Translational Studies in Analgesic Pharmacology: Analgesic Synergy in Clinical Pain. A Phase 2 Study Comparing a Single Dose of a 1:1 Combination of Methadone and Morphine With Morphine Alone in Patients With Post-operative Pain.
Phase: PHASE2
Conditions: Pain
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center 
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Amended:10/14/08
 
 
 
 
 
 
 
Translational studies in analgesic pharmacology: analgesic synergy in clinical pain. A phase 
2 study comparing a single dose of a 1:1 combination of methadone and morphine with 
morphine alone in patients with post-operative pain. 
 
 
 
 
 
 
THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
 
Principal Investigator: 
Natalie Moryl, MD 
Neurology: Pain and Palliative Care 
 
Co-Principal Investigator(s): Eugenie Obbens, MD 
Neurology: Pain and Palliative Care 
Vivek Malhotra, MD 
Anesthesiology and Critical Care: Pain 
 
Investigator(s): 
Joel Sheinfeld, MD 
Surgery: Urology 
Howard Thaler, PhD 
Epidemiology and Biostatistics: Biostatistics 
Roger Wilson, MD 
Anesthesiology and Critical Care: Pain 
Andrew Faskowitz, DO 
Neurology: Pain and Palliative Care 
Roma Tickoo, MD 
Neurology: Pain and Palliative Care 
Kirk Stevens, MD 
Neurology: Pain and Palliative Care 
Khan Abdulquader, MD 
Neurology: Pain and Palliative Care 

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Consenting Professional(s): Andrew Faskowitz, DO 
Damian Martino, MD 
Cristina Tamasdan, MD 
Dana Tarcatu, MD 
Roma Tickoo, MD 
Natalie Moryl, MD 
Eugenie Obbens, MD 
Kirk Stevens, MD 
Khan Abdulquader, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 

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Table of Contents
Amended: 10/14/08
 
 
 
 
 
Translational studies in analgesic pharmacology: analgesic synergy in clinical pain. A phase 
2 study comparing a single dose of a 1:1 combination of methadone and morphine with 
morphine alone in patients with post-operative pain. 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA… … … … …… … … … … …… … … …..2 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS… … … …… … … … … …… … … … … …… … 3 
3.0 
BACKGROUND AND RATIONALE …… … … … … …… … … … … …… … … … … ….3 
4.0 
STUDY DESIGN…… … … … … … …… … … … … …… … … … … …… … … … … …… ..8 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS…………………………………………….9 
6.0 
CRITERIA FOR PATIENT/SUBJECT ELIGIBILITY… …… … … … … … …… … … ..10 
6.1 
PATIONT/SUBJECT INCLUSION 
CRITERIA………………………………………………………………………10 
6.2 
PATIONT/SUBJECT EXCLUSION 
CRITERIA………………………………………………………………………11 
7.0 
RECRUITMENT PLAN… … … …… … … … … …… … … … … … …… … … … … …… ...11 
8.0 
PRETREATMENT EVALUATION… … … … … …… … … … … …… … … … … …… … 11 
9.0 
TREATMENT/INTERVENTION PLAN… … … …… … … … … … …… … … … … …… 12 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION…… … … … … …… … … 13 
11.0 
TOXICITIES/SIDE EFFECTS… … … … … …… … … … … …… … … … … …… … … … .14 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE /OUTCO ME ASSESSMENT… … …...14 
13.0 
CRITERIA FOR REMOVAL FROM THE STUDY… … … …… … … … … …… … … ...15 
14.0 
BIOSTATISTICS… … … …… … … … … …… … … … … …… … … … … …… … … … ….15 
15.0 
SUBJECT REGISTRATION AND RANOMIZATION PROCE DURES… … … … …...16 
15.1 
PATIENT/SUBJECT REGISTRATION………………………………………..16 
15.2 
RANDOMIZATION………………………………………………………….....16 
16.0 
DATA MANAGEMENT ISSUES…… … … … … … …… … … … … …… … … … … …… 17 
16.1 
QUALITY ASSURANCE……………………………………………………….17 
16.2 
DATA AND SAFETY MONITORING…………………………………………17 
17.0 
PROTECTION OF HUMAN SUBJE CT S… …… … … … … …… … … … … … …… … … 18 
17.1 
PRIVACY……………………………………………………………………….18 
17.2 
SERIOUS ADVERSE EVENT (SAE) REPORTING…………………………..18 
18.0 
INFORMED CONSENT PROCEDURES… … …… … … … … … …… … … … … …… … 19 
18.1 
RESEARCH AUTHORIZATION………………………………………………19 
19.0 
REFERENCE(S)… … … …… … … … … …… … … … … …… … … … … …… … … … … … 20 
20.0 
APPENDICE(S)… …… … … … … …… … … … … … …… … … … … …… … … … … …… .22 

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1.0
PROTOCOL SUMMARY AND/OR SCHEMA 
Amended:10/14/08
Page 2 of 40 
 
 
 
Translational studies in analgesic pharmacology: analgesic synergy in clinical pain. A phase 2 
study comparing a single dose of a 1:1 combination of methadone and morphine with 
morphine alone in patients with post-operative pain. 
 
The objective of this proposal is to compare the analgesic effects of a combination of 
morphine and methadone with morphine alone to determine synergistic activity of mu opioid 
analgesics in humans. 
 
This is a randomized, double blind, parallel arm study (See Appendix 1). 
 
We will administer a single dose of 1 mg of IV methadone plus 1 mg of morphine or 2 mg of 
IV morphine to patients one day after retroperitoneal lymph node dissection. We are planning 
for 70 patients to complete the study, 35 in each group. 
 
All patients will receive Patient Controlled Analgesia (PCA) with IV morphine. The total 
amount of opioid available to patients will be equivalent to the standard amounts used after 
retroperitoneal lymph node dissection.  Informed consent will be obtained from all patients 
pre-operatively. The PCA settings will start after the surgery at 1 mg/hour continuous infusion 
and 1mg every 10 minutes as needed. Clinician activated boluses (CAB) of morphine 5 mg IV 
will be available to the patient. The day after the surgery, the PCA will be stopped for the 
period of the study and we will ask the patient to request pain medication as soon as he feels 
at least moderate pain. During the period of the trial the physician will have no other clinical or 
other responsibilities. A physician will be available to monitor the time to the patient’s request 
for pain medications, assess pain intensity and administer the drugs to replace the PCA 
promptly upon the patient’s request. No more than 2 patients per the doctor per floor will be 
enrolled on the same day. When the patient requests pain medication, baseline pain intensity 
will be assessed and open label 2 mg of morphine administered. After administration of 
morphine the patient’s pain relief, pain intensity, and side effects reported by the patient will 
be assessed every 10 minutes, and/or at the time the patient requests analgesia medication. In 
addition, respiratory rate will be recorded during these intervals. Immediately upon the second 
request for analgesia, the study drug in a double blind fashion (1 mg of IV methadone plus 1 
mg of morphine or 2 mg of IV morphine), will be administered by the doctor. After 
administration of the study drug, pain relief, pain intensity, side effects reported by the patient 
and respiratory rate will be assessed every 10 minutes, and/or at the time the patient requests 
analgesia medication. Upon the third request for analgesia medication the study is completed, 
and the PCA will be restarted at the pre-study dose.  We will also collect information about 
the total dose of morphine received while on IV PCA, the dose of morphine received during 
the last hour before stopping the PCA, and the time from stopping PCA to first request for 
analgesic medication. 

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Morphine 2 mg intravenously will be administered upon the first request for an analgesic 
medication. Upon the second request, depending on the randomization, the patient will receive 
morphine 2 mg intravenously or a combination of morphine 1 mg and methadone 1 mg 
intravenously. There will be no dose escalation. 
 
 
 
Upon the 1st Request for 
Analgesic Medication 
Upon the 2nd Request for 
Analgesic Medication 
Randomized to 
Group 1 
morphine 2 mg 
morphine 2 mg 
Randomized to 
Group 2 
morphine 2 mg 
morphine 1 mg and methadone 1 
mg 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• 
The objective of this study is to compare the analgesic effects of a combination of 
morphine and methadone with morphine alone to determine synergistic activity of 
mu opioid analgesics in humans. 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Much is known about basic mechanisms of nociception and analgesia in animal models of 
experimental pain (1). Very few of these basic mechanisms, however, have been confirmed in 
humans suffering clinical pain (2). A better mechanistic classification of clinical pain 
syndromes offers the possibility of improved analgesic therapies and more rational drug 
development strategies (3,4). 
 
Biochemical and functional characterizations of mu receptor subtypes have been accomplished 
in the laboratory, but the specific pharmacological profiles of mu opioid receptor subtypes 
have not been confirmed in clinical pain studies. For example, animal models reveal 
incomplete cross-tolerance among many mu opioids (5-9).  In the treatment of cancer pain, 
clinicians commonly switch a patient who is highly tolerant to one mu selective 
opioid to another mu selective opioid in a process termed “opioid rotation” (10-11). Switching 
the patient to a different opioid often restores analgesia at a lower dose. This incomplete 
cross-tolerance suggests that drugs previously classed as “mu selective” may actually be 
acting via different mu receptor subtypes. At our institution, pain specialists sometimes add 
methadone to the regimen of patients on high doses of other opioids in an attempt to forego 
the need for a new increase in opioid dose. These clinical attempts to take advantage of the 
incomplete cross tolerance and possible synergy among different opioids have not been 
studied, and their efficacy is therefore unknown. 

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We have obtained experimental data that demonstrate a profound analgesic synergy between 
morphine and methadone when co-administered systemically in mice [see data] (12). 
 
If this type of synergy can be demonstrated in clinical pain, it will be a relatively unique 
example of translating concepts of fundamental aspects of opioid actions seen in the 
laboratory to the clinical area, and provide a basis for offering new and scientifically- based 
analgesic regimens. This may provide better pain relief with less opioid related side effects in 
clinical practice. 
 
While studying the potency of methadone in single dose studies, its analgesic potency was 
found to be equivalent to the potency of morphine when the drugs were administered 
parenterally (13). 
 
A double-blinded investigation was performed to assess pain scores and opioid requirements in 
the first 24 hours post-operatively after the same doses of morphine and methadone (0.3 
mg/kg) was administered intra-operatively parenterally as a single dose. No difference in the 
amount of analgesic requirements post-operatively or the visual analogue scale pain score was 
observed between the group that received morphine and the group that received methadone 
(14). 
 
In another double-blind study, morphine and methadone efficacy was examined in a post- 
operative pain control model. Patients in each group received a 20-mg dose of the opioid 
(morphine or methadone) intra-operatively. Rescue doses of the same opioid were available. 
There was no significant difference in the amount of supplementary opioid requirements 
between the two groups in the immediate post-operative period (about 8 hours) (15). 
 
The third double-blind randomized trial compared post-operative analgesia after peri- 
operative loading doses of methadone and morphine. Methadone or morphine, 0.25 mg/kg, 
was given intravenously at induction of anesthesia and rescues were administered in the 
recovery room. The mean analgesic doses of morphine and methadone were similar (0.43 
mg/kg and 0.45 mg/kg, respectively), with no significant difference in pain control or opioid 
requirements between the two groups in the post-operative period (about 12 hours). After 12 
hours, the group receiving repeated administration of methadone had lower pain scores and 
less supplementary opioid requirement (16). 
 
These studies support the equianalgesic effect of morphine and methadone when administered 
as single doses parenterally in the post-operative pain model in humans. We conclude that to 
evaluate synergy, we need to conduct a single dose study to avoid the confounding effects of 
methadone accumulation. 

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Pre-clinical data: 
 
The proposed clinical study is based on the following experimental studies. 
 
Methods: 
In these studies, analgesia was measured in mice 30 min post-injection (unless otherwise 
stated) using the radiant heat tail-flick assay (12). Baseline latencies ranged between 2.0 and 
3.2 sec. A maximal cutoff latency of 10 sec was set to minimize tissue damage. Analgesia 
was assessed quantitatively as a doubling or greater of the baseline latency for each mouse. 
Drugs were administered systemically via subcutaneous injections. Groups of mice were 
compared using the Fisher Exact Test. ED50 values and 95% confidence limits were 
calculated by the Litchfeild-Wilcoxin method. 
Synergy was evaluated using isobolographic analysis. Significance was defined as the lack of 
overlap of 95% CL for the predicted and observed analgesia. 
To examine the gastrointestinal transit immediately after subcutaneous (s.c.) injection, mice 
received a per os (p.o.) charcoal meal (10% charcoal with 2.5% gum tragacanth, w/v). Thirty 
minutes after the charcoal meal, the animals were sacrificed by cervical dislocation and the 
distance the meal traveled was measured. 
 
Results: 
The analgesia provided by the combination of morphine and L-methadone (73%) is 
significantly greater than the sum of their independent actions (20%), P< .001. The 
interaction of the morphine metabolite M6G with L-methadone (60%) is three times greater 
than the additive effect of the two drugs (20%; P< .001) (Fig. 1A and 1B). 

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Figures 1A and 1B. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The interactions of oxymorphone, oxycodone, fentanyl, alfentanil, meperidine and [Dmt1]- 
DALDA with L-methadone were shown to be additive and not synergistic (Fig. 1A). The 
same compounds were also co-administered with morphine, but no statistically significant 
synergistic interactions were found (Fig. 1B). 
 
The ED50 values of morphine and L-methadone administered individually were 3.8 mg/kg 
(2.6, 5.4) and 1.9 mg/kg (1.4, 2.4), respectively. However, when co-administered, the ED50 
of the morphine/L-methadone combination is 0.52/0.26 mg/kg (0.35, 0.8; 0.17, 0.4), 3.5 times 
less than their ED50 values when administered individually. Isobolographic analysis of this 
interaction indicates synergistic interactions between morphine and L-methadone; the ED50 
of the combination of drugs falls below the line of additivity of the two individual ED50 
values (Fig. 2A). 

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Figure 2. 
 
 
  
 
As an example of isobolographic analysis of a drug combination where synergy is not present, 
fentanyl and L-methadone are shown (Fig. 2E). Administered individually, fentanyl has an 
ED50 value of 0.25 mg/kg (0.013, 0.03). When administered with L-methadone, the ED50 
value is 0.011/0.9 mg/kg (0.0058, 0.015; 0.015, 1.2) When plotted on the isobole, this ED50 
value falls along the line of additivity and is therefore not considered synergistic. Fentanyl 
and alfentanil were given twenty minutes post L-methadone injection (ten minutes prior to 
testing) in order for the peak effects to coincide. 
 
Synergy seen between L-methadone and morphine was restricted to analgesia and did not 
extend to other mu opioid receptor actions, such as gastrointestinal transit. 

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Figures 3A and 3B. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Morphine decreased gastrointestinal transit relative to saline treated animals (28.1 + 1.5 cm) by 
26% (20.7 + 1.9 cm) at the 0.5 mg/kg dose. Gastrointestinal transit was reduced by 36% (18 + 
1.9 cm) in the 0.25 mg/kg L-methadone treated animals. When we administered the 
combination of morphine and L-methadone (0.5 and 0.25 mg/kg, respectively), transit was 
inhibited by 42% (16.2 + 1.9 cm). The expected additive effect of the combination of 
morphine and L-methadone would be an inhibition of 62.5%. Morphine and L-methadone, 
when co-administered in the gastrointestinal transit assay did not therefore exhibit a synergistic 
side effect (Fig. 3B). This is in contrast, therefore, to the effect seen with the same doses of 
morphine and L-methadone when co-administered in the tail-flick assay, where a 
profound analgesic synergy is observed  (Fig. 3A). Both analgesia and gastrointestinal transit 
are mu receptor actions and are readily reversed by naloxone. 
 
Conclusion: 
These animal experiments demonstrate synergistic analgesic effects between some mu opioid 
agonists such as morphine and methadone, but not others such as methadone and fentanyl. The 
finding of enhanced analgesia without enhanced bowel dysmotility also demonstrates an 
interesting dissociation of mu opioid actions. Furthermore, the lack of synergy in inhibition of 
gastrointestinal transit suggests that co-administration of morphine and methadone to patients 
will result in increased analgesia without worsening constipation and, therefore, may constitute 
a useful strategy in the treatment of pain. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a randomized, double blind, parallel arm study. We will administer a single dose of 1 
mg of IV methadone plus 1 mg of morphine or 2 mg of IV morphine to patients one day after 
surgery (See Appendix 1). 

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4.2 
Intervention 
 
All patients will receive Patient Controlled Analgesia (PCA) with IV morphine as per routine 
post-operative analgesic care. The total amount of morphine available to patients will be 
equivalent to the standard amounts used after surgery. Informed consent will be obtained from 
all patients pre-operatively. The PCA settings will start in the recovery room at 1 mg/hour 
continuous infusion and 1mg every 10 minutes as needed, clinician activated boluses will be 
available, and the PCA will be titrated to pain control as needed. 
 
The day after the surgery, the PCA will be stopped temporarily, and we will ask the patient to 
request pain medication as soon as he feels at least moderate pain (See Appendix 1). If two 
hours pass before a first request for pain medication is made, the patient will be removed from 
the protocol. During the period of the trial the doctor will have no other clinical or other 
responsibilities. A doctor will be available to monitor the time to the patients’ request for pain 
mediations, assess pain intensity and administer the drugs to replace the PCA promptly upon 
the patient’s request. No more than 2 patients per doctor per floor will be enrolled on the 
same day. 
 
Upon the first request for analgesia, immediately before administration of morphine 2 mg and 
every 10 minutes after administration of morphine 2 mg, we will record the patient's pain 
relief, pain intensity, respiratory rate, and side effects as reported by the patient. If four hours 
pass before a second request for pain medication is made, the patient will removed from the 
protocol. 
 
Upon the second request for analgesia, immediately before administration of the blinded study 
drug (1 mg of IV methadone plus 1 mg of morphine or 2 mg of IV morphine), every 10 minutes 
thereafter, and at the time of the third request for analgesia, we will record the 
patient's pain relief, pain intensity, respiratory rate, and side effects as reported by the patient. 
 
Upon a third request for analgesia, the study is completed and the PCA will be restarted at the 
pre-study dose. If four hours pass before a third request for pain medication is made, the 
patient will removed from the protocol. 
 
 
 
5.0 
THERA PEUTIC/DIAG NOSTIC AGENTS 
 
Morphine, a phenanthrene derivative, is the prototype opioid agonist. All other opiates are 
compared to morphine in determining their relative analgesic potency. Because of its 
widespread availability, it is the drug of choice for the treatment of post-operative pain and 
severe pain associated with cancer (17). There is no ceiling to its analgesic effect, although 
side effects, particularly sedation, respiratory depression and confusion may intervene before 
optimal analgesia is achieved (18, 19). It is metabolized in the liver, where it undergoes 
glucuronidation at the 3 and 6 positions. In single dose studies it is equipotent to methadone 
(20).The duration of analgesia is 3-4 hours. Because of the low dose used, we do not expect 

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significant side effects in patients who have been already receiving morphine for over 12 
hours. 
 
Methadone, the 50/50 racemic combination of d-methadone and l-methadone, has been in 
widespread use for decades and has been studied extensively. There is no evidence of organ 
toxicity from chronic opioid use, including chronic methadone use (21). The main concern 
when using methadone for the treatment of pain is its long and unpredictable half-life which, 
with chronic administration, is associated with the risk of delayed opioid toxicity with side 
effects such as sedation, confusion and respiratory depression. For this reason methadone is 
generally viewed as a second line opioid, generally used after other opioids with a more 
predictable dose-response have been tried. This is a single dose study and therefore drug 
accumulation will not occur. Because of the low dose used, we do not expect toxic effects or 
significant side effects in patients who would be receiving morphine for over 12 hours by the 
time the study begins. 
 
Preservative-free methadone and morphine combination (1 mg morphine+1 mg methadone) and 
parenteral morphine (2 mg of morphine IV) will be prepared, vialed and blinded by the 
MSKCC pharmacy. The methadone injection will be provided in single use vials containing 1 
mg/ml, 0.5 ml, or 1 mg/ml, 2 ml. The morphine injection will be provided in vials containing 
5 mg/ml, 1ml. Morphine and methadone are compatible for 7 days.  Drugs will be dispensed 
by the pharmacy to the clinical investigator in a blinded fashion on the day of the study. 
 
 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Planned retroperitoneal lymph node dissection usually requiring post-operative analgesia with 
PCA at 1 mg continuous infusion and 1 mg every 10 minutes as needed (See Appendix 2). 
 
 
 
6.1 
Subject Inclusion Criteria 
 
• 
Retroperitoneal lymph node dissection 
 
• 
Planned post-operative analgesia with PCA at 1 mg continuous infusion 
and 1 mg every 10 minutes 
 
• 
18 years of age or older 
 
• 
English-speaking 
 
• 
Give informed consent to participate in this study 

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6.2 
Subject Exclusion Criteria 
 
• 
Known hypersensitivity to methadone or morphine 
 
• 
Patients with past or present history of substance abuse 
 
• 
Patients with a history of methadone treatment 
 
• 
Patients with a history of chronic pain requiring daily analgesic use for 
more than 3 months 
 
• 
Patients treated with opioids within one month from the scheduled surgery 
 
• 
Creatinine clearance less than 50 mg/kg (using Cockcroft-Gault Equation). 
 
• 
Neurologic or psychiatric disease sufficient, in the doctor's opinion, to 
compromise data collection 
 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited in the pre-operative period. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
Demographic (age, ethnicity) and clinical data, including weight, height, past medical and 
surgical history, past treatment with opioids, concurrent drug therapies, drug-related side 
effects, and serum creatinine clearance within one month of surgery will be collected (See 
Appendix 3). We will also collect the data on the total dose of morphine received while on 
IV PCA, dose of morphine received during the last hour before stopping the PCA, and the 
time from stopping the PCA to first request for analgesic medication (See Appendix 4). 
 
 
 
 
9.0 
TREATM ENT/INTERVENTION PLAN 
 
We will administer a single dose of 1 mg of methadone with 1 mg IV of morphine or 2 
mg of IV morphine alone to patients the day following surgery. 
 
Following surgery, all patients will receive Patient Controlled Analgesia (PCA) with IV 
morphine. As per post-operative standard care, the PCA settings will start at 1 mg/hour 

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continuous infusion and 1mg every 10 minutes as needed and titrated up as needed. 
CABs as needed will be available (See Appendix 1). 
 
The day after the surgery the PCA will be stopped for the period of the study. We will 
ask the patient to request pain medication as soon as he feels moderate pain. The doctor 
will be present to monitor the time of the patient’s request, assess pain intensity and 
administer drugs to replace the PCA promptly upon the patient’s request. If two hours 
pass before a first request for pain medication is made, the patient will be removed from 
the protocol. Not more than two patients per doctor per floor will be enrolled on the 
same day. During the period of the trial, the doctor will have no clinical or other 
responsibilities. 
 
 
 
1. When the patient requests pain medication, baseline pain intensity will be assessed and 
open label 2 mg of morphine IV administered. After administration of morphine, the 
patient's pain relief, pain intensity, respiratory rate, and side effects reported by the 
patient will be assessed every 10 minutes, and at the time of the second request for 
analgesia medication. If four hours pass before a second request for pain medication is 
made, the patient will be removed from the protocol. 
 
2. Immediately upon a second request for analgesia, the study drug in a double blind 
fashion (1 mg of methadone IV plus 1 mg of morphine IV or 2 mg of morphine IV), will 
be administered by the doctor. After administration of the study drug, the patient's pain 
relief, pain intensity, respiratory rate, and side effects reported by the patient will be 
assessed every 10 minutes, and at the time of the third request for analgesia medication. 
 
3. Upon a third request for analgesia medication or after four hours if no medication is 
requested, the study is completed and the PCA will be restarted at the pre-study dose.  If 
four hours pass before a third request for pain medication is made, the patient will 
removed from the protocol. 
 
 
 
 
The total amount of opioid available to patients will be equivalent to the standard 
amounts used after retroperitoneal lymph node dissection. 
 
 
 
 
 
10.0  EVALUATION DURING TREATMENT/INTERVENTION 
 
Immediately after the first request for the analgesia, before administration of the open label 
morphine 2 mg IV, every 10 minutes thereafter and at the time of the second request for the 
analgesia, we will record (See Appendix 4): 

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- 
Pain relief scores on a 0-100% scale 
 
- 
Pain intensity scores on a 0-10, 11 point, verbal scale 
 
- 
Respiratory rate 
 
- 
Side effects from the pain medication and their severity rated by the patient on a 0-3 
scale (none, mild, moderate, severe) 
 
- 
Time to the second request for the pain medication 
 
- 
Global assessment. The patients will be asked: “How effective was the medication in 
relieving your pain?” The patient will choose among: 1) not effective 2) slightly 
effective 3) moderately effective 4) very effective 5) extremely effective. 
 
 
 
Immediately before administration of the study drug, i.e. morphine 2 mg IV or morphine 1 mg 
with methadone 1 mg IV, every 10 minutes and at the time of the third request for analgesia, we 
will record (See Appendix 5): 
 
- 
Pain relief scores on a 0-100% scale 
 
- 
Pain intensity scores on a 0-10, 11 point, verbal scale 
 
- 
Respiratory rate 
 
- 
Side effects from the pain medication and their severity rated by the patient on a 0-3 
scale (none, mild, moderate, severe) 
 
- 
Global assessment.  The patients will be asked: “How effective was the medication in 
relieving your pain?” The patient will choose among: 1) not effective 2) slightly 
effective 3) moderately effective 4) very effective 5) extremely effective. 
 
- 
Time to the third request for the pain medication (upon which the study is completed) 
  
 
11.0 TOXICITIES/SIDE EFFECTS 
 
Methadone has been in widespread use for decades and has been studied extensively. The 
most frequently observed side effects include sedation, nausea, vomiting, constipation, 
confusion and hallucinations, which are more pronounced in ambulatory patients and less 
common at lower doses. Methadone accumulation is not a concern in the current study 
because of the single dose design. Methadone-related side effects are easily reversed by 
naloxone. 

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Morphine is the standard opioid used for post-operative care. Subjects will receive a dose of 2 
mg morphine intravenously, immediately when they request the analgesia medication. This 
dose may be slightly lower or higher than the dose of morphine received via continuous 
infusion previously. This may result in temporary improvement or worsening of pain control. 
The most serious side effect is respiratory depression, particularly with rapid administration. 
Low doses of intravenous morphine have little effect on cardio-vascular stability. High dose 
morphine may cause sympathetic over activity, dysphoria and convulsions. Nausea, vomiting, 
constipation, headache, anxiety, pruritus and urinary retention may be seen at lower doses and 
easily reversed by naloxone. 
 
Given the relatively small amount of opioid used in the study drug (morphine 1 mg plus 
methadone 1 mg), we do not expect any side effects. However, due to the potential for 
synergism and, therefore, potentiation of the effect, we will closely monitor the patient for the 
presence of side effects (see Section 10, Evaluation During Treatment). NCI Common Toxicity 
Criteria 3.0 will be used to categorize and grade toxicity. Toxicities of grade 2 or less will be 
treated symptomatically. For patients with grade 3 or 4 toxicities, morphine and methadone 
will be stopped and an appropriate alternative analgesic regimen will be started. 
 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPO NSE/OUTCOM E ASSESSMENT 
 
Primary endpoint will be the difference between the pain relief offered by a combination of 1 
mg morphine with 1 mg methadone intravenously (IV) and 2 mg of IV morphine alone. 
The outcome measure will be pain relief evaluated as the area under the curve (AUC) 
(Houde). AUC is the area under the drug level-time curve made by plotting pain relief (0- 
100%) to the time to the next request for pain medication (see Appendix 6). 
Time (t) for each AUC will include: 
For area A: 
-t0, time of the first request for the analgesia and open administration of 2 mg morphine; 
-t2, 3,...n, time of assessments 10 minutes apart; 
-tn, time of the second request for the analgesia and study drug administration. 
For area B: 
-t0, time of the second request for the analgesia and study drug administration; 
-t2, 3,...n, time of assessments 10 minutes apart; 
-tn, time of the third request for the analgesia and completion of the study. 
Effectiveness of the study drug will be estimated by comparing it to the open label 2 mg 
morphine IV. Ratio of pain relief offered by a combination of 1 mg morphine and 1 mg 
methadone IV to the analgesia provided by open label 2 mg morphine IV will be compared to 
the ratio of pain relief offered by 2mg morphine given in the blind fashion to the open label 2 
mg morphine IV (see Appendix 6). 
Hypothesis: AUC B2/A ratio is higher than the AUC B1/A ratio. 

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13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
• Patients that develop complications after surgery resulting in: inability to use the PCA, 
inability to evaluate the patient or new pain beyond the post-surgical pain. 
• Patients who require immediate post-operative opioid analgesia other than PCA 
morphine. 
• Patients who require no analgesic medication 2 hours following the PCA being 
stopped. 
• Patients who require no analgesic medication 4 hours following open label morphine 2 
mg IV administration. 
• Patients who require no analgesic medication 4 hours following the study drug (1 mg 
of methadone IV plus 1 mg of morphine IV or 2 mg of morphine IV). 
• Patients that require new analgesic medications or analgesic adjuvants (including 
steroids) for the treatment of pain. 
 
 
 
14.0 BIOSTATISTICS 
 
The primary comparison will be the difference in pain relief recorded as the "area under the 
curve" (AUC) between the initial 2 mg morphine dose and the study drug. 
AUC will be estimated by plotting % of pain relief over the time (see Appendix 6). 
Time (t) for each AUC will include: 
For area A: 
-t0, time of the first request for the analgesia and opened administration of 2 mg morphine; 
-t2, 3,.., time of assessments 10 minutes apart 
-tn, time of the second request for analgesic medication and study drug administration. 
 
For area B: 
-t0 time of the second request for analgesic medication and study drug administration; 
-t2, 3,.., time of assessments 10 minutes apart; 
-tn, time of the third request for analgesic medication and completion of the study. 
 
Pain relief at the time of the request for pain medication will be considered baseline and each 
patient will serve as his own control. Should the pain relief score at the time of the second 
pain medication administration be reported higher than the baseline, projected AUC will be 
used, extending it to the baseline. 
 
AUC for 2 mg morphine (area B1) and AUC for a combination of 1 mg morphine and 1 mg 
methadone (area B2) will be compared to the AUC for open label 2 mg morphine (area A). 

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If the true difference between mean ratio B/A for morphine plus methadone vs morphine alone 
is .68 times the within-group standard deviation, then with 35 patients completing the study 
per arm there would be an 80% chance of a significant comparison with a two-sided t-test at 
p<0.05. 
 
The main analysis will be the analysis of covariance, using baseline pain as a covariate, and 
analyze time-to-first-rescue (the time from stopping PCA to first request for analgesic 
medication), and changes in pain intensity as secondary outcomes. We will also collect the 
information about the total dose of morphine received while on IV PCA and the dose of 
morphine received during the last hour before stopping the PCA and the time from stopping 
PCA to first request for analgesic medication to stratify subjects during analysis. 
 
We are planning to review the data after 10 cases and may need to adjust the dose of morphine 
as well as morphine and methadone accordingly, by doubling the dosage. With the change of 
the dose, a new patient accrual will be started. The data for the initial opioid dose will be 
analyzed separately. 
 
 
 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1  Researcb Participant Registration 
 
The following person(s) can obtain informed consent: 
Andrew Faskowitz, DO 
Dana Tarcatu, MD 
Cristina Tamasdan, MD 
Roma Tickoo, MD 
Damian Martino, MD 
Natalie Moryl, MD 
Eugenie Obbens, MD 
Kirk Stevens, MD 
Khan Abdulquader, MD 
 
Confirm in the electronic medical record that the patient has received the Notice of Privacy 
Practice. This must be obtained before the eligibility confirmation and obtaining of the 
research informed consent. 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain written informed consent, by following procedures defined in section entitled 
Informed Consent Procedures. 

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All particpants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am - 5:30pm at (646) 735-8000. The PPR fax numbers are (646) 735-0008 and (646) 
735-0003. Registrations can be phoned in or faxed. The completed signature page of the 
informed consent form, the completed signature page of the Research Authorization and a 
completed Eligibility Checklist must be faxed to PPR. 
 
During the registration process registering individuals will be required to answer specific 
eligibility questions and provide the following information: 
 
Registering Individual 
[Last, First Name] 
Notice of Privacy Status 
[Yes, No, N/A] 
Research Authorization 
[Date] 
MSKCC IRB Protocol# 
Attending of Record (if applicable)        [Last, First Name] 
Consenting Professional                          [Last, First Name] 
Informed Consent Date 
Participant's Full Name 
[Last, First Name] 
Participant MRN 
 
 
 
15.2  Randomization 
After meeting eligibility criteria, the patient will be assigned to the morphine/methadone 
combination arm or morphine alone arm randomly, using simple randomization. 
Randomization Codes will be generated by the Clinical Research Database (CRDB) in 
conjunction with the Department of Epidemiology and Biostatistics after signing the consent. 
Medications will be dispensed by the hospital pharmacy in a double-blind manner on the 
days of the study. 
 
 
 
 
16.0 DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the protocol study team. 
 
The data collected for this study will be entered into a secure database. Source documentation 
will be available to support the computerized patient record. 

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16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated 
to assess missing data and inconsistencies. Accrual rates and the extent and 
accuracy of evaluations and follow-up will be monitored periodically throughout 
the study period, and potential problems will be brought to the attention of the 
study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by 
the study team, at a minimum of two times per year, more frequently if indicated. 
 
 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.  The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and 
II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Given the relatively small amount of opioid used in the study drug (morphine 1 mg plus 
methadone 1 mg), we do not expect any side effects. However, due to the potential for 
synergism and, therefore, potentiation of the effect, we will closely monitor the patient for the 

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presence of side effects (see Section 10, Evaluation During Treatment). NCI Common 
Toxicity Criteria will be used to categorize and grade toxicity. Toxicities of grade 2 or less 
will be treated symptomatically. For patients with grade 3 or 4 toxicities, morphine and 
methadone will be stopped and an appropriate alternative analgesic regimen will be started. 
 
 
 
17.1 Privacy 
 
It is the responsibility of the Research Staff to ensure that protocol patients have received 
the Center’s Notice of Privacy Practices. The doctors will obtain acknowledgment before 
the patient participates in this study. 
 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form. A Research Authorization form must be completed 
by the Principal Doctor and approved by the IRB and Privacy Board. 
 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Serious adverse events (requiring immediate reporting as described in this section) 
include, but are not limited to the following: 
 
 
• Any death which occurs while the patient is enrolled in the study including the 
follow-up period, or within 30 days of completing the study. 
• Life threatening event 
• Prolongation of an existing hospitalization 
• Medically important event ** 
• Disability/Incapacity (persistent or significant) 
 
**Medically important events that may not result in death, be life-threatening or require 
hospitalization, may be considered a serious adverse experience when, based upon 
appropriate medical judgment, the experience may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in the 
definition. 
 
 
 
 
17.2 Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB as soon as possible but no later than 5 calendar 
days. The IRB requires a Clinical Research Database (CRDB) AE report to be delivered 

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to the Institutional SAE Manager (307 East 63rd Street, 1st Floor) containing the following 
information: 
Fields populated from the CRDB: 
• Subject’s name 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
All patients must provide written informed consent prior to registration and treatment. Those 
physicians authorized to obtain informed consent are listed on the title page. 
 
 
 
18.1 
Research Authorization 
 
Procedures for obtaining Research Authorization: Before any protocol-specific 
procedures are carried out, doctors and/or designated staff will fully explain the details of 
the protocol, study procedures, and the aspects of patient privacy concerning research 
specific information. In addition to signing the IRB Informed Consent, all patients must 
sign the Research Authorization component of the informed consent form. The 
Research Authorization requires a separate set of signatures from the patient. The 
original signed documents will become part of the patient’s medical record, and each 
patient will receive a copy of the signed documents. 

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19.0 
REFERENCE(S) 
 
 
 
 
1. Woolf CJ. Pain. 2000 Neurobiol Dis 7:504-510. 
 
2. Woolf CJ, Max MB. Mechanism-based pain diagnosis: issues for analgesic drug 
development. 2001 Anesthesiology 95:241-249. 
 
3. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser 
JD, Payne R and Torebjork E. Toward a mechanism-based classification of pain? 1998 Pain 
77:227-229. 
 
4. Rowbotham MC, Fields HL. The relationship of pain, allodynia and thermal sensation in 
post-herpetic neuralgia. 1996 Brain 119:347-354. 
 
5. Nielsen CK, Ross FB, Smith MT. Incomplete, asymmetric, and route-dependent cross- 
tolerance between oxycodone and morphine in the Dark Agouti rat. 2000 J Pharmacol Exp 
Ther 295:91-99. 
 
6. Pasternak GW. Incomplete cross tolerance and multiple mu opioid peptide receptors. 2001 
Trends Pharmacol Sci 22:67-70. 
 
7. Sosnowski M, Yaksh TL. Differential cross-tolerance between intrathecal morphine and 
sufentanil in the rat. 1990 Anesthesiology 73:1141-1147. 
 
8. Rossi GC, Brown GP, Leventhal L, Yang K, Pasternak GW. Novel receptor mechanisms 
for heroin and morphine-6 beta-glucuronide analgesia. 1996 Neurosci Lett 216:1-4. 
 
9. Neilan CL, Nguyen TM, Schiller PW, Pasternak GW. Pharmacological characterization of 
the dermorphin analog [Dmt(1)]DALDA, a highly potent and selective mu-opioid peptide. 
2001 Eur J Pharmacol 419(1):15-23. 
 
10. Manfredi PL, Borsook D, Chandler SW, Payne R. Intravenous methadone for cancer pain 
unrelieved by morphine and hydromorphone: clinical observations. 1997 Pain 70:99-101. 
 
11. Mercadante S. Opioid rotation for cancer pain: rationale and clinical aspects. 1999 Cancer 
86:1856-1866. 
 
12. Bolan EA, Tallarida RJ, Pasternak GW. Synergy between mu opioid ligands: evidence for 
functional interactions among mu opioid receptor subtypes. 2002 J Pharmacol Exp Ther 
303:557-562. 

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13. Beaver WT, Wallenstein SL, Houde RW, Rogers A. A clinical comparison of the analgesic 
effects of methadone and morphine administered intramuscularly, and of orally and parenterally 
administered morphine. 1967 Clinical Pharmacology and Therapeutics 8:415- 
442. 
 
14. Laur DF, Sinkovich J, Betley K. A comparison of intraoperive morphine sulfate and 
methadone hydrochloride on postoperative visual analogue scale pain scores and narcotic 
requirements, 1995 CRNA: The Clinical Forum for Nurse Anesthetists 6:21-25. 
 
15. Gourlay GK, Willis RJ, Lamberty J. A double-blind comparison of the efficacy of 
methadone and morphine in postoperative pain control. 1986 Anesthesiology 64:322-327. 
 
16. Chui PT, Gin T. A double-blind randomized trial comparing postoperative analgesia after 
perioperative loading doses of methadone or morphine. 1992 Anaesth Intensive Care 20:46- 
51. 
 
17. Donnelly S, Davis MP, Walsh D, Naughton M. World Health Organization. Morphine in 
cancer pain management: a practical guide. 2002 Support Care Cancer 10:13-35. 
 
18. Cherny N, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H, Mercadante S, 
Pasternak G, Ventafridda V. Expert Working Group of the European Association of Palliative 
Care Network. Strategies to manage the adverse effects of oral morphine: an evidence-based 
report. 2001 J Clin Oncol 19:2542-2554. 
 
19. Kloke M, Rapp M, Bosse B, Kloke O. Toxicity and/or insufficient analgesia by opioid 
therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 
patients observed at a single center. 2000 Support Care Cancer 8:479-486. 
 
20. Houde RW, Wallenstein SL, Beaver WT. Evaluation of analgesics in patients with cancer 
pain. 1966 In Lasagna L (Ed), International encyclopedia of pharmacology and therapeutics, 
Section 6, Clinical pharmacology, Vol.1 Pergamon Press, Oxford, England, 59-98. 
 
21. Kreek MJ. Methadone-related opioid agonist pharmacotherapy for heroin addiction. 
History, recent molecular and neurochemical research and future in mainstream medicine. 
2000 Ann N Y Acad Sci 909:186-216. 
 
 
 
 
 
 
20.0 APPENDICES 
 
Appendix 1, Proposed Study Design Schema 
Appendix 2, Inclusion and Exclusion Criteria 
Appendix 3, Pretreatment Evaluation 

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Appendix 4, Assessment Form 1 (After Morphine Administration) 
Appendix 5, Assessment Form 2 (After Study Drug Administration) 

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5 
 
SYNERGY: Appendix 1: Proposed Study Design Schema 
  
 
 
 
Proposed Study Design for Morphine-Methadone Synergy Study 
 
 
 
surgery 
 
 
 
 
 
Morphine 
IV 
PCA 1mg/1 mg / 
10 started 
and 
titrated 
up 
 
 
Morphine 
IV 
PCA stopped 
 
1st request for 
pain 
medica ti o n- 
Morphine 
1mg 
IV is given 
 
2nd request for 
pain 
medica ti o n- 
Study 
drug 
is given 
3rd request 
for 
pain 
medica ti o n- 
Study 
is 
Comple te d, 
PCA restarte d 
 
 
 
 
 
 
 
Investig a tor 
is present 
on the floor to 
administer 
pain medica tio n s 
 
 
 
 
Pre-op Asse ssm e n t 
and Random i za ti on , 
1 
2 
Post-o p Day 1 
Asse ssm e nt 
 
3 
 
Assess m en t 
(Pain, Respir ator y 
Rate and Side Effects) 
q 20 min 
and upon the 3rd request 
for 
pain medica ti o n 
4 
Assess m en t 
(Pain, Respir ator y 
Rate and Side Effects) q 20 min 
and upon the 3rd request 
for 
pain medica tio n 
5 
 
 
 
 
Study 
drug: randomi ze d 
to morphine 
1 mg IV or morphine 
0.5 mg and 0.5 mg IV (double blind) 

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SYNERGY: Appendix 2: Inclusion and Exclusion Criteria 
 
PRE-OP ASSESSMENT FOR RANDOMIZATION 
 
Date:   
/  
/  
 
 
 
 
Inclusion criteria 
Scheduled for retroperitoneal lymph node dissection 
18-y-o or older 
English-speaking 
Informed consent signed 
Exclusion criteria 
Anesthesiologist disapproves morphine continuous 
H/o hypersensitivity to morphine or methadone 
H/o substance abuse 
H/o methadone treatment 
H/o opioid treatment for chronic pain 
H/o opioids within 1 month 
Creatinine clearance less than 50% 
Neurological or psychiatric disorder interfering with data collection 
(doctors discretion)- with comments (use additional sheet if necessary) 
Comments 

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SYNERGY: Appendix 3: Pre-treatment Evaluation 
 
 
 
 
Patient name: 
MRN: 
 
 
 
 
 
Age 
Ethnicity 
Weight 
Height 
Past Medical History 
Past Surgical History 
H/o Opioid Use 
Current Medications 
Drug-related side effects 
using NCI scale 
(sleepiness, confusion, 
hallucinations, 
nausea/vomiting, others), 
0-3, 4-point scale 

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SYNERGY: Appendix 4: Assessment Form 1 
  
 
 
1st Treatment (Morphine) 
 
 
Date:   
/  
/  
 
 
 
Patient name: 
MRN: 
 
Randomization #: 
 
 
 
BEFORE DISCONTINUATION OF PCA: 
• 
On a scale of 0-10, where 0 is no pain and 10 is the worst pain you can imagine, 
how would you rate the intensity of your pain right now? 
 
• 
On a scale of 0-10, where 0 is no pain and 10 is the worst pain you can imagine, 
how would you rate the intensity of your pain when you try to move? 
 
Baseline PCA 
Basal: 
Rescue: 
Lockout Interval: 
PCA Stopped at: 
Morphine 
PCA 
 
Started 
(Time):                                    
Total 
Dose 
Received:                                                      
Dose Received in the Last 1 Hour:                                
 
 
 
1ST TREATMENT (MORPHINE ALONE) 
 
Time of the First Request for Analgesic Medication:   
 
 
Time from Discontinuation of IV PCA to the First 
Request for Analgesic Medication:   
 

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At the time of the first request for analgesic medication 
 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
Imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
 
Follow-up 10 minutes after treatment started 
 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 20 minutes after treatment started 
 
 
6. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
  
 
Follow-up 30 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 

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Follow-up 40 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
  
 
 
Follow-up 50 minutes after treatment started 
 
1, 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 60 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
5. 
Side effec ts reported by the patient:   
 
 
Follow-up 70 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 80 minutes after treatment started 

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1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 90 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 100 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 110 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 120 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 

Amended:10/14/08
Page 31 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
 
 
 
 
Follow-up 130 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 140 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 150 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 160 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 170 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 

Amended:10/14/08
Page 32 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 180 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 190 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 200 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 210 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 

Amended:10/14/08
Page 33 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
 
 
Follow-up 220 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
 
Follow-up 230 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 240 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
  
 
 
TIME OF THE SECOND REQUEST FOR ANALGESIC MEDICATION:   
 

Amended:10/14/08
Page 34 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
 
 
SYNERGY: Appendix 5: Assessment Form 2 
 
2nd Treatment (Study Drug) 
 
 
Date:   
/  
/  
 
 
Randomization #: 
 
 
 
Patient name: 
MRN: 
 
 
 
2nd TREATMENT (STUDY DRUG) 
 
Time of the Second Request for Analgesic Medication:   
 
 
Time from the First Request for Analgesic Medication:   
 
 
 
 
At the time of the second request for analgesic medication 
 
 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 10 minutes after treatment started 
 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
  
 
Follow-up 20 minutes after treatment started 
 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 

Amended:10/14/08
Page 35 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 30 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
 
 
 
Follow-up 40 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
  
 
 
Follow-up 50 minutes after treatment started 
 
1, 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 60 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 

Amended:10/14/08
Page 36 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
 
 
3. 
Respirations per minute:  
 
  
6. 
Side effec ts reported by the patient:   
 
 
Follow-up 70 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 80 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 90 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 100 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 110 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 

Amended:10/14/08
Page 37 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 120 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 130 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 140 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 150 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 

Amended:10/14/08
Page 38 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
Follow-up 160 minutes after treatment started 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
3. 
Respirations per minute:  
 
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
Follow-up 170 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
5. 
Side effec ts reported by the patient:   
 
 
Follow-up 180 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
 
 
Follow-up 190 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 

Amended:10/14/08
Page 39 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
 
 
 
 
Follow-up 200 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
 
 
Follow-up 210 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts report ed by the patien t:   
 
  
 
Follow-up 220 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 
  
 
Follow-up 230 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 

Amended:10/14/08
Page 40 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
 
 
 
 
 
 
 
Follow-up 240 minutes after treatment started 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
  
4. 
Side effec ts reported by the patient:   
 
 
 
 
 
TIME OF THE THIRD REQUEST FOR ANALGESIC MEDICATION:   
 
  
 
At time of third request for analgesic medication 
 
1. 
On a scale of 0-100%, where 0 is no pain relief and 100% is complete 
pain relief, how would you rate your pain relief right now? 
 
2. 
On a scale of 0-10, where 0 is no pain and 10 is the worse pain you can 
imagine, how would you rate the intensity of your pain right now? 
 
3. 
Respirations per minute:  
 
 
 
4. 
Side effec ts reported by the patient:   
 

Amended:10/14/08
Page 41 of 40 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 05-025A(7)
 
 
Pain Relief, 0-100%
First request  for Pain Meds-- 
Morphine 2 mg IV given 
2nd request for Pain Meds-- 
Study drug given 
3rd Request for Pain Meds-- 
Study is Completed 
 
 
 
 
 
SYNERGY: Appendix 6: Schema, Pain Relief as Measured as the Area Under the Curve 
 
 
 
 
Pain Relief, 0-100%, Measured as the Area Under the Curve 
 
 
 
120% 
 
 
100% 
 
 
80% 
 
 
 
60% 
 
 
40% 
 
 
20% 
 
 
 
 
 
 
A 
B1 or B2 
A- Area Under the 
Curve for 2 mg 
Morphine IV 
B1-Area Under the 
Curve for First  study 
Drug- 2mg Morphine 
IV 
B2- Area Under The 
Curve for Study Drug- 
1 mg Morphine with 1 
mg Methadone IV 
 
 
0% 
0 
20 
40 
60 
80 
100 
120 
140 
160 
180 
Time, minu te s