Trial Outcomes & Findings for A Study to Assess the Effect of AZD4041 on Respiratory Drive in Recreational Opioid Users. (NCT NCT05587998)

NCT ID: NCT05587998

Last Updated: 2024-11-15

Results Overview

ETCo2 measurement is performed in the clinical pharmacology setting studies for the evaluation of respiratory function. EtCO2 is monitored and measured using a standardized methodology and configuration using MICROSREAM\^TM consumables to sample gas via nasal cannulae and the CAPNOSTREAM\^TM20P bedside monitor according to Altasciences SOP on Capnography. Using this configuration, for the spontaneously breathing healthy volunteer participant, baseline EtCO2 measurements is expected to fall within the range of 34 to 48 mmHg. An increase in EtCO2 is defined as an increase of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). Number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg on Day 1 are reported.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 45 participants
• Primary outcome timeframe: Day 1
• Results posted on: 2024-11-15

Participant Flow

Participant milestones

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 Participants will receive a single intravenous (IV) dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Overall Study STARTED	29	16
Overall Study Treated	26	15
Overall Study COMPLETED	25	13
Overall Study NOT COMPLETED	4	3

Reasons for withdrawal

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 Participants will receive a single intravenous (IV) dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Overall Study Withdrawal by Subject	1	1
Overall Study Not treated	3	1
Overall Study Non-compliance with study procedures	0	1

Baseline Characteristics

A Study to Assess the Effect of AZD4041 on Respiratory Drive in Recreational Opioid Users.

Baseline characteristics by cohort

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.	Total n=41 Participants Total of all reporting groups
Age, Continuous	33.2 Years STANDARD_DEVIATION 6.76 • n=5 Participants	34.8 Years STANDARD_DEVIATION 5.75 • n=7 Participants	33.8 Years STANDARD_DEVIATION 6.39 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	14 Participants n=7 Participants	37 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants n=5 Participants	15 Participants n=7 Participants	38 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	19 Participants n=5 Participants	12 Participants n=7 Participants	31 Participants n=5 Participants
Race (NIH/OMB) White	7 Participants n=5 Participants	3 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 1

Population: The safety population included all participants who received at least 1 dose of morphine.

ETCo2 measurement is performed in the clinical pharmacology setting studies for the evaluation of respiratory function. EtCO2 is monitored and measured using a standardized methodology and configuration using MICROSREAM^TM consumables to sample gas via nasal cannulae and the CAPNOSTREAM^TM20P bedside monitor according to Altasciences SOP on Capnography. Using this configuration, for the spontaneously breathing healthy volunteer participant, baseline EtCO2 measurements is expected to fall within the range of 34 to 48 mmHg. An increase in EtCO2 is defined as an increase of at least 10 mmHg compared to baseline or > 50 mmHg (sustained for at least 30 seconds). Number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or > 50 mmHg on Day 1 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 1	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Day 15

Population: The safety population included all participants who received at least 1 dose of morphine.

ETCo2 measurement is performed in the clinical pharmacology setting studies for the evaluation of respiratory function. EtCO2 is monitored and measured using a standardized methodology and configuration using MICROSREAM^TM consumables to sample gas via nasal cannulae and the CAPNOSTREAM^TM20P bedside monitor according to Altasciences SOP on Capnography. Using this configuration, for the spontaneously breathing healthy volunteer participant, baseline EtCO2 measurements is expected to fall within the range of 34 to 48 mmHg. An increase in end tidal carbon dioxide (EtCO2) is defined as an increase of at least 10 mmHg compared to baseline or > 50 mmHg (sustained for at least 30 seconds). Number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or > 50 mmHg on Day 15 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 15	2 Participants	1 Participants

PRIMARY outcome

Timeframe: Day 1

Population: The safety population included all participants who received at least 1 dose of morphine.

A reduction in SpO2 is defined as a reduction from baseline to < 92% (sustained for at least 30 seconds). Number of participants with reduction in SpO2 to < 92% on Day 1 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 1	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Day 15

Population: The safety population included all participants who received at least 1 dose of morphine.

A reduction in SpO2 is defined as a reduction from baseline to < 92% (sustained for at least 30 seconds). Number of participants with reduction in SpO2 to < 92% on Day 15 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 15	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 1 and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes only those participants who had reduction in SpO2 to \< 92% (sustained for at least 30 seconds). On Day 1, number of participants with reduction in SpO2 to \< 92% (sustained for at least 30 seconds) was 0.

Mean time to reduction from baseline in SpO2 to < 92% (sustained for at least 30 seconds) is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=1 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Time to Reduction in SpO2 to < 92% Day 15	0.986 Hours Standard Deviation NA Since, there was only one participant evaluable in this arm, standard deviation is not applicable.	—

SECONDARY outcome

Timeframe: Day 1 and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes only those participants who had reduction in SpO2 to \< 92% (sustained for at least 30 seconds). On Day 1, number of participants with reduction in SpO2 to \< 92% (sustained for at least 30 seconds) was 0.

Mean duration of reduction from baseline in SpO2 to < 92% (sustained for at least 30 seconds) is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=1 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Duration of Reduction in SpO2 to < 92% Day 15	1.083 Minutes Standard Deviation NA Since, there was only one participant evaluable in this arm, standard deviation is not applicable.	—

SECONDARY outcome

Timeframe: Day 1, Day 8, and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.

Maximum post-dose reduction of SpO2 adjusted for baseline is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Post-dose Reduction of SpO2 Adjusted for Baseline Day 1	3.775 Percent Reduction in SpO2 Standard Deviation 1.5019	3.256 Percent Reduction in SpO2 Standard Deviation 1.6150
Post-dose Reduction of SpO2 Adjusted for Baseline Day 8	3.286 Percent Reduction in SpO2 Standard Deviation 1.7564	2.751 Percent Reduction in SpO2 Standard Deviation 1.7650
Post-dose Reduction of SpO2 Adjusted for Baseline Day 15	3.366 Percent Reduction in SpO2 Standard Deviation 2.3449	2.757 Percent Reduction in SpO2 Standard Deviation 1.7037

SECONDARY outcome

Timeframe: Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes the number of participants who were evaluable for the specified outcome measure.

Mean post-dose SpO2 is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=13 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Post-dose SpO2	96.990 Percent SpO2 Standard Deviation 1.6167	97.900 Percent SpO2 Standard Deviation 1.2076

SECONDARY outcome

Timeframe: Day 1 and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes those participants who had EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). On Day 1, number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) was 0.

Mean time to each increased EtCO2 episode of at least 10 mmHg compared to baseline or > 50 mmHg (sustained for at least 30 seconds) is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=2 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=1 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Time to Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg Day 15	2.812 Hours Standard Deviation 1.6494	2.083 Hours Standard Deviation NA Since, there was only one participant evaluable in this arm, standard deviation is not applicable.

SECONDARY outcome

Timeframe: Day 1 and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes those participants who had EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). On Day 1, number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) was 0.

Mean duration of each increased EtCO2 episode of at least 10 mmHg compared to baseline or > 50 mmHg (sustained for at least 30 seconds) is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=2 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=1 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Duration of Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg Day 15	8.202 Minutes Standard Deviation 6.8859	0.750 Minutes Standard Deviation NA Since, there was only one participant evaluable in this arm, standard deviation is not applicable.

SECONDARY outcome

Timeframe: Day 1, Day 8, and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.

Maximum post-dose increase in EtCO2 adjusted for baseline is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Post-dose Increase in EtCO2 Adjusted for Baseline Day 15	7.261 mmHg Standard Deviation 2.5220	7.462 mmHg Standard Deviation 1.9624
Post-dose Increase in EtCO2 Adjusted for Baseline Day 1	6.501 mmHg Standard Deviation 1.9432	7.177 mmHg Standard Deviation 1.6955
Post-dose Increase in EtCO2 Adjusted for Baseline Day 8	3.141 mmHg Standard Deviation 2.8440	3.452 mmHg Standard Deviation 2.1808

SECONDARY outcome

Timeframe: Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes the number of participants who were evaluable for the specified outcome measure.

Mean post-dose EtCO2 is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=13 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Post-dose EtCO2	41.870 mmHg Standard Deviation 2.8188	40.923 mmHg Standard Deviation 2.4410

SECONDARY outcome

Timeframe: Day 1, Day 8, and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine.

Number of participants with RR of < 6 breaths/min (sustained for at least 30 seconds) are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Reduced Respiratory Rate (RR) of < 6 Breaths/Min	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 1, Day 8, and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants with RR of \< 6 breaths/min (sustained for at least 30 seconds) was 0.

Mean time to each reduced respiratory rate episode of < 6 breaths/min (sustained for at least 30 seconds) is reported.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1, Day 8, and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants with RR of \< 6 breaths/min (sustained for at least 30 seconds) was 0.

Mean duration of each reduced respiratory rate episode of < 6 breaths/min (sustained for at least 30 seconds) is reported.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1, Day 8, and Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Here, number analyzed (n) denotes those participants who were evaluable at the specified time point.

Maximum post-dose decrease in RR adjusted for baseline is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Post-dose Decrease in RR Adjusted for Baseline Day 1	4.852 Breaths/min Standard Deviation 1.7684	5.523 Breaths/min Standard Deviation 2.2649
Post-dose Decrease in RR Adjusted for Baseline Day 8	4.133 Breaths/min Standard Deviation 2.5477	4.667 Breaths/min Standard Deviation 2.1252
Post-dose Decrease in RR Adjusted for Baseline Day 15	5.133 Breaths/min Standard Deviation 2.4346	6.116 Breaths/min Standard Deviation 2.2576

SECONDARY outcome

Timeframe: Day 15

Population: The safety population included all participants who received at least 1 dose of morphine. Number of participants analyzed (N) denotes the number of participants who were evaluable for the specified outcome measure.

Mean post-dose RR is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=13 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Post-dose RR	13.577 Breaths/minute Standard Deviation 2.0284	13.477 Breaths/minute Standard Deviation 2.7037

SECONDARY outcome

Timeframe: Day 1 through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) Any TEAEs	26 Participants	14 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) Any TESAEs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 1 through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, Number of TEAEs are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of TEAEs	134 Events	102 Events

SECONDARY outcome

Timeframe: Day 1 through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, number of TEAEs by severity (mild, moderate, or severe) are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of TEAEs by Severity Mild	129 Events	99 Events
Number of TEAEs by Severity Moderate	5 Events	3 Events
Number of TEAEs by Severity Severe	0 Events	0 Events

SECONDARY outcome

Timeframe: Day 1 through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, number of TEAEs by relationship (related or unrelated to the study drug) are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of TEAEs by Relationship Related	125 Events	94 Events
Number of TEAEs by Relationship Unrelated	9 Events	8 Events

SECONDARY outcome

Timeframe: Screening (Day -30 to -3) through Day 24 (end of study)

Population: The safety population included all participants who received at least 1 dose of morphine.

Number of participants with clinically significant abnormal vital signs are reported. Abnormal clinical vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, heart rate, and oral temperature).

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Clinically Significant Abnormal Vital Signs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Screening (Day -30 to -3) through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

Number of participants with clinically significant abnormal ECGs are reported. Abnormal clinical ECG parameters are defined as any abnormal finding during analysis of 12-lead safety ECGs, 12-lead digital ECGs, and ECG telemetry.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs)	2 Participants	1 Participants

SECONDARY outcome

Timeframe: Screening (Day -30 to Day -3) through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

Number of participants with clinically significant abnormal laboratory values are reported. Abnormal clinical laboratory parameters are defined as any abnormal finding during analysis of hematology, clinical chemistry, coagulation, and urinalysis.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Clinically Significant Abnormal Laboratory Values	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Screening (Day -30 to Day -3) through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

Number of participants with clinically significant abnormal physical examination findings are reported. The physical examination included a general review of the following body systems (at minimum): head and neck, cardiovascular, respiratory, gastrointestinal, brief neurological and general appearance, unless a symptom oriented physical exam is indicated.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Clinically Significant Abnormal Physical Examination Findings	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Screening (Day -30 to Day -3) through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

Number of participants with clinically significant neurological examinations findings are reported. Neurological examinations included assessments of basic mental status, cranial nerves, motor function, reflexes, sensation, proprioception, coordination, and gait.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Clinically Significant Neurological Examinations Findings	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Screening (Day -30 to Day -3) through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

The C-SSRS is a suicidal ideation and behavior rating scale with yes/no responses. Items 1-5 rates an individual's degree of suicidal ideation on a 0 (wish to be dead) to 5 (active suicidal ideation with specific plan and intent and behaviors) scale. C-SSRS outcomes are categories and have binary responses (yes/no). Suicidal ideation is considered when the participant responds a 'yes' to any one of the five suicidal ideation questions (Categories 1-5) on the C-SSRS at any time during treatment. Items 6-10 of C-SSRS rates suicidal behavior where outcome is a simple yes/no response. Suicidal behavior was considered if participant answers a 'yes' to any one of the five suicidal behavior questions (Categories 6-10) on C-SSRS at any time during treatment. Number of participants with suicidal behavior and ideation per C-SSRS assessments are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments Suicidal Ideation	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments Suicidal Behaviours	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Screening (Day -30 to Day -3) through end of study (Day 24)

Population: The safety population included all participants who received at least 1 dose of morphine.

Number of participants with type of medical intervention used for each event of significantly increased EtCO2, reduced SpO2, or RR are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Number of Participants With Type of Medical Intervention Used for Each Event of Significantly Increased EtCO2, Reduced SpO2, or RR	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: Pharmacokinetic (PK) population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

The Cmax of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites Morphine (Day 1)	96.24 ng/mL Geometric Coefficient of Variation 22.07	95.51 ng/mL Geometric Coefficient of Variation 16.95
Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites Morphine (Day 15)	88.32 ng/mL Geometric Coefficient of Variation 24.14	88.54 ng/mL Geometric Coefficient of Variation 20.74
Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 1)	313.7 ng/mL Geometric Coefficient of Variation 25.54	352.9 ng/mL Geometric Coefficient of Variation 14.03
Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 15)	291.0 ng/mL Geometric Coefficient of Variation 23.34	300.8 ng/mL Geometric Coefficient of Variation 10.58
Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 1)	56.40 ng/mL Geometric Coefficient of Variation 21.46	64.44 ng/mL Geometric Coefficient of Variation 10.60
Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 15)	53.54 ng/mL Geometric Coefficient of Variation 19.06	59.88 ng/mL Geometric Coefficient of Variation 12.96

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

The Tmax of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites Morphine (Day 1)	0.08 Hour Interval 0.08 to 0.1	0.08 Hour Interval 0.08 to 0.08
Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites Morphine (Day 15)	0.08 Hour Interval 0.08 to 0.1	0.08 Hour Interval 0.08 to 0.17
Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 1)	0.25 Hour Interval 0.08 to 1.0	0.25 Hour Interval 0.08 to 0.53
Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 15)	0.27 Hour Interval 0.08 to 1.03	0.27 Hour Interval 0.08 to 1.02
Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 1)	0.76 Hour Interval 0.25 to 1.5	0.50 Hour Interval 0.25 to 1.0
Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 15)	1.00 Hour Interval 0.25 to 1.5	0.50 Hour Interval 0.28 to 1.5

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

The AUC0-t of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites Morphine (Day 1)	132.5 h*ng/mL Geometric Coefficient of Variation 26.78	124.5 h*ng/mL Geometric Coefficient of Variation 23.59
Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites Morphine (Day 15)	135.5 h*ng/mL Geometric Coefficient of Variation 29.08	128.2 h*ng/mL Geometric Coefficient of Variation 17.33
Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 1)	1996 h*ng/mL Geometric Coefficient of Variation 18.55	2067 h*ng/mL Geometric Coefficient of Variation 15.21
Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 15)	2120 h*ng/mL Geometric Coefficient of Variation 19.43	2194 h*ng/mL Geometric Coefficient of Variation 15.11
Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 1)	315.3 h*ng/mL Geometric Coefficient of Variation 17.76	342.0 h*ng/mL Geometric Coefficient of Variation 18.68
Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 15)	342.7 h*ng/mL Geometric Coefficient of Variation 16.45	380.3 h*ng/mL Geometric Coefficient of Variation 18.66

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

The (AUC0-∞) of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites Morphine (Day 1)	140.5 h*ng/mL Geometric Coefficient of Variation 26.30	133.8 h*ng/mL Geometric Coefficient of Variation 21.19
Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites Morphine (Day 15)	142.6 h*ng/mL Geometric Coefficient of Variation 28.33	140.8 h*ng/mL Geometric Coefficient of Variation 17.87
Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 1)	2259 h*ng/mL Geometric Coefficient of Variation 20.29	2404 h*ng/mL Geometric Coefficient of Variation 17.43
Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 15)	2284 h*ng/mL Geometric Coefficient of Variation 17.84	2363 h*ng/mL Geometric Coefficient of Variation 15.32
Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 1)	372.6 h*ng/mL Geometric Coefficient of Variation 48.69	389.4 h*ng/mL Geometric Coefficient of Variation 17.13
Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 15)	371.2 h*ng/mL Geometric Coefficient of Variation 16.37	408.3 h*ng/mL Geometric Coefficient of Variation 19.38

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

The t1/2λz of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites Morphine (Day 1)	3.131 Hour Geometric Coefficient of Variation 49.58	3.493 Hour Geometric Coefficient of Variation 53.29
Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites Morphine (Day 15)	3.090 Hour Geometric Coefficient of Variation 32.23	4.483 Hour Geometric Coefficient of Variation 109.0
Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 1)	10.04 Hour Geometric Coefficient of Variation 62.79	11.37 Hour Geometric Coefficient of Variation 46.87
Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 15)	11.13 Hour Geometric Coefficient of Variation 40.00	12.39 Hour Geometric Coefficient of Variation 24.99
Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 1)	10.16 Hour Geometric Coefficient of Variation 118.2	10.38 Hour Geometric Coefficient of Variation 51.10
Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 15)	10.82 Hour Geometric Coefficient of Variation 34.77	12.27 Hour Geometric Coefficient of Variation 32.34

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

The tlast of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites Morphine (Day 1)	12.00 Hours Interval 8.0 to 36.0	12.00 Hours Interval 8.0 to 24.0
Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites Morphine (Day 15)	12.00 Hours Interval 8.0 to 24.1	12.00 Hours Interval 8.0 to 24.0
Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 1)	36.00 Hours Interval 12.0 to 36.1	36.00 Hours Interval 24.0 to 36.15
Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites Morphine-3-glucuronide (Day 15)	48.00 Hours Interval 24.0 to 48.1	36.00 Hours Interval 36.0 to 48.0
Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 1)	36.00 Hours Interval 12.0 to 36.1	36.00 Hours Interval 24.0 to 36.15
Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites Morphine-6-glucuronide (Day 15)	36.03 Hours Interval 24.0 to 48.1	36.00 Hours Interval 36.0 to 48.0

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

The CL of morphine are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Total Body Clearance (CL) of Morphine Day 1	142.4 L/h Geometric Coefficient of Variation 26.30	149.4 L/h Geometric Coefficient of Variation 21.19
Total Body Clearance (CL) of Morphine Day 15	140.2 L/h Geometric Coefficient of Variation 28.33	142.0 L/h Geometric Coefficient of Variation 17.87

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

The Vz of morphine are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Volume of Distribution Based on the Terminal Phase (Vz) of Morphine Day 1	643.2 Liter Geometric Coefficient of Variation 41.23	753.0 Liter Geometric Coefficient of Variation 55.77
Volume of Distribution Based on the Terminal Phase (Vz) of Morphine Day 15	625.1 Liter Geometric Coefficient of Variation 36.38	918.5 Liter Geometric Coefficient of Variation 97.58

SECONDARY outcome

Timeframe: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.

The Cmax,ss of AZD4041 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Maximum Observed Concentration at Steady-state (Cmax,ss) of AZD4041 Day 8	717.8 ng/mL Geometric Coefficient of Variation 23.95	—
Maximum Observed Concentration at Steady-state (Cmax,ss) of AZD4041 Day 15	660.7 ng/mL Geometric Coefficient of Variation 22.14	—

SECONDARY outcome

Timeframe: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.

The tmax,ss of AZD4041 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Time to Reach Maximum Observed Concentration at Steady State (Tmax,ss) of AZD4041 Day 8	0.50 Hour Interval 0.25 to 1.5	—
Time to Reach Maximum Observed Concentration at Steady State (Tmax,ss) of AZD4041 Day 15	1.57 Hour Interval 0.23 to 7.98	—

SECONDARY outcome

Timeframe: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.

The AUCτ of AZD4041 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Area Under Plasma Concentration-time Curve Over a Dosing Interval (AUCτ) of AZD4041 Day 8	7114 h*ng/mL Geometric Coefficient of Variation 31.15	—
Area Under Plasma Concentration-time Curve Over a Dosing Interval (AUCτ) of AZD4041 Day 15	7711 h*ng/mL Geometric Coefficient of Variation 28.34	—

SECONDARY outcome

Timeframe: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.

The t1/2λz of AZD4041 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Terminal Elimination Half-life (t1/2λz) of AZD4041 Day 8	14.44 Hour Geometric Coefficient of Variation 63.21	—
Terminal Elimination Half-life (t1/2λz) of AZD4041 Day 15	12.14 Hour Geometric Coefficient of Variation 39.71	—

SECONDARY outcome

Timeframe: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.

The Cav of AZD4041 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Average Concentration Over a Dosing Interval (Cav) of AZD4041 Day 8	296.4 ng/mL Geometric Coefficient of Variation 31.15	—
Average Concentration Over a Dosing Interval (Cav) of AZD4041 Day 15	321.3 ng/mL Geometric Coefficient of Variation 28.34	—

SECONDARY outcome

Timeframe: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.

The CLss/F of AZD4041 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Apparent Total Body Clearance at Steady State (CLss/F) of AZD4041 Day 8	3.514 L/h Geometric Coefficient of Variation 31.15	—
Apparent Total Body Clearance at Steady State (CLss/F) of AZD4041 Day 15	3.242 L/h Geometric Coefficient of Variation 28.34	—

SECONDARY outcome

Timeframe: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.

The Vzss/F of AZD4041 are reported

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Apparent Volume of Distribution at Steady State Based on the Terminal Phase (Vzss/F) of AZD4041 Day 8	73.19 Liter Geometric Coefficient of Variation 57.65	—
Apparent Volume of Distribution at Steady State Based on the Terminal Phase (Vzss/F) of AZD4041 Day 15	56.79 Liter Geometric Coefficient of Variation 37.29	—

SECONDARY outcome

Timeframe: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.

The Ctrough,ss of AZD4041 are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Observed Lowest Concentration Before the Next Dose is Administered at Steady State (Ctrough,ss) of AZD4041 Day 8	133.8 ng/mL Geometric Coefficient of Variation 66.35	—
Observed Lowest Concentration Before the Next Dose is Administered at Steady State (Ctrough,ss) of AZD4041 Day 15	149.5 ng/mL Geometric Coefficient of Variation 67.10	—

SECONDARY outcome

Timeframe: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041 and who were evaluable at the specified time point.

The Aeτ of AZD4041 is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Amount of AZD4041 Excreted Unchanged in Urine (Aeτ)	390400 ng Geometric Coefficient of Variation 63.03	—

SECONDARY outcome

Timeframe: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041 and who were evaluable at the specified time point.

The Feτ/F of AZD4041 is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Apparent Fraction of AZD4041 Excreted Unchanged in Urine (Feτ/F)	1.562 Percentage Geometric Coefficient of Variation 63.03	—

SECONDARY outcome

Timeframe: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041 and who were evaluable at the specified time point.

The CLR of AZD4041 is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Renal Clearance (CLR) of AZD4041	0.04757 L/h Geometric Coefficient of Variation 78.33	—

SECONDARY outcome

Timeframe: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041.

The t1/2 of AZD4041 is reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=22 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Terminal Elimination Half-life (t1/2) of AZD4041	14.48 Hour Geometric Coefficient of Variation 111.7	—

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

Plasma concentration of morphine over time was reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Plasma Concentration of Morphine Over Time Day 15 (8 hour)	2.85 ng/mL Geometric Coefficient of Variation 34.4	2.93 ng/mL Geometric Coefficient of Variation 34.0
Plasma Concentration of Morphine Over Time Day 1 (Predose)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.
Plasma Concentration of Morphine Over Time Day 1 (0.08 hour)	96.24 ng/mL Geometric Coefficient of Variation 22.1	95.51 ng/mL Geometric Coefficient of Variation 16.9
Plasma Concentration of Morphine Over Time Day 1 (0.25 hour)	57.04 ng/mL Geometric Coefficient of Variation 23.9	54.16 ng/mL Geometric Coefficient of Variation 20.8
Plasma Concentration of Morphine Over Time Day 1 (0.5 hour)	40.89 ng/mL Geometric Coefficient of Variation 25.5	38.50 ng/mL Geometric Coefficient of Variation 22.8
Plasma Concentration of Morphine Over Time Day 1 (1 hour)	29.42 ng/mL Geometric Coefficient of Variation 29.8	26.58 ng/mL Geometric Coefficient of Variation 22.9
Plasma Concentration of Morphine Over Time Day 1 (1.5 hour)	25.13 ng/mL Geometric Coefficient of Variation 25.3	21.07 ng/mL Geometric Coefficient of Variation 24.7
Plasma Concentration of Morphine Over Time Day 1 (2 hour)	19.43 ng/mL Geometric Coefficient of Variation 25.0	17.24 ng/mL Geometric Coefficient of Variation 27.6
Plasma Concentration of Morphine Over Time Day 1 (3 hour)	14.00 ng/mL Geometric Coefficient of Variation 24.2	11.82 ng/mL Geometric Coefficient of Variation 33.9
Plasma Concentration of Morphine Over Time Day 1 (4 hour)	9.92 ng/mL Geometric Coefficient of Variation 27.7	9.50 ng/mL Geometric Coefficient of Variation 30.0
Plasma Concentration of Morphine Over Time Day 1 (6 hour)	4.99 ng/mL Geometric Coefficient of Variation 33.6	4.77 ng/mL Geometric Coefficient of Variation 35.4
Plasma Concentration of Morphine Over Time Day 1 (8 hour)	3.05 ng/mL Geometric Coefficient of Variation 31.1	2.99 ng/mL Geometric Coefficient of Variation 33.7
Plasma Concentration of Morphine Over Time Day 1 (12 hour)	1.21 ng/mL Geometric Coefficient of Variation 19.1	1.32 ng/mL Geometric Coefficient of Variation 25.6
Plasma Concentration of Morphine Over Time Day 1 (24 hour)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.
Plasma Concentration of Morphine Over Time Day 1 (36 hour)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.
Plasma Concentration of Morphine Over Time Day 15 (predose)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.
Plasma Concentration of Morphine Over Time Day 15 (0.08 hour)	88.32 ng/mL Geometric Coefficient of Variation 24.1	88.54 ng/mL Geometric Coefficient of Variation 20.7
Plasma Concentration of Morphine Over Time Day 15 (0.25 hour)	56.83 ng/mL Geometric Coefficient of Variation 24.9	53.14 ng/mL Geometric Coefficient of Variation 22.4
Plasma Concentration of Morphine Over Time Day 15 (0.5 hour)	39.88 ng/mL Geometric Coefficient of Variation 29.3	38.55 ng/mL Geometric Coefficient of Variation 25.0
Plasma Concentration of Morphine Over Time Day 15 (1 hour)	30.09 ng/mL Geometric Coefficient of Variation 33.0	27.00 ng/mL Geometric Coefficient of Variation 22.1
Plasma Concentration of Morphine Over Time Day 15 (1.5 hour)	24.31 ng/mL Geometric Coefficient of Variation 28.5	22.00 ng/mL Geometric Coefficient of Variation 18.0
Plasma Concentration of Morphine Over Time Day 15 (2 hour)	20.54 ng/mL Geometric Coefficient of Variation 31.2	18.09 ng/mL Geometric Coefficient of Variation 21.6
Plasma Concentration of Morphine Over Time Day 15 (3 hour)	14.16 ng/mL Geometric Coefficient of Variation 29.1	13.99 ng/mL Geometric Coefficient of Variation 19.6
Plasma Concentration of Morphine Over Time Day 15 (4 hour)	10.74 ng/mL Geometric Coefficient of Variation 33.5	10.00 ng/mL Geometric Coefficient of Variation 23.6
Plasma Concentration of Morphine Over Time Day 15 (6 hour)	5.06 ng/mL Geometric Coefficient of Variation 41.5	4.87 ng/mL Geometric Coefficient of Variation 35.8
Plasma Concentration of Morphine Over Time Day 15 (12 hour)	1.42 ng/mL Geometric Coefficient of Variation 30.0	1.36 ng/mL Geometric Coefficient of Variation 26.1
Plasma Concentration of Morphine Over Time Day 15 (24 hour)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.
Plasma Concentration of Morphine Over Time Day 15 (36 hour)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

Plasma concentration of morphine-3-glucuronide over time are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (predose)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (0.08 hours)	261.17 ng/mL Geometric Coefficient of Variation 42.9	330.85 ng/mL Geometric Coefficient of Variation 16.9
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (0.25 hours)	287.69 ng/mL Geometric Coefficient of Variation 28.3	336.02 ng/mL Geometric Coefficient of Variation 12.7
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (0.5 hours)	282.31 ng/mL Geometric Coefficient of Variation 27.1	311.44 ng/mL Geometric Coefficient of Variation 10.9
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (1 hours)	257.89 ng/mL Geometric Coefficient of Variation 27.7	276.48 ng/mL Geometric Coefficient of Variation 14.7
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (1.5 hours)	244.91 ng/mL Geometric Coefficient of Variation 22.4	247.20 ng/mL Geometric Coefficient of Variation 15.5
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (2 hours)	222.77 ng/mL Geometric Coefficient of Variation 20.1	215.93 ng/mL Geometric Coefficient of Variation 18.5
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (3 hours)	179.81 ng/mL Geometric Coefficient of Variation 24.0	163.04 ng/mL Geometric Coefficient of Variation 39.6
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (4 hours)	146.71 ng/mL Geometric Coefficient of Variation 24.6	146.83 ng/mL Geometric Coefficient of Variation 19.0
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (6 hours)	97.80 ng/mL Geometric Coefficient of Variation 24.3	92.21 ng/mL Geometric Coefficient of Variation 21.7
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (8 hours)	65.29 ng/mL Geometric Coefficient of Variation 23.1	57.07 ng/mL Geometric Coefficient of Variation 30.3
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (12 hours)	30.21 ng/mL Geometric Coefficient of Variation 44.6	35.03 ng/mL Geometric Coefficient of Variation 43.0
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (24 hours)	23.17 ng/mL Geometric Coefficient of Variation 32.8	27.71 ng/mL Geometric Coefficient of Variation 32.8
Plasma Concentration of Morphine-3-glucuronide Over Time Day 1 (36 hours)	12.53 ng/mL Geometric Coefficient of Variation 48.8	14.19 ng/mL Geometric Coefficient of Variation 39.6
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (predose)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (0.08 hours)	235.04 ng/mL Geometric Coefficient of Variation 42.8	255.36 ng/mL Geometric Coefficient of Variation 31.2
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (0.25 hours)	262.41 ng/mL Geometric Coefficient of Variation 34.6	289.85 ng/mL Geometric Coefficient of Variation 14.2
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (0.5 hours)	263.96 ng/mL Geometric Coefficient of Variation 34.7	278.58 ng/mL Geometric Coefficient of Variation 16.7
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (1 hours)	254.13 ng/mL Geometric Coefficient of Variation 21.3	264.39 ng/mL Geometric Coefficient of Variation 11.8
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (1.5 hours)	234.80 ng/mL Geometric Coefficient of Variation 19.5	243.99 ng/mL Geometric Coefficient of Variation 13.7
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (2 hours)	213.71 ng/mL Geometric Coefficient of Variation 19.6	218.39 ng/mL Geometric Coefficient of Variation 14.8
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (3 hours)	176.05 ng/mL Geometric Coefficient of Variation 22.2	179.70 ng/mL Geometric Coefficient of Variation 16.0
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (4 hours)	144.41 ng/mL Geometric Coefficient of Variation 24.8	145.37 ng/mL Geometric Coefficient of Variation 19.5
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (6 hours)	91.78 ng/mL Geometric Coefficient of Variation 41.4	91.87 ng/mL Geometric Coefficient of Variation 15.8
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (8 hours)	62.28 ng/mL Geometric Coefficient of Variation 28.5	59.38 ng/mL Geometric Coefficient of Variation 21.4
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (12 hours)	39.26 ng/mL Geometric Coefficient of Variation 34.7	30.01 ng/mL Geometric Coefficient of Variation 47.6
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (24 hours)	24.87 ng/mL Geometric Coefficient of Variation 31.9	27.49 ng/mL Geometric Coefficient of Variation 24.3
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (36 hours)	11.78 ng/mL Geometric Coefficient of Variation 53.7	16.90 ng/mL Geometric Coefficient of Variation 26.2
Plasma Concentration of Morphine-3-glucuronide Over Time Day 15 (48 hours)	6.76 ng/mL Geometric Coefficient of Variation 38.0	8.40 ng/mL Geometric Coefficient of Variation 30.5

SECONDARY outcome

Timeframe: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number analyzed (n) denotes those participants who had adequate plasma samples.

Plasma concentration of morphine-6-glucuronide over time are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (predose)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (0.08 hours)	22.52 ng/mL Geometric Coefficient of Variation 53.0	32.79 ng/mL Geometric Coefficient of Variation 23.4
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (0.25 hours)	42.25 ng/mL Geometric Coefficient of Variation 35.8	56.30 ng/mL Geometric Coefficient of Variation 17.1
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (0.5 hours)	51.95 ng/mL Geometric Coefficient of Variation 27.4	62.02 ng/mL Geometric Coefficient of Variation 8.9
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (1 hours)	51.22 ng/mL Geometric Coefficient of Variation 24.5	57.49 ng/mL Geometric Coefficient of Variation 16.2
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (1.5 hours)	46.95 ng/mL Geometric Coefficient of Variation 17.7	50.15 ng/mL Geometric Coefficient of Variation 13.6
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (2 hours)	41.86 ng/mL Geometric Coefficient of Variation 16.0	42.36 ng/mL Geometric Coefficient of Variation 22.5
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (3 hours)	31.64 ng/mL Geometric Coefficient of Variation 18.3	29.23 ng/mL Geometric Coefficient of Variation 37.9
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (4 hours)	23.97 ng/mL Geometric Coefficient of Variation 20.3	25.24 ng/mL Geometric Coefficient of Variation 20.2
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (6 hours)	14.95 ng/mL Geometric Coefficient of Variation 23.5	14.55 ng/mL Geometric Coefficient of Variation 24.0
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (8 hours)	9.05 ng/mL Geometric Coefficient of Variation 22.3	8.32 ng/mL Geometric Coefficient of Variation 32.7
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (12 hours)	3.83 ng/mL Geometric Coefficient of Variation 41.4	4.88 ng/mL Geometric Coefficient of Variation 46.8
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (24 hours)	3.45 ng/mL Geometric Coefficient of Variation 43.1	4.30 ng/mL Geometric Coefficient of Variation 37.1
Plasma Concentration of Morphine-6-glucuronide Over Time Day 1 (36 hours)	1.76 ng/mL Geometric Coefficient of Variation 45.5	1.91 ng/mL Geometric Coefficient of Variation 40.9
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (predose)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (0.08 hours)	20.40 ng/mL Geometric Coefficient of Variation 55.9	23.45 ng/mL Geometric Coefficient of Variation 44.8
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (0.25 hours)	37.25 ng/mL Geometric Coefficient of Variation 43.5	46.21 ng/mL Geometric Coefficient of Variation 21.8
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (0.5 hours)	48.42 ng/mL Geometric Coefficient of Variation 34.5	56.18 ng/mL Geometric Coefficient of Variation 19.4
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (1 hours)	51.86 ng/mL Geometric Coefficient of Variation 18.6	57.32 ng/mL Geometric Coefficient of Variation 13.0
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (1.5 hours)	47.25 ng/mL Geometric Coefficient of Variation 15.7	52.46 ng/mL Geometric Coefficient of Variation 14.1
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (2 hours)	41.51 ng/mL Geometric Coefficient of Variation 16.4	46.16 ng/mL Geometric Coefficient of Variation 15.5
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (3 hours)	32.10 ng/mL Geometric Coefficient of Variation 14.8	34.90 ng/mL Geometric Coefficient of Variation 17.5
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (4 hours)	25.57 ng/mL Geometric Coefficient of Variation 15.6	26.76 ng/mL Geometric Coefficient of Variation 19.0
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (6 hours)	14.39 ng/mL Geometric Coefficient of Variation 34.7	15.20 ng/mL Geometric Coefficient of Variation 20.3
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (8 hours)	8.93 ng/mL Geometric Coefficient of Variation 23.6	9.15 ng/mL Geometric Coefficient of Variation 25.8
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (12 hours)	5.57 ng/mL Geometric Coefficient of Variation 37.0	4.39 ng/mL Geometric Coefficient of Variation 54.5
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (24 hours)	3.84 ng/mL Geometric Coefficient of Variation 34.4	4.43 ng/mL Geometric Coefficient of Variation 32.2
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (36 hours)	1.73 ng/mL Geometric Coefficient of Variation 47.3	2.51 ng/mL Geometric Coefficient of Variation 27.0
Plasma Concentration of Morphine-6-glucuronide Over Time Day 15 (48 hours)	NA ng/mL Geometric Coefficient of Variation NA Data was not reported as the value was below the lower limit of quantification.	1.34 ng/mL Geometric Coefficient of Variation 33.5

SECONDARY outcome

Timeframe: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose, and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose

Population: PK population included all participants in the safety population who received at least 1 dose of morphine or AZD4041 and have at least 1 PK concentration after dosing. Number of participants analyzed (N) denotes those participants who received at least one dose of AZD4041. Number analyzed (n) denotes those participants who had adequate plasma samples.

Plasma concentration of AZD4041 over time are reported.

Outcome measures

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=25 Participants Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Plasma Concentration of AZD4041 Over Time Day 8 (4 hours)	508.05 ng/mL Geometric Coefficient of Variation 30.2	—
Plasma Concentration of AZD4041 Over Time Day 8 (6 hours)	353.26 ng/mL Geometric Coefficient of Variation 33.5	—
Plasma Concentration of AZD4041 Over Time Day 8 (predose)	133.83 ng/mL Geometric Coefficient of Variation 66.4	—
Plasma Concentration of AZD4041 Over Time Day 8 (0.08 hours)	186.27 ng/mL Geometric Coefficient of Variation 47.3	—
Plasma Concentration of AZD4041 Over Time Day 8 (0.25 hours)	435.07 ng/mL Geometric Coefficient of Variation 44.6	—
Plasma Concentration of AZD4041 Over Time Day 8 (0.5 hours)	690.91 ng/mL Geometric Coefficient of Variation 28.7	—
Plasma Concentration of AZD4041 Over Time Day 8 (1 hours)	623.75 ng/mL Geometric Coefficient of Variation 28.5	—
Plasma Concentration of AZD4041 Over Time Day 8 (1.5 hours)	602.16 ng/mL Geometric Coefficient of Variation 32.6	—
Plasma Concentration of AZD4041 Over Time Day 8 (2 hours)	576.78 ng/mL Geometric Coefficient of Variation 25.2	—
Plasma Concentration of AZD4041 Over Time Day 8 (3 hours)	531.67 ng/mL Geometric Coefficient of Variation 29.9	—
Plasma Concentration of AZD4041 Over Time Day 8 (8 hours)	327.88 ng/mL Geometric Coefficient of Variation 34.6	—
Plasma Concentration of AZD4041 Over Time Day 8 (12 hours)	227.32 ng/mL Geometric Coefficient of Variation 41.2	—
Plasma Concentration of AZD4041 Over Time Day 8 (24 hours)	136.56 ng/mL Geometric Coefficient of Variation 57.7	—
Plasma Concentration of AZD4041 Over Time Day 15 (predose)	149.54 ng/mL Geometric Coefficient of Variation 67.1	—
Plasma Concentration of AZD4041 Over Time Day 15 (0.08 hours)	192.53 ng/mL Geometric Coefficient of Variation 53.2	—
Plasma Concentration of AZD4041 Over Time Day 15 (0.25 hours)	369.16 ng/mL Geometric Coefficient of Variation 52.5	—
Plasma Concentration of AZD4041 Over Time Day 15 (0.5 hours)	467.16 ng/mL Geometric Coefficient of Variation 45.1	—
Plasma Concentration of AZD4041 Over Time Day 15 (1 hours)	504.23 ng/mL Geometric Coefficient of Variation 33.6	—
Plasma Concentration of AZD4041 Over Time Day 15 (1.5 hours)	546.10 ng/mL Geometric Coefficient of Variation 35.0	—
Plasma Concentration of AZD4041 Over Time Day 15 (2 hours)	523.23 ng/mL Geometric Coefficient of Variation 33.4	—
Plasma Concentration of AZD4041 Over Time Day 15 (3 hours)	566.76 ng/mL Geometric Coefficient of Variation 23.2	—
Plasma Concentration of AZD4041 Over Time Day 15 (4 hours)	524.01 ng/mL Geometric Coefficient of Variation 34.6	—
Plasma Concentration of AZD4041 Over Time Day 15 (6 hours)	432.55 ng/mL Geometric Coefficient of Variation 29.7	—
Plasma Concentration of AZD4041 Over Time Day 15 (8 hours)	380.48 ng/mL Geometric Coefficient of Variation 33.5	—
Plasma Concentration of AZD4041 Over Time Day 15 (12 hours)	264.56 ng/mL Geometric Coefficient of Variation 39.4	—
Plasma Concentration of AZD4041 Over Time Day 15 (24 hours)	157.21 ng/mL Geometric Coefficient of Variation 53.4	—
Plasma Concentration of AZD4041 Over Time Day 15 (36 hours)	54.33 ng/mL Geometric Coefficient of Variation 94.5	—
Plasma Concentration of AZD4041 Over Time Day 15 (48 hours)	33.77 ng/mL Geometric Coefficient of Variation 133.2	—
Plasma Concentration of AZD4041 Over Time Day 15 (72 hours)	7.97 ng/mL Geometric Coefficient of Variation 240.0	—

Adverse Events

Morphine Then AZD4041 Then Morphine + AZD4041

Serious events: 0 serious events

Other events: 26 other events

Deaths: 0 deaths

Morphine Then Placebo Then Morphine + Placebo

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Morphine Then AZD4041 Then Morphine + AZD4041 n=26 participants at risk Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.	Morphine Then Placebo Then Morphine + Placebo n=15 participants at risk Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.
Eye disorders Visual impairment	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Gastrointestinal disorders Abdominal discomfort	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Gastrointestinal disorders Abdominal pain	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	13.3% 2/15 • Number of events 2 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Gastrointestinal disorders Constipation	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	13.3% 2/15 • Number of events 2 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Gastrointestinal disorders Diarrhoea	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Gastrointestinal disorders Dry mouth	7.7% 2/26 • Number of events 2 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Gastrointestinal disorders Nausea	26.9% 7/26 • Number of events 9 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	40.0% 6/15 • Number of events 11 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Gastrointestinal disorders Toothache	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Gastrointestinal disorders Vomiting	30.8% 8/26 • Number of events 11 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	40.0% 6/15 • Number of events 11 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Cardiac disorders Atrioventricular block second degree	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Chest discomfort	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Discomfort	15.4% 4/26 • Number of events 5 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	13.3% 2/15 • Number of events 3 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Feeling abnormal	15.4% 4/26 • Number of events 4 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	20.0% 3/15 • Number of events 4 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Feeling hot	46.2% 12/26 • Number of events 14 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	46.7% 7/15 • Number of events 10 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Feeling of relaxation	11.5% 3/26 • Number of events 3 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Gait disturbance	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Injection site haematoma	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Injection site reaction	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Non-cardiac chest pain	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
General disorders Vessel puncture site haematoma	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Cardiac disorders Extrasystoles	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Investigations Alanine aminotransferase increased	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Investigations End-tidal Co2 increased	7.7% 2/26 • Number of events 2 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Investigations Oxygen saturation decreased	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Musculoskeletal and connective tissue disorders Myalgia	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lipoma	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Nervous system disorders Dizziness	15.4% 4/26 • Number of events 6 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Nervous system disorders Head discomfort	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Nervous system disorders Headache	11.5% 3/26 • Number of events 5 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	33.3% 5/15 • Number of events 6 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Nervous system disorders Hypoaesthesia	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Nervous system disorders Paraesthesia	11.5% 3/26 • Number of events 3 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Cardiac disorders Palpitations	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Nervous system disorders Sedation	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Nervous system disorders Somnolence	46.2% 12/26 • Number of events 14 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	46.7% 7/15 • Number of events 8 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Psychiatric disorders Euphoric mood	46.2% 12/26 • Number of events 17 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	80.0% 12/15 • Number of events 18 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Respiratory, thoracic and mediastinal disorders Sneezing	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Skin and subcutaneous tissue disorders Dermatitis contact	15.4% 4/26 • Number of events 4 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	26.7% 4/15 • Number of events 4 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Skin and subcutaneous tissue disorders Eczema	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Skin and subcutaneous tissue disorders Erythema	7.7% 2/26 • Number of events 2 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Skin and subcutaneous tissue disorders Hyperhidrosis	7.7% 2/26 • Number of events 2 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Skin and subcutaneous tissue disorders Pruritus	34.6% 9/26 • Number of events 11 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	13.3% 2/15 • Number of events 2 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Cardiac disorders Ventricular extrasystoles	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Skin and subcutaneous tissue disorders Urticaria	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Vascular disorders Hot flush	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Cardiac disorders Ventricular tachycardia	3.8% 1/26 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Eye disorders Asthenopia	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	13.3% 2/15 • Number of events 2 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Eye disorders Lacrimation increased	3.8% 1/26 • Number of events 2 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	0.00% 0/15 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.
Eye disorders Vision blurred	0.00% 0/26 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.	6.7% 1/15 • Number of events 1 • Day 1 through end of study (Day 24) The safety population included all participants who received at least 1 dose of morphine.

Additional Information

Global Clinical Lead

AstraZeneca

Phone: +1-877-240-9479

Email: information.center@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee AstraZeneca has 60 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.
• Publication restrictions are in place

Restriction type: OTHER