Clinical trial NCT02223377
Conditions: Pain Post Operative Nausea and Vomiting
Sponsor: McMaster University
Start date: 2015-01-01; Completion date: 2019-03-01
Enrollment: 402 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Currently nearly 70% or more surgeries are being done as ambulatory (day care) procedures as they offer significant benefit to the patients as well as to the hospitals. Inadequate pain relief (30%-40%) and nausea-vomiting form the leading factors affecting the quality of care and hence its efficiency. Opioids form the primary modality to treat moderate to severe pain, but can also cause significant nausea-vomiting and other side effects. Although hydromorphone is five times more potent than morphine, in equianalgesic doses they both could provide similar pain relief. They both exert no ceiling effect for their analgesia, and hence incomplete or inadequate analgesia is related to the appearance of side effects. In this study the investigators shall assess the proportion of patients who satisfy the outcome of 'satisfactory analgesia with minimal nausea-vomiting' in ambulatory surgeries, assessed at 2 hours after surgery. Patients would be randomized to receive either morphine or hydromorphone in the surgical recovery area. All personnel involved with the study would be blinded. The investigators will also look to assess the time to discharge and other side effects. This will help to choose the better drug, thereby improving pain relief and side effects, and also the efficiency of health care delivery.

Detailed description:
There has been an exponential increase in the number of day case surgical procedures also called as ambulatory surgeries (AS), over the last 2 years.(1) Currently around 70% of procedures are being done as AS, with known benefits to patients and hospitals.(2) Its efficiency and cost effectiveness depends upon its organization and delivery of services. Pain and PONV are recognized as the leading factors affecting the quality of services delivered under AS,(1,3) and they affect the recovery, discharge, and overall satisfaction of patients.(4,5) According to literature, postsurgical pain could be inadequately treated in 30%-60% of patients and 30%-40% of AS patients suffer from significant PONV.(3,6,7) It is estimated that a single episode of PONV can prolong the PACU stay by 25 mins,(8) and patients rate PONV to be the most undesirable outcome associated with anesthesia.(4) Despite the increasing use of non-opioid analgesics, opioid analgesics have remained the primary modality in moderate to severe pain.(7) They cause several side effects such as drowsiness, sedation, PONV, itching and respiratory depression. Appropriate selection of opioid medications becomes significantly important to deliver safe and effective analgesia with minimal side effects. Although M has been the most commonly used medication, HM is also being increasingly used.(9) We do not yet know whether HM is more effective than M in AS patients. Both M and HM exert no ceiling effect for their analgesia, and by this nature incomplete or inadequate analgesia is related to the appearance of side effects.(10) Hence clinical effectiveness of opioids, relative to each other, is reflected not just by satisfactory analgesia, but by a combination of 'satisfactory analgesia with limited side effects'. Clinical observation suggests that HM is clinically better by providing superior or equivalent analgesia with decreased side effects.(9) HM is a semi-synthetic morphine derivative that differs from M in its position 6 of the benzol ring, where it has a keto-group instead of a hydroxy group, making it 5-10 times more potent and enhances its distribution to cerebral tissues, making for easier titration.(9) The t1/2 Ke0 (transfer life from plasma to effect site) is 1.6hr - 4 hr for M, compared to 18-38 min for HM.(9,10) It is observed that health care providers may be willing to provide higher dose of HM compared to M in EMU, as its actual quantity of drug is much smaller and therefore appears to cause less concern.(12, 13) Our literature review showed that there are no previous studies comparing these 2 medications in AS patients. The lone systematic review compared various acute and chronic pain studies, in various routes of drug administration.(9) Of the 11 studies identified; only 4 were done in acute pain settings.(13-16) Two of them were done by the same author in ER settings. Chang et al noted that HM reduced the mean pain scores by 1.3 units \[95% CI= (-2.2 to -0.5)\] compared to M in 198 adults treated in ER.(12,13). However it did not show much difference in geriatric population.14 In perioperative settings, Hong et al studied the difference in nausea between the 2 medications in 50 patients using PCA and found no difference.(15) Rapp et al studied various effects between the 2 medications in 61 surgical patients using PCA. There is not much clarity about their primary outcome; however they found the effects to be similar.(16) Both these studies had smaller sample sizes. The meta-analysis performed demonstrated that the HM does provide better analgesia than M, with a small effect size; Cohen's d=0.266 (p=0.012).(9) Looked at acute pain alone it was statistically significant (p=0.006), compared to chronic pain (p=0.889). It was noted that that there is a definite lack of comparative studies between them in surgical settings.

Arms: arm 1: Analgesia with equipotent doses of Morphine and Hydromorphone will be administered in titrated doses. Doses are 1ml=1mg of morphine or 0.2 mg of hydromorphone. Potency ratio of 1:5 (M: HM).

0.05mg/kg morphine units (rounding off to the nearest 1 ml or 0.5 ml) arm 2: Analgesia with equipotent doses of Morphine and Hydromorphone will be administered in titrated doses. Doses are 1ml=1mg of morphine or 0.2 mg of hydromorphone. Potency ratio of 1:5 (M: HM).

0.05mg/kg morphine units (rounding off to the nearest 1 ml or 0.5 ml)
Interventions: intervention 1: Morphine intervention 2: Hydromorphone
Intervention descriptions: intervention 1: 1st dose: syringe of 0.04mg/kg morphine units (rounding off to the nearest 1 ml or 0.5 ml); with a maximum of 3 mg of morphine equivalents is administered. Repeat doses: 0.02 mg/kg morphine units every 5-10 minutes to titrate for analgesia and side effects (rounding off to the nearest 1 ml or 0.5 ml) intervention 2: 1st dose: syringe of 0.04mg/kg morphine units (rounding off to the nearest 1 ml or 0.5 ml); with a maximum of 3 mg of morphine equivalents is administered. Repeat doses: 0.02 mg/kg morphine units every 5-10 minutes to titrate for analgesia and side effects (rounding off to the nearest 1 ml or 0.5 ml)

Protocol documents:
Prot_SAP_000.pdf: 
Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 1 of 21 
 
 
Abbreviations to terms used  
 
 
 
 
 
 
 
Background and Rationale 
There has been an exponential increase in the number of day case surgical procedures also called 
as ambulatory surgeries (AS), over the last 2 years.(1) Currently around 70% of procedures are 
being done as AS, with known benefits to patients and hospitals.(2) Its efficiency and cost 
effectiveness depends upon its organization and delivery of services. Pain and PONV are 
recognized as the leading factors affecting the quality of services delivered under AS,(1,3) and 
they affect the recovery, discharge, and overall satisfaction of patients.(4,5) According to 
literature, postsurgical pain could be inadequately treated in 30%-60% of patients and 30%-40% 
of AS patients suffer from significant PONV.(3,6,7) It is estimated that a single episode of PONV 
can prolong the PACU stay by 25 mins,(8) and patients rate PONV to be the most undesirable 
outcome associated with anesthesia.(4) Despite the increasing use of non-opioid analgesics, 
opioid analgesics have remained the primary modality in moderate to severe pain.(7) They cause 
several side effects such as drowsiness, sedation, PONV, itching and respiratory depression. 
Appropriate selection of opioid medications becomes significantly important to deliver safe and 
effective analgesia with minimal side effects. Although M has been the most commonly used 
medication, HM is also being increasingly used.(9) We do not yet know whether HM is more 
effective than M in AS patients. Both M and HM exert no ceiling effect for their analgesia, and 
by this nature incomplete or inadequate analgesia is related to the appearance of side effects.(10) 
Hence clinical effectiveness of opioids, relative to each other, is reflected not just by satisfactory 
analgesia, but by a combination of ‘satisfactory analgesia with limited side effects’. Clinical 
observation suggests that HM is clinically better by providing superior or equivalent analgesia 
with decreased side effects.(9) HM is a semi-synthetic morphine derivative that differs from M in 
its position 6 of the benzol ring, where it has a keto-group instead of a hydroxy group, making it 
SAME: Satisfactory Analgesia with Minimal Emesis 
PACU: Post Anesthesia Care Unit 
PONV: Post Operative Nausea Vomiting 
NAS: Numerical Analogue Scale 
VDS: Verbal Descriptive Scale 
EMU: Equivalent Morphine Units 
PCA: Patient Controlled Analgesia 
CPSP: Chronic postsurgical pain 
M: Morphine 
HM: Hydromorphone 
AS: Ambulatory Surgeries 
ER: Emergency Room 
OR: Operating Room 
DSU: Day Surgery Unit 
RA: Research Assistant 
CRF: Case Record Form 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 2 of 21 
 
 
5–10 times more potent and enhances its distribution to cerebral tissues, making for easier 
titration.(9) The t1/2 Ke0 (transfer life from plasma to effect site) is 1.6hr – 4 hr for M, compared 
to 18-38 min for HM.(9,10) It is observed that health care providers may be willing to provide 
higher dose of HM compared to M in EMU, as its actual quantity of drug is much smaller and 
therefore appears to cause less concern.(12, 13) Our literature review showed that there are no 
previous studies comparing these 2 medications in AS patients. The lone systematic review 
compared various acute and chronic pain studies, in various routes of drug administration.(9) Of 
the 11 studies identified; only 4 were done in acute pain settings.(13-16) Two of them were done by 
the same author in ER settings. Chang et al noted that HM reduced the mean pain scores by 1.3 
units [95% CI= (-2.2 to -0.5)] compared to M in 198 adults treated in ER.(12,13). However it did 
not show much difference in geriatric population.14 In perioperative settings, Hong et al studied 
the difference in nausea between the 2 medications in 50 patients using PCA and found no 
difference.(15) Rapp et al studied various effects between the 2 medications in 61 surgical patients 
using PCA. There is not much clarity about their primary outcome; however they found the 
effects to be similar.(16) Both these studies had smaller sample sizes. The meta-analysis 
performed demonstrated that the HM does provide better analgesia than M, with a small effect 
size; Cohen’s d=0.266 (p=0.012).(9) Looked at acute pain alone it was statistically significant 
(p=0.006), compared to chronic pain (p=0.889). It was noted that that there is a definite lack of 
comparative studies between them in surgical settings.  
Patients Symptoms after Discharge 
It is being appreciated that, research and health care delivery have not focussed much on the post 
discharge symptoms after day surgeries. In this direction, two crucial aspects are to be 
considered. Compared to inpatients, ambulatory surgery patients have less efficient access to 
health services.(18) It is wrong to assume that the burden of pain, nausea and other symptoms, 
after ambulatory surgery patients, is not substantial. A significant number of patients suffer from 
continuing pain even at 24 hours, or a week after surgery.(19) Up to 1/3rd or more number of 
patients suffer from nausea or vomiting after surgery. Studies have shown that differences in 
anesthetic management, and choice of medications (even with non-analgesic medications such as 
propofol or sevoflurane) have made a difference in patient’s perception of pain in ambulatory 
surgeries in the first 24 hrs, and beyond.(19) A systematic review noted that only around 30%-
42% of studies on ambulatory surgery patients, assessed for pain, nausea, and vomiting after 
discharge.(20) Due to significant heterogeneity, and study limitations, appropriate figures of 
observed incidence could not be calculated. Several of the included studies were also not well 
designed. Similarly, day surgery patients can also suffer from chronic postsurgical pain (CPSP), 
at 1 year or more after surgeries. It has been observed that up to 10%-50% patients, and 2%-11% 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 3 of 21 
 
 
patients, suffer from moderate and severe level of CPSP.(21) The definition of CPSP, in terms of 
the duration after surgery, has not been clearly identified. However, persistence beyond 2 months 
is normally considered as CPSP.(22) Specific to day surgeries, not many studies have assessed the 
incidence of CPSP and its predictive factors. A recent, large observational study, involving 908 
patients, observed a CPSP (moderate to severe) rate of 15.3% after day surgeries. (23) They found 
that surgical specialty, preoperative pain, preoperative analgesic use, acute postoperative pain, 
surgical fear, lack of optimism and poor preoperative quality of life, as factors predictive of 
CPSP.  
Hence, we will also look for any differences in pain, nausea and vomiting over the first 24 hrs 
after the surgery, along with chances of readmission or ER visits within the same period, post 
discharge. At 3 months, we will look for the incidence of persisting pain after surgery.   
Hypothesis  
In patients who undergo ambulatory surgical procedures causing at least moderate pain, 
hydromorphone (HM) increases the proportion of patients who would demonstrate ‘satisfactory 
analgesia [=<4/10 NAS] with minimal or no postoperative nausea-vomiting (PONV) [<2/5 
VDS]’ as compared to morphine (M), when both are administered intravenously, in 
equianalgesic doses, and are compared at 2 hours after surgery in PACU.  
 
2. Specific Objectives  
The primary objective of this study is to compare the proportion of patients with SAME 
(satisfactory analgesia and minimal emesis) after AS, when using M compared with HM, during 
the immediate postoperative hospital stay.  
 
Secondary objectives include: 
1. Total dose of analgesic used in PACU, in morphine equivalents, 
2. Time to discharge or readiness to discharge from the DSU, 
3. Proportion of pain, and its comparison after discharge, within 24 hours, 
4. Proportion of nausea, and its comparison after discharge, within 24 hours, 
5. Proportion of vomiting, and its comparison after discharge, within 24 hours, 
6. Incidence of CPSP at 3 months after discharge 
 
The tertiary objectives include:  
 
1. Proportion of patients with severe itching,  


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 4 of 21 
 
 
2. Proportion of patients with significant sedation,  
3. Proportion of patients with significant respiratory depression,  
4. Patient satisfaction score at the time of discharge,  
5. Time to discharge or readiness to discharge from the PACU,  
6. Use of ketorolac as a rescue medication, 
 
METHODS 
The study is designed as a multisite, 2 arm, parallel, superiority design with randomization of 
patients and blinding of patients, health care providers (physicians and nurses) and research 
personnel (research coordinator and data analyst). Patients will be stratified based on site and 
laparoscopic/open surgeries. Intention to treat approach will be used for design and analysis.  
 
Patient Selection and Recruitment: Patients’, who undergo AS of the abdominal and pelvic 
regions, within the scope of general surgical (GS), gastrointestinal (GI) and gynecological 
(GYN) specialties, shall be considered. Patients shall be considered for the study if they fulfill 
the following selection criteria. They would be screened on the day of their preoperative 
appointment, assessed for eligibility and then if they agree, obtain consent.   
The inclusion criteria will include: age 18 yrs to 70 yrs ; ambulatory surgeries producing at least 
moderate pain-such as cholecystectomy, appendicectomy, ovarian cystectomy, inguinal hernia 
repair, abdominal wall hernias; and an ability to communicate in English.  
Exclusion criteria will include: allergy to M or HM; patient on regular chronic opioid 
medication; patient uncontrolled systemic disease; severe obesity with a BMI >35; significant 
psychological impairment; history of drug addiction or dependence; any planned regional or 
nerve block other than local anesthesia infiltration; patients with confirmed sleep apnea; 
emergency surgeries and urological surgeries. 
Suitable patients will be screened before their visit to ‘pre-anesthetic visit’. During their visit, 
they will be approached by a trained RA, involved with the study. Relevant information will be 
provided, along with a letter of information about the research study. Consent of willing patients 
will be obtained, along with their baseline, and demographic variables. The consent will include 
the study process, and also willingness to be followed, and contacted at 24 hours and at 3 months 
after surgery.  
On the day of surgery, at DSU, patients’ consent will be confirmed. Relevant baseline variables 
of the recruited patients shall be noted (appendix 1). The concerned OR anesthesiologist is 
informed of the patient’s inclusion to the study and reinforced about the study methodology 
(appendix 2).  


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 5 of 21 
 
 
 
Allocation and Randomization: Treatment allocation will be done using a random, computer 
generated table, with an allocation ratio of 1:1, using random permuted block sizes. Stratification 
based on each centre (3 sites).  These syringes (4*10 mls)-in sealed packages, labelled with serial 
numbers and no identifiers for the medication, shall be deposited in a safe drug locker, within the 
fridge, at the respective PACU. The actual randomization, for each patient happens as they enter 
into the PACU after surgery. The PACU nurse allotted for that patient will obtain the next 
medication package in series to be used for that patient. To ensure that the respective patient and 
medication is matched for subsequent analysis, the nurse will attach the medication sequence 
number on the patient study records, with no identifiers of actual drug. The PACU nurse shall 
also note down the patient hospital ID on the medication syringe, once it is taken out, to ensure 
there is no mix up.  
 
Blinding: The study allocation will be blinded to patients, treating nurses, physicians, research 
assistant and investigators. The allocation order will be available only to the person responsible 
for randomizing and the pharmacists involved in the study at each centre.  
 
Application of Intervention:  
The Operating Room Protocol: Patients included in the study need to be managed according the 
OR protocol provided in Appendix 2. In brief, the patient will only have a GA, with local 
infiltration provided at the end of the surgery. Long acting opioid medications (morphine and 
hydromorphone) are not administered in the OR. LA infiltration is done within a range of 20-30 
mls (based on laparoscopic or open surgeries) using 0.25% bupivacaine with or without 
adrenaline.  
 
PACU Stay: The actual study intervention (hence randomization) will only become applicable 
once the patient is moved to the PACU.  Every patient will be treated as per the protocol during 
the intraoperative management, which primarily restricts the use of any study opioids. The 
details are provided in appendix 2. The nurse looking after the study patient in PACU will 
administer the medication as per the study protocol. This would include analgesia with 
equipotent doses of M or HM administered in titrated doses. Syringes will be pre-prepared from 
the pharmacy in EMUs; 1ml=1mg of morphine or 0.2 mg of hydromorphone. We shall consider 
a potency ratio of 1:5 (M: HM), considered equivalent in literature.(9) Analgesia will be provided 
according to the following guideline.  A similar method has been advised to be safe and effective 
for titrated analgesia in PACU.(24) Readiness to discharge from PACU and outcomes are noted at 
2 hrs, or at the time of discharge to DSU. 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 6 of 21 
 
 
 
 
PACU Protocol (titrate the opioid medication to achieve desired pain score) 
 Patient to be asked for their pain score, and if it is more than 4 out of 10 (NAS): to receive 
the 1st dose within 5 minutes after coming to PACU: 0.04mg/kg morphine units (rounding off 
to the nearest 1 ml or 0.5 ml); with a maximum of 3 mg of morphine equivalents. 
 Repeat doses: 0.02 mg/kg morphine units every 5-10 minutes to titrate for analgesia and side 
effects (rounding off to the nearest 1 ml or 0.5 ml) 
 If no side effects observed-titrate to have analgesia: NAS =<4/10.  
 If Nausea-Vomiting observed: record it in the CRF provided and treat it with antiemetics 
(Ondansetron 1-4 mg IV, Dimenhydrinate 25-50 mg) 
 If patient is too sedated (<3-Ramsey Sedation Scale)-withhold the next dose and restart the 
bolus if the score is >3 
 If respiratory depression present, withhold the next dose, treat with Naloxone if necessary. 
 Ketorolac IV 15-30 mg as rescue medication if patient does not tolerate the study opioid or if 
the patient does not satisfy the success of satisfactory analgesia at more than 1 hr. 
 
DSU Stay and Protocol: 
At the end of 2 hours or after satisfactory completion of primary endpoints, patients shall be 
transferred to DSU. At the DSU, in both groups, patients shall be given oral Oxycocet 
(combination of oxycodone and paracetamol) or Tylenol 3 (combination of codeine and 
paracetamol), as a PRN medication, if necessitated by the patient’s pain. Nurses shall note down 
the occurrence of any pain and nausea necessitating treatment in the patient’s CRF. Readiness to 
discharge home is noted down for each patient. The RA shall collect the CRFs from PACU and 
DSU and deposit safely in a locked filing cabinet. 
 
Planned Outcomes: Our combined primary outcome will be proportion of patients with SAME, 
as compared between the 2 groups. Analgesia will be based on NAS 0-10 (appendix 3), and 
PONV will be based on VDS 0-5 (appendix 3). These observations will be made at the end of 2 
hrs or before (corresponding to the time of discharge from PACU), by the PACU nurse, in the 
specified CRF. All the other outcomes to be recorded within the hospital, along with the time of 
their measurement and proposed analysis method are noted in table 1. 
 
Sample Size Calculation: It was calculated based on the primary, binary outcome of proportion 
of patients with SAME, which will be compared using a chi-square test. According to literature, 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 7 of 21 
 
 
approximately 30%-40% of patients are provided with inadequate analgesia after their AS,(25, 26) 
with a similar number also known to suffer from PONV after AS.(3, 24) Our chart reviews 
suggests that approximately 20% of patients suffer from inadequate analgesia with PONV using 
morphine. For a 2-sided test, with an alpha of 0.05 and a power of 90%, and with an estimated 
effect size of 10% (p1= 80% and p2= 90%), a sample size of 266 per group was calculated. 
However, for recruitment we shall have a target of 275 per group, for a total of 550 patients 
(rounding off).  For the primary outcome analysis, we expect minimal loss through attrition as 
the study involves a follow up of few hours. The expected recruitment is approximately 20 cases 
per month at each of the 3 sites. We expect the trial to run for 10-12 months.   
 
 
Table 1: Study Outcomes, and their Measurement and Analysis 
OUTCOME 
MEASURE 
TYPE 
MEASUREMENT 
TIME OF 
MEASUREMENT 
ANALYSIS 
METHOD 
Primary outcome 
Satisfactory 
Analgesia with 
minimal PONV 
Binary 
NAS=<4/10 
 
VDS<2/5 
At 2hrs or at the time 
of discharge from 
PACU 
Chi-square 
Severe Itching 
Binary 
VAS>5/10 
At 2hrs or at the time 
of discharge from 
PACU 
Chi-square or 
Fisher’s test (as 
appropriate) 
Severe Sedation 
Binary 
Ramsey Score >3/6 
At 2hrs or at the time 
of discharge from 
PACU 
Chi-Square or 
Fisher’s test (as 
appropriate) 
Severe Respiratory 
Depression  
Count 
All cases needing 
treatment as counts 
At 2hrs or at the time 
of discharge from 
PACU 
Chi-square or 
Fisher’s test (as 
appropriate) 
Use of Ketorolac 
Continuous 
Total dose used per 
patients as a rescue 
therapy  
At 2hrs or at the time 
of discharge from 
PACU 
T test 
Mean dose of 
Analgesic Used 
Continuous 
Dose of Analgesic used 
per patient in EMU 
At the time of hospital 
discharge 
T test 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 8 of 21 
 
 
Patient 
Satisfaction-Mean 
score (0-10) 
Continuous 
Mean Score calculated 
between 0 to 5 scale 
At the time of hospital 
discharge 
T test 
Time to discharge 
from PACU 
Continuous 
Mean time in hrs 
At 2hrs or at the time 
of discharge from 
PACU 
T test 
Time to discharge 
from the hospital 
Continuous 
Mean time in hrs 
At the time of hospital 
discharge 
T test 
 
Outcomes at Post-operative Day 1:  
Patients will be approached by 1-2 phone calls shall be done during the next day; if unanswered, 
a repeat call will be made on the subsequent day (2nd day after discharge); for responders, the 
following questions will be asked. 
 
1. What was your average pain score over the last 24 hrs, in 0-10 NAS scale, after you were 
discharged home? 
 
2. After discharge, did you have nausea-severe enough to require medications at home? 
 
3. After discharge, did you have vomiting-severe enough to require medications at home? 
 
4. After discharged home, did you require a visit to ER, or readmission? 
 
Outcomes at 3 months: 
Patients will be contacted by a mailed package at 3 months after surgery to collect the following 
outcomes. 
 
1 
Do you have Persistent Pain (which started with or after surgery), at or 
near the surgical area? 
Yes or No 
2 
Intensity of Pain 
NAS: 0-10 
3 
Brief Pain Inventory-Interference Items 
7 Items: each item scored between 0-10 
 
4 
Global Impression of Change 
Likert scale 
1-7 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 9 of 21 
 
 
5 
Analgesic Use:  
Did you have to use any pain medications for more than 1 month, to 
help with pain, which started with or after Surgery? 
Yes or No 
 
Statistical Analysis: The study will be analyzed using an intention to treat approach. The 
individual outcomes along with their respective analyses method have been listed within the 
table 1. Broadly the dichotomous outcomes will be reported as proportions and analyzed using a 
chi-square test to detect a significant difference (p<0.05). Precision will be reported using 95% 
CI. Continuous outcomes will be analyzed using an unpaired 2-tailed student t test for 
significance (p<0.05). Means and standard deviations shall be reported along with 95% CI. We 
also plan to perform logistic multivariable regression analysis to account for the influence of 
baseline covariates, which are listed in appendix 1. A sensitivity analysis will be performed to 
compare the effects of laparoscopic surgeries vs open surgeries.  
 
Trial Management: This trial will be conducted at 3 hospital sites affiliated with McMaster 
University, Hamilton: St Joseph’s Hospital, McMaster University Hospital and Juravinski 
Hospital.  
 
Data Management and Quality Control: All study data including CRFs of each patient, shall 
be securely stored at the central office. A summary table indicating study timeline from 
enrollment to final follow-up (http://www.spirit-statement.org/title/) shall be included for each 
patient.(27) CRF’s will be collected as paper forms. They shall be periodically cross-checked for 
completeness and entered into a suitable electronic master file. All reports of incorrect 
randomizations, protocol violations or incomplete data shall be noted.  
 
Risk Assessment and Protocol Adherence: This trial does not entail any higher risk than the 
standard of care to the patients. This is a pragmatic trial and involves the use of medications of 
known benefit and in clinically acceptable doses. It also involves using only short acting opioids 
in the form of fentanyl or sufentanyl or remifentanyl in small boluses or infusion. Although for 
some this might differ from their normal practice, we do not anticipate this to be a major issue as 
the surgeries would be of 1-2 hrs duration and can be effectively and safely managed with short 
acting opioids until patients are shifted to PACU. Protocol also involves the use of study 
medications in PACU at an initial dose of 0.05mg/kg, followed by 0.03/mg/kg EMU boluses. 
Studies have shown that IV Morphine titration in PACU, after moderately painful surgeries 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 10 of 21 
 
 
require a mean morphine dose of 0.17 +/- 0.10 mg/kg.(17,28) Only doses as high as 0.15mg/kg 
were found to be associated with significant adverse effects.(29)  
 
Potential Pitfalls (Study Limitations): Despite being a randomized study, there exists the 
possibility of bias due to unequal distribution of unknown covariates. The primary outcome of 
SAME is being measured using subjective pain scale of NAS and VDS for emesis. Although 
there are inherent limitations of such scales, we think they are widely used in practice and are 
well validated. We have considered a potency ratio of 1: 5 (M: HM) as it is commonly used and 
supported by the literature. However, we do accept that there is a much wider range described in 
some studies.  
 
 
STUDY SIGNIFICANCE:  
The potential impact of the study could change the routine practice for anesthesiologists and 
other care providers. By choosing a better medication, physicians can be confident of their 
choice based on clear evidence, instead of a trial and error method in PACU management which 
usually leads to increased time with inferior results. The perceived advantages include better 
analgesia, less side effects, early discharge, reduced use of medications, less overall cost, and 
better patient satisfaction. These are truly reflective of what are proposed to be the most ideal 
outcomes for AS setting. (2) These results could facilitate early discharge will require lesser costs 
due to savings on manpower. The study will also provide an estimate of incidence of pain, 
nausea and vomiting after discharge, within the first 24 hrs after surgery. The burden of such a 
problem will help to organize better health service provision in future, for patients of day 
surgeries. The study will also give us an indication of incidence of persistent postoperative pain; 
and also whether better control of their acute pain makes an impact on the incidence and severity 
of persistent pain at 3 months.  


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 11 of 21 
 
 
REFERENCES 
1. Sarin P, Philip BK, Mitani A, Eappen S, Urman RD. Specialized ambulatory anesthesia 
teams contribute to decreased ambulatory surgery recovery room length of stay. Ochsner J. 
2012 Summer;12(2):94-100. 
2. Troy AM, Cunningham AJ. Ambulatory surgery: an overview. Curr Opin Anaesthesiol. 2002 
Dec;15(6):647-57. 
3. Shnaider I, Chung F. Outcomes in day surgery. Curr Opin Anaesthesiol. 2006 
Dec;19(6):622-9. 
4. Macario A, Weinger M, Carney S, Kim A. Which clinical anesthesia outcomes are important 
to avoid? The perspective of patients. Anesth Analg. 1999 Sep;89(3):652-8. 
5. Chatterjee S, Rudra A, Sengupta S. Current concepts in the management of postoperative 
nausea and vomiting. Anesthesiol Res Pract. 2011;2011:748031.  
6. Lovatsis D, José JB, Tufman A, Drutz HP, Murphy K. Assessment of patient satisfaction 
with postoperative pain management after ambulatory gynaecologic laparoscopy. J Obstet 
Gynaecol Can. 2007 Aug;29(8):664-7. 
7. White PF. Pain management after ambulatory surgery - where is the disconnect? Can J 
Anaesth. 2008 Apr;55(4):201-7. 
8. Habib AS, Chen YT, Taguchi A, Hu XH, Gan TJ. Postoperative nausea and vomiting 
following inpatient surgeries in a teaching hospital: a retrospective database analysis. Curr 
Med Res Opin. 2006 Jun;22(6):1093-9. 
9. Felden L, Walter C, Harder S, Treede RD, Kayser H, Drover D, Geisslinger G,Lötsch J. 
Comparative clinical effects of hydromorphone and morphine: a meta-analysis. Br J Anaesth. 
2011 Sep;107(3):319-28.  
10. Tramèr MR. Strategies for postoperative nausea and vomiting. Best Pract Res Clin 
Anaesthesiol. 2004 Dec;18(4):693-701.  
11. Aubrun F, Mazoit JX, Riou B. Postoperative intravenous morphine titration. Br J Anaesth. 
2012 Feb;108(2):193-201.  
12. Patanwala AE, Keim SM, Erstad BL. Intravenous opioids for severe acute pain in the 
emergency department. Ann Pharmacother. 2010 Nov;44(11):1800-9. 
13. Chang AK, Bijur PE, Meyer RH, Kenny MK, Solorzano C, Gallagher EJ. Safety and efficacy 
of hydromorphone as an analgesic alternative to morphine in acute pain: a randomized 
clinical trial. Ann Emerg Med 2006; 48: 164–72.  
14. Chang AK, Bijur PE, Baccelieri A, Gallagher EJ. Efficacy and safety profile of a single dose 
of hydromorphone compared with morphine in older adults with acute, severe pain: a 
prospective, randomized, clinical trial. Am J Geriatr Pharmacother 2009; 7: 1–10.  


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 12 of 21 
 
 
15. Hong D, Flood P, Diaz G. The side effects of morphine and hydromorphone patient-
controlled analgesia. Anesth Analg 2008; 107: 1384–9.  
16. Rapp SE, Egan KJ, Ross BK, Wild LM, Terman GW, Ching JM. A multidimensional 
comparison of morphine and hydromorphone patient-controlled analgesia. Anesth Analg 
1996; 82: 1043–8. 
17. Odom-Forren J, Rayens MK, Gokun Y et al. The Relationship of Pain and Nausea in 
Postoperative Patients for One Week after Ambulatory Surgery. Clin J Pain. 2014 Nov 3. 
[Epub ahead of print], Anesthesiology 2002; 96:994–1003). 
18. Wu CL, Berenholtz SM, Pronovost PJ, Fleisher LA. Systematic review and analysis of 
postdischarge symptoms after outpatient surgery. Anesthesiology. 2002 Apr;96(4):994-1003. 
19. Ogurlu M, Sari S, Küçük M, Bakis M, Ugur B, Eshraghi YE, Galimberti F, Turan A. 
Comparison of the effect of propofol and sevoflurane anaesthesia on acute and chronic 
postoperative pain after hysterectomy. Anaesth Intensive Care. 2014 May;42(3):365-70. 
20. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. 
Lancet. 2006 May 13;367(9522):1618-25. 
21. Macrae WA. Chronic pain after surgery. Br J Anaesth 2001; 87(1): 88-98. 
22. Hoofwijk DM, Fiddelers AA, Peters ML, et al. Prevalence and Predictive Factors of Chronic 
Postsurgical Pain and Poor Global Recovery One Year after Outpatient Surgery. Clin J 
Pain.2015 Jan 6. 
23. Aubrun F, Mazoit JX, Riou B. Postoperative intravenous morphine titration. Br J Anaesth. 
2012 Feb;108(2):193-201. 
24. Schug SA, Chong C. Pain management after ambulatory surgery. Curr Opin Anaesthesiol. 
2009 Dec;22(6):738-43. 
25. Rawal N. Analgesia for day-case surgery. Br J Anaesth. 2001 Jul;87(1):73-87. 
26. Chan A-W, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 Explanation and Elaboration: 
Guidance for protocols of clinical trials. BMJ 2013;346:e7586.  
27. Aubrun F, Langeron O, Quesnel C, Coriat P, Riou B. Relationships between measurement of 
pain using visual analog score and morphine requirements during postoperative intravenous 
morphine titration. Anesthesiology. 2003 Jun;98(6):1415-21. 
28. Aubrun F, Amour J, Rosenthal D, Coriat P, Riou B. Effects of a loading dose of morphine 
before i.v. morphine titration for postoperative pain relief: a randomized, double-blind, 
placebo-control study. Br J Anaesth. 2007 Jan;98(1):124-30.  
29. Boogaerts JG, Vanacker E, Seidel L, Albert A, Bardiau FM. Assessment of postoperative 
nausea using a visual analogue scale. Acta Anaesthesiol Scand. 2000 Apr;44(4):470-4. 
 
 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 13 of 21 
 
 
APPENDIX 1: Study Patient Case Record Form with Details to be Recorded 
 
DEMOGRAPHICS AND PATIENT INFORMATION TO BE OBTAINED FROM PATIENT 
RECORDS 
Study Number:  
 
 
Site:  SJH 
MUMC  
JH 
1 
Patient’s Hospital ID Number 
 
 
2 
Age 
 
 
3 
Gender 
M                   F 
 
4 
Height 
 
 
5 
Weight 
 
 
6 
Allergy to NSAIDS 
Y                    N 
 
7 
Allergy to LAs 
Y                    N 
 
 
INFORMATION TO BE GAINED FROM THE PATIENT MEETING  
1 
APFEL Score (for PONV prediction) 
 
Collected on 4 items-
separately 
2 
HADS Score (Hospital Anxiety Depression 
Scale) 
 
Collected on 14 items-
separately 
3 
PCS (Pain Catastrophizing Scale) 
 
Collected on 13 items -
separately 
4 
Presence of Preoperative Pain in the Surgical 
Area 
Y                  N 
 
5 
If YES: is it Mild/ Moderate/ Severe 
 
 
6 
Presence of Chronic Pain (>4 months) in Other 
Parts of the Body 
Y                  N 
 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 14 of 21 
 
 
7 
If YES: is it Mild/ Moderate/ Severe 
 
 
SURGICAL DETAILS TO BE OBTAINED FROM THE SURGICAL RECORDS 
1 
Date of Surgery 
 
 
2 
Diagnosis (Intraoperative) 
 
 
3 
Actual Surgical Procedure 
 
 
4 
Laparoscopic or Open 
L                    O 
 
5 
Surgeon 
 
Initials 
6 
Start Time of Surgery 
 
 
7 
End Time of Surgery 
 
 
8 
Duration of Surgery 
 
 
9 
Total Local Anesthetic Infiltration 
(mls) 
 
 
 
ANESTHESIA DETAILS TO BE OBTAINED FROM THE ANESTHETIC RECORD 
1 
Anesthesiologist 
 
Initials 
2 
Dexamethasone 4mg or 8mg 
Y                  N 
 
3 
Midazolam  
1 mg              2 mg 
 
4 
Propofol (total dose used) 
 
 
5 
Remifentanyl (total dose used) 
 
 
6 
Fentanyl (total dose used) 
 
 
7 
Sufentanyl (total dose used) 
 
 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 15 of 21 
 
 
8 
Any continuous infusion used 
Propofol              
 
Remifentanyl    
 
9 
Ondansetron Prophylaxis Dose 
 
Given prior to extubation 
10 
Was there a delay in transferring 
patient to the PACU (applicable 
when the PACU is on hold-and 
protocol needs to be initiated by the 
OR anesthesiologist) 
Y                   N 
 
 
APFEL SCORE: for Prediction of Post-Operative Nausea Vomiting 
RISK FACTOR 
SCORE (each gets 0 or 1) 
Postoperative Opioids 
 
Non-smoker 
 
Female Gender 
 
History of PONV or Motion Sickness 
 
Total Score 
 
 
 
 
 
 
 
 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 16 of 21 
 
 
PCS: Patient Catastrophyzing Score:   Copyright 1995 Michael JL Sullivan 
Everyone experiences painful situations at some point in their lives. Such experiences may include 
headaches, tooth pain, joint or muscle pain. People are often exposed to situations that may cause pain 
such as illness, injury, dental procedures or surgery. 
 
We are interested in the types of thoughts and feelings that you have when you are in pain. Listed below 
are thirteen statements describing different thoughts and feelings that may be associated with pain. Using 
the following scale, please indicate the degree to which you have these thoughts and feelings when you 
are experiencing pain. 
 
0 – not at all;  1 – to a slight degree;  2 – to a moderate degree;    
3 – to a great degree; 4 – all the time 
When I’m in pain ... 
1☐  I worry all the time about whether the pain will end.  
2☐  I feel I can’t go on.  
3☐  It’s terrible and I think it’s never going to get any better.  
4☐  It’s awful and I feel that it overwhelms me.  
5☐  I feel I can’t stand it anymore.  
6☐  I become afraid that the pain will get worse.  
7☐  I keep thinking of other painful events.  
8☐  I anxiously want the pain to go away.  
9☐  I can’t seem to keep it out of my mind.  
10☐  I keep thinking about how much it hurts.  
11☐  I keep thinking about how badly I want the pain to stop.  
12☐  There’s nothing I can do to reduce the intensity of the pain.  
13☐  I wonder whether something serious may happen.  
  
 
...Total 
Updated 11/11 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 17 of 21 
 
 
HADS: HOSPITAL ANXIETY DEPRESSION SCORE
 
 
 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 18 of 21 
 
 
OUTCOMES AT 24 HOURS 
 
24 hours after surgery (telephonic follow up) 
 
One-two calls shall be done during the next day; if unanswered, a repeat call will be made on the 
subsequent day (2nd day after discharge) 
 
For responders, the following questions will be asked. 
 
1. What was your average pain score over the last 24 hrs, in 0-10 NAS scale, after you were discharged 
home? 
2. After discharge, did you have nausea-severe enough to require medications at home? 
3. After discharge, did you have vomiting-severe enough to require medications at home? 
4. After discharged home, did you require a visit to ER, or readmission? 
 
OUTCOMES AT 3 MONTHS AFTER SURGERY 
1. Persisting pain after Surgery:  
Yes   or          No 
 
2. If Yes: Intensity of Pain: a score between 0-10 
       
3. Brief Pain Inventory Items Score: 
 
Mark the box beside the number that describes how, during the past 24 hours, pain has interfered 
 with your: 
1 
General Activity 
0-does not interfere 
10-completely interferes 
 
2 
Mood 
0-does not interfere 
10-completely interferes 
 
3 
Walking Ability 
0-does not interfere 
10-completely interferes 
 
4 
Normal Work (includes both work outside the home 
and housework) 
0-does not interfere 
10-completely interferes 
 
5 
Relations with people 
0-does not interfere 
10-completely interferes 
 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 19 of 21 
 
 
6 
Enjoyment of life 
0-does not interfere 
10-completely interferes 
 
7 
Sleep 
0-does not interfere 
10-completely interferes 
 
 
 
4. Patient Global Impression of Change:  
Since surgery, how would you describe the change (if any) in ACTIVITY LIMITATIONS, SYMPTOMS, 
EMOTIONS, and OVERALL QUALITY OF LIFE, related to your painful condition? Please circle the 
number below that matches your degree of change since beginning care at this clinic for the above stated 
chief complaint.  
No change 
Almost the 
same 
A little better 
Somewhat 
better 
Moderately 
better 
Better 
A great deal 
better 
1 
2 
3 
4 
5 
6 
7  
 
5. Analgesic Use:  
Did you have to use any pain medications for more than 1 month, to help with pain, which started 
with or after Surgery? 
 
Yes: 
 
No: 
APPENDIX 2: STANDARD ANESTHESIA PROTOCOL 
 Only General Anesthetic  
 No regional other than local infiltration as appropriate-to be documented 
 Midazolam 1-2 mg –to be given as appropriate-to be documented 
 Propofol-Induction in titrated doses 
 Rocuronium-Muscle relaxant in titrated doses 
 Intraop opioids: Remifentanyl-bolus or infusion 
 
 
  Fentanyl-25-50 mcg bolus 
  
 
  Sufentanyl-5-20 mcg bolus 
 No long acting opioids to be given during the surgery 
 No NSAIDS to be given during the surgery 
 Antiemetic prophylaxis with Dexamethasone 4mg to 8mg soon after induction in all 
patients, except with history of allergy.  


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 20 of 21 
 
 
 
APPENDIX 3: Outcome Measurement Scales 
1. Numerical Analogue Scale for Pain (NAS) 
 
 
 
2. Verbal Descriptive Scale for PONV:  the presence and severity of PONV (reference 9) 
0 
no nausea 
1 
mild nausea 
2 
moderate nausea-may need treatment 
3 
frequent vomiting –controlled with antiemetics 
4 
severe vomiting-uncontrolled with antiemetics. 
 
 
3. Severity of Respiratory Depression: Presence of one or both of the following 
o presence of Respiratory Rate below 10  
o Presence of Oxygen saturation <90\ 
 
4. Ramsay Sedation Scale 
 
 
 


Most Effective Opioid Analgesia in Ambulatory Surgeries: a randomized control, investigator 
blinded, parallel group with superiority design study of Morphine versus Hydromorphone 
Dr. Harsha Shanthanna, Principal Investigator SJHH 
Dr. James Paul, Principal Investigator HHS 
 
 
Protocol Version Date:  Version 5 / June 23, 2015 
Page 21 of 21 
 
 
5. Patient Satisfaction Score and Severity of Itching: Visual Analogue Scale 
0 
 
 
 
 
 
 
 
 
 
 
        10 
 
Totally 
Unsatisfied 
Completely 
Satisfied