in Table 1.

Table 1.  Radiation effective dose and organ dose exposures during gastric volume measurement using99mTc-SPECT imaging
  1. HE is radiation-effective dose to the body. This dose to the whole body has the same risk as the individual doses to each of the organs. Effective dose is used to compare risks among various types of X-ray and radionuclide studies.

  2. RBM, red bone marrow; Esoph, oesophagus; Stom, stomach.

  3. Modified with permission from Kim et al. (Am J Gastroenterol 2001; 96: 3099–3105).

99, mTc106190.

This method has been validated in vitro and in vivo.22 In healthy volunteers, simultaneous measurements of postprandial gastric volume changes with SPECT and the barostat balloon device were strongly correlated (r = 0.9).22 In dyspeptic patients, the SPECT technique has reproduced the changes in gastric volume21 reported using the barostat device.16 Changes in SPECT volumes have reproduced changes in gastric wall tone, assessed with the barostat technique, in response to pharmacological interventions.17, 23 We have also shown the high intraobserver reproducibility of this technique for measuring gastric volumes.15

Data analysis

Satiation volume and postprandial symptoms.

We recorded the time and volume ingested to reach maximum satiation (satiation volume), and the VAS scores for each postprandial symptom 30 min after completing ingestion of Ensure. The primary endpoints were the satiation volume and the postprandial fullness score. In previous studies these have been shown to be the most reliable end-point variables measured by the nutrient drink test.24

Gastric volumes during fasting and in response to feeding.

The primary end-point to assess the effect of asimadoline on gastric volume was the fasting gastric volume, since we were exploring the mechanisms by which asimadoline decreases satiation (increases satiation volume). This was based on previous data showing that gastric volume before meal, rather than postprandially, determines the volume of a liquid nutrient ingested at maximum satiation.25 Thus, in a sample of 134 healthy subjects, we observed that the volume of the stomach pre-meal and post-meal were significant determinants of subsequent food intake. However, the influence of post-meal gastric volume on food intake was dependent on the premeal volume.25 Gastric volume in response to feeding was obtained by averaging the gastric volume throughout the postprandial period (32 min), as in previous studies.17, 22

Power assessment and statistical analysis

The study was powered for the primary endpoints based on published data from our laboratory using the same methodology used in the present study.15, 17, 22 With a sample size of 13 in each group, assuming normal distribution of the data and the inclusion of baseline covariates, we had > 95% power to detect a 300 mL difference in volume intake, a 30 mm difference in the VAS score for postprandial symptoms and a 70 mL difference in fasting gastric volume.

Treatment effect was assessed based on an intention-to-treat (ITT) analysis. Analysis of covariance (ancova) was used to assess overall treatment effects on satiation and gastric volumes. When overall treatment effect was significant (P < 0.05), specific contrasts were then used to test each dose vs. placebo. The results (P-values) for these contrasts are reported for each outcome variable. The covariates in these analyses included age, gender, body mass index (BMI) and baseline (pre-treatment) response values for those outcomes measured pre- and post-drug. This was done to adjust for potential baseline differences among groups. Potential effect interactions with gender, age or BMI were also tested.

Data are reported as adjusted mean ± standard error.


Study conduct and participants

Thirty-nine healthy subjects were randomized, with equal number assigned to placebo, or asimadoline 0.5 or 1.5 mg. There were nine females and four males in each treatment group. Participants' demographic characteristics are presented in Table 2. Age, gender and BMI were not significantly different in the three groups. There were no dropouts during the study, and compliance was 100% for all participants.

Table 2.  Demographic variables
(n = 13)
0.5 mg
(n = 13)
1.5 mg
(n = 13)
  1. Values are mean ± s.e.

Age (years)31 ± 2.431 ± 2.733 ± 2.6
Gender (F/M)9/49/49/4
BMI (kg/m2)24 ± 1.124 ± 0.926 ± 1.3

Volume to maximum satiation and postprandial fullness

Compared to placebo, asimadoline 0.5 mg decreased postprandial fullness score (P = 0.027) without affecting the volume of Ensure ingested to reach maximum satiation (P = 0.635). Asimadoline 1.5 mg reduced satiation perception during the meal, increasing the volume of Ensure ingested to reach maximum satiation. The average increase in volume ingested with asimadoline 1.5 mg over placebo was 194 mL (P = 0.008).

There was a significant treatment–gender interaction in the effect of asimadoline on satiation volume (P = 0.048. Figure 3). Although this treatment–gender interaction was not statistically significant on postprandial fullness (P = 0.212), actual fullness scores were lower with asimadoline in females, but not in males. Figure 3 shows the satiation volumes and fullness scores overall and separated by gender. Note also the increase in satiation volumes in males.

Figure 3.

Satiation volume and postprandial fullness. The left panel shows the volume (in mL) of Ensure to reach maximum satiation overall (a) and separated by gender (b). The right panel shows fullness VAS scores (in mm) 30 min after a meal, overall (a) and separated by gender (b). Note that females do not drink a greater volume but experience less postprandial fullness with asimadoline. Males have a greater satiation volume with asimadoline, and this does not increase postprandial perception of fullness. Data shown are means [ancova means adjusted for gender and baseline (pre-treatment) values] and standard errors. *P < 0.05 contrast with placebo.

Other postprandial symptoms

Overall, there was no treatment effect on postprandial bloating (0.190), nausea (P = 0.464) or pain (P = 0.433). The VAS scores for these symptoms are shown in Table 3.

Table 3.  Postprandial symptoms
(n = 13)
0.5 mg
(n = 13)
1.5 mg
(n = 13)
  1. Values are mean ± standard error (adjusted for gender and baseline-pre-treatment-values).

Nausea43.0 ± 5.234.3 ± 5.337.0 ± 5.4
Bloating47.5 ± 7.047.0 ± 7.063.9 ± 7.2
Pain24.6 ± 4.320.4 ± 4.228.2 ± 4.3

Gastric volume during fasting and after feeding

There was a significant treatment–gender interaction effect on both fasting (P = 0.003) and postprandial gastric volumes (P = 0.039). Gastric volumes during fasting and postprandially in females and males are shown in Table 4. Compared to placebo, asimadoline 0.5 mg (not 1.5 mg) increased gastric volumes in females during fasting (P = 0.047) and postprandially (P = 0.009). Conversely, asimadoline 0.5 mg (not 1.5 mg) decreased gastric volume in males (P = 0.008) during fasting. The effect of asimadoline on gastric volume did not explain the effect observed on satiation volume (P = 0.371) or postprandial fullness (P = 0.399).

Table 4.  Gastric volumes during fasting and after 300 mL of Ensure
(n = 13)
0.5 mg
(n = 13)
1.5 mg
(n = 13)
  • Values are mean ± standard error.

  • P < 0.05 contrast with placebo.

Fasting volume
 Males279 ± 31155 ± 31*258 ± 31
 Females209 ± 20269 ± 20*228 ± 20
Postprandial volume
 Males822 ± 41744 ± 41727 ± 41
 Females720 ± 28827 ± 28*743 ± 28

Adverse events

No serious adverse events were reported. Only three patients (two in the placebo and one in the 0.5 mg asimadoline group) reported adverse events. In the placebo group, one participant experienced nausea and vomiting during three days; a second participant in the placebo group reported nausea and vomiting after the satiety tests. One participant in the 0.5 mg asimadoline group had a urinary tract infection during the study. None of the patients that received the higher dose of asimadoline reported any adverse event.


We have shown that a single oral dose of asimadoline is well tolerated and that clinical effects are demonstrable 1 h after administration. We have shown that the lower dose of asimadoline (0.5 mg) tested does not affect satiation during meal ingestion but it decreases the perception of fullness 30 min post-meal. In contrast, the higher dose of asimadoline (1.5 mg) decreased perception of satiation during ingestion (allowing ingestion of greater volumes of the nutrient liquid meal to achieve full satiation) and tended to decrease postprandial fullness. The latter is a relevant change since fullness scores were lower despite higher volumes of Ensure ingested.

We have also shown that asimadoline (0.5 mg) induces changes in gastric volume; however, these changes appear to be unrelated to the effects of asimadoline on satiation and postprandial fullness.

Asimadoline decreased perception of fullness. However, we did not observe any effect on the other symptoms assessed (nausea, bloating and pain). These differences may reflect the fact that different mechanisms may be involved in the perception of stimuli such as meal-related fullness, in contrast to the perception of noxious stimuli.26, 27 Since we evaluated healthy individuals, we cannot exclude a potential ‘floor effect’ due to the high proportion of subjects reporting very low postprandial symptoms scores at baseline (50% and 25% of participants had scores of < 10 mm for pain and nausea, respectively). We cannot exclude the possibility suggested by other reports that asimadoline's antinociceptive activity is more pronounced under hyperalgesic conditions.9

We did not observe an increase in symptom scores with the highest asimadoline dose tested (1.5 mg). This is relevant, since hyperalgesia has been observed paradoxically with higher doses of asimadoline in animals and humans.28

We explored potential differences in the responses to asimadoline in males and females based on known gender differences in κ-opioid induced analgesia.29 Although our sample was relatively small (27 females and 12 males), this study suggests that asimadoline's effects may be different in males and females. Thus, males appear to experience the effects of the drug while still ingesting the meal, since they were able to ingest more Ensure before feeling completely full or satiated. On the other hand, females drank the same amount of Ensure but experienced less fullness after the meal, as assessed by visual analogue scales. There may several explanations for the observed differences between males and females, including differences in the magnitude of the effect. Thus in females the reduction in satiation or fullness perception may be lower compared to males, and may not be enough to continue ingestion; however, levels of fullness were reduced at the end of the meal. In contrast both ingested volume (which reflects perception of satiation/fullness during meal ingestion) and postprandial fullness scores were altered in males. In fact, this is consistent with greater analgesic responses to κ-opioids reported in males compared to females in different animal models.30, 31 This difference may be related to gonadal hormones.29 However, in view of the small number of male subjects in our study, the gender-related differences in the satiation response to asimadoline observed will require confirmation in a larger study.

In our previous, asimadoline increased colonic volume in fasting conditions.14 In this study we measured gastric volume during fasting and postprandially to assess whether asimadoline increases gastric volume and to assess the potential role of gastric volume on asimadoline's effects on satiation and postprandial fullness. A significant change in gastric volumes was observed only with the lower dose of asimadoline (0.5 mg), and this effect was different in males (who had decreased volumes) and females (who had increased volumes). These effects of asimadoline on gastric volumes do not explain the effects of the drug on symptoms. These results refute our initial hypothesis that asimadoline might decrease perception of gastric stimuli through increased gastric relaxation. This should not be surprising, since there is abundant evidence that perception of gastric stimuli is not determined only by gastric relaxation.32 Many other factors, including gastric emptying, compliance, sensation and central processing of sensorial afferent signals, interact and account for the variability in the perception of gastrointestinal stimuli.33 Previous studies also have shown such a poor correlation between perception and gastric relaxation or accommodation to a meal34, 35 or gastric volume.17

In the rat, reduction of sensory afferent discharge by asimadoline inhibits perception and viscero-motor reflexes.11, 36 Overall, our data support the hypothesis that asimadoline decreases visceral perception by acting through peripheral receptors on afferent (sensory) pathways as demonstrated in animal models,11, 13, 36 and not through changes in gastric volume.

In conclusion we have shown that asimadoline 0.5 mg taken orally 1 h prior to a meal reduces postprandial fullness, and the 1.5 mg dose allows greater ingestion without inducing postprandial symptoms in healthy humans. These effects, and the lack of deleterious effects of this compound on gastrointestinal motor responses, suggest that asimadoline would be a suitable medication to be tested further in patients with functional dyspepsia.


This study was supported in part by a grant from Merck KGaA, Darmstadt, Germany and by nursing support available through General Clinical Research Center grant #RR00585 (Physiology Core) from the National Institutes of Health (NIH). M.C. is supported by grants #R01-DK54681 and #K24-DK02638 from the NIH. S. D.-A. was supported by the Falk Fellowship for Clinical Research Training at the Mayo Foundation. We thank Ms. Mary Lempke, R. Ph., and Ms. Cindy Stanislav for pharmacy and secretarial support, respectively.