A Randomized, Open-Label Study to Assess the Pain, Toxicity, and Quality of Life Effects of Adding Venlafaxine to the Pain Management Regimen for Patients Treated With Chemoradiation for Head and Neck Cancer
Phase: PHASE2
Conditions: Stage III Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8, Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8
Sponsor: Roswell Park Cancer Institute

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PROTOCOL TITLE: 
A Randomized, Open-Label Study to Assess the Pain, Toxicity and Quality 
of Life Effects of Adding Venlafaxine to the Pain Management Regimen for 
Patients Treated with Chemoradiation for Head and Neck Cancer 
PROTOCOL NUMBER: 
I 61117 
 
PRINCIPAL INVESTIGATOR: 
Anurag K Singh, MD 
Roswell Park Cancer Institute 
Elm and Carlton Street 
Buffalo, New York 14263 
716-845-5715 
Anurag.Singh@RoswellPark.org 
 
VERSION NUMBER: 
3 
DATE: 
June 05, 2020 
Confidentiality Statement 
Any and all information presented in this document shall be treated as confidential and 
shall remain the exclusive property of the party(ies) mentioned above. The use of such 
confidential information must be restricted to the recipient for the agreed purpose and 
must not be disclosed, published, or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of the 
party(ies) above.

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Table of Contents 
1.0 
Objectives ............................................................................................................................ 3 
2.0 
Background .......................................................................................................................... 3 
3.0 
Inclusion and Exclusion Criteria .......................................................................................... 5 
4.0 
Local and Study-Wide Number of Subjects ...................................................................... 11 
5.0 
Local and Study-Wide Recruitment Methods.................................................................... 11 
6.0 
Multi-Site Research ........................................................................................................... 11 
7.0 
Study Timelines ................................................................................................................. 11 
8.0 
Study Endpoints ................................................................................................................. 11 
9.0 
Design ................................................................................................................................ 12 
10.0 Treatment ........................................................................................................................... 13 
11.0 Procedures Involved........................................................................................................... 17 
12.0 Withdrawal of Subjects ...................................................................................................... 21 
13.0 Risks to Subjects ................................................................................................................ 22 
14.0 Potential Benefits to Subjects ............................................................................................ 22 
15.0 Data and Specimen Banking .............................................................................................. 22 
16.0 Measurement of Effect ....................................................................................................... 22 
17.0 Safety Evaluation ............................................................................................................... 22 
18.0 Data Management and Confidentiality .............................................................................. 26 
19.0 Statistical Plan .................................................................................................................... 28 
20.0 Provisions to Monitor the Data to Ensure the Safety of Subjects ...................................... 30 
21.0 Vulnerable Populations ...................................................................................................... 30 
22.0 Community-Based Participatory Research ........................................................................ 30 
23.0 Sharing of Results with Subjects ....................................................................................... 30 
24.0 Setting ................................................................................................................................ 30 
25.0 Provisions to Protect the Privacy Interests of Subjects ...................................................... 30 
26.0 Resources Available........................................................................................................... 31 
27.0 Prior Approvals .................................................................................................................. 31 
28.0 Compensation for Research-Related Injury ....................................................................... 31 
29.0 Economic Burden to Subjects ............................................................................................ 31 
30.0 Consent Process ................................................................................................................. 32 
31.0 Process to Document Consent in Writing .......................................................................... 33 
32.0 Drugs or Devices................................................................................................................ 33 
33.0 REFERENCES .................................................................................................................. 33 
 

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1.0 
Objectives 
 
 
1.1 The primary objective is to assess the pain-reduction effects of adding 
venlafaxine to a regimen of gabapentin and methadone to control pain 
during and after chemoradiation.   
1.2 The secondary objective is to assess the effect of venlafaxine of the rate of 
toxicities possibly or probably related to the pain control regimen.  
1.3 Tertiary objectives include the effect of Venlafaxine on other quality of life 
scores, patient nutrition, hydration status, and opioid requirements during 
and after CRT. 
1.4 Our hypothesis is that the addition of Venlafaxine to Gabapentin and 
Methadone will decrease pain, improve quality of life, and reduce opioid 
requirements in patients undergoing CRT for head and neck cancer. 
2.0 
Background 
2.1 Squamous cell head and neck cancer is diagnosed in approximately 50,000 
Americans annually, and at least 60% of these patients present with locally 
advanced, non-metastatic disease. Most fatalities result from uncontrolled 
local and/or regional disease. The standard of care currently for these 
patients is concurrent chemotherapy and radiation which can be an 
extremely toxic treatment regimen for patients. The treatment lasts 
approximately 7 weeks and can lead to severe mucositis and irritation to the 
structures of the pharynx and larynx which imparts severe pain and pain-
related dysphagia on these patients. Extreme pain and dysphagia very 
frequently leads to anorexia and dehydration to the point of patients 
requiring placement of PEG tubes, of which approximately 10% require the 
PEG tube to remain in place long-term.(1, 2) Standard treatment at Roswell 
Park Cancer Institute for pain, dysphagia, and mucositis during and after 
treatment had been to use escalating Lortab elixir and transdermal fentanyl 
patches in these patients. From our clinical experience, virtually all patients 
require pain medication during CRT and it has been our practice to initiate a 
pain regimen early in treatment. Experiences with patients seen in the pain 
clinic provided insight into the use of a combination of gabapentin, 
oxycodone and methadone, additionally with a regimen centered on 
escalating gabapentin. With doses titrated up to 3600mg/day, gabapentin has 
demonstrated improvement of pain, mood, sleep and quality of life in 
patients with diabetic peripheral neuropathy.(3) In 2008, Sharp H, et al., at 
the NCI and in collaboration with Singh AK (PI of this study and NCI 
study) showed that gabapentin can be effective for painful mucosal 
neuropathy with near resolution of symptoms in head and neck cancer 
patients.(4) In 2010, Bar Ad et al. of the Radiation Oncology department at 
the University of Pennsylvania published a review of the use of gabapentin 
in cancer-related pain syndromes and in combination with opioid analgesics. 

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The analysis suggested effectiveness of gabapentin in improving the pain 
control in patients with neuropathic cancer pain, already treated with 
opiates. Moreover, gabapentin appeared promising in reducing the need for 
high total doses of opioids and avoiding unplanned treatment interruptions 
for patients with head and neck malignancies treated with radiotherapy or 
concurrent chemoradiotherapy (5, 6) Prophylactic use of gabapentin at the 
start of CRT has been shown to delay PEG tube use and leads to sooner 
removal of PEG tubes, a finding attributed to better swallowing function 
secondary to improved pain control (7). Recent data presented at the 
ASTRO Multidisciplinary Head and Neck Cancer Symposium, 
demonstrated that prophylactic gabapentin reduced unintentional weight loss 
during CRT (8). From these analyses and our clinical experience, our 
practice is to initiate gabapentin at the start of CRT. Furthermore, the 
combination of gabapentin and morphine has been shown to effect better 
pain relief at lower doses of each drug when compared with gabapentin or 
morphine alone in patients with painful diabetic neuropathy or post-herpetic 
neuralgia. The combination of both drugs was associated with a beneficial 
effect on pain-related interference with daily activity, mood, sleep and 
quality of life.(9)  
2.2 To this end, Singh AK (PI of this study) initiated clinical trial I 262314 
which compared the safety and efficacy of two pain regimens: 1) escalating 
gabapentin with escalating Lortab elixir and transdermal fentanyl patches as 
needed and 2) low dose gabapentin with methadone and oxycodone as 
needed. Preliminary data has suggested potential benefits to both escalating 
gabapentin and methadone as a breakthrough medication. Consistent with 
previous literature, the use of gabapentin appears to reduce the proportion of 
patients who require opioids, delays the onset of opioid initiation, and 
improves patient-reported overall health and pain scores, with the most 
significant effects seen in the arm with escalating gabapentin. Additionally, 
there is evidence that methadone reduced pain and had an overall broader 
improvement in patient-reported mucositis scores. Enrollment is closed for 
this study, therefore in an effort to further optimize the therapeutic benefit of 
low-abuse-potential and non-opioid medications for improving pain control 
and quality of life, we are aiming to investigate the potential benefits of 
venlafaxine. 
2.3 Historically, antidepressants, particularly tricyclic antidepressants (TCAs), 
have been used for their proven treatment efficacy of neuropathic pain. (10-
12) TCAs, however, have an unfavorable side effect profile in part due to 
their significant anticholinergic effects with associated cardiotoxicity, thus 
limiting their use in the modern era. As an alternative with a more favorable 
side-effect profile, serotonin and norepinephrine reuptake inhibitors (SNRIs) 
have demonstrated similar efficacy to TCAs for neuropathic conditions.(13) 
In 2002, Tasmuth et. al. reported on the use of venlafaxine for the treatment 
of neuropathic pain following breast cancer treatment. In this randomized 
placebo controlled trial, venlafaxine was found to improve patient-reported 
daily pain relief and maximum reported neuropathic pain.(14) In 2004, 

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Rowbotham et al. reported on venlafaxine for painful diabetic neuropathy in 
a multicenter, double-blind, placebo-controlled trial. At a dose of 150-
225mg, venlafaxine significantly reduced pain intensity by week 6 
compared to placebo.(15) Furthermore, Simpson identified an additive 
benefit of venlafaxine to maximum-tolerated gabapentin for pain control and 
quality of life in patients with painful diabetic neuropathy. This study 
demonstrated the combination of 150mg/day of venlafaxine with up to 
3600mg/day of gabapentin improved pain relief, mood disturbance and 
quality of life compared to gabapentin-alone. It was also noted the 
combination of medications was well tolerated.(16) The aim of this study is 
to evaluate the potential benefit of this combination of venlafaxine and 
gabapentin, specifically in patients undergoing chemoradiation for head and 
neck cancer. 
2.4 Clinical Studies 
• The European Association for Palliative Care concluded from investigating 
multiple studies that controlled-release oxycodone is comparable to instant-
release oxycodone, morphine and hydromorphone in management of 
moderate to severe cancer pain. The studies also indicated that side effects 
appear to be lesser than those associated with morphine and that it is a valid 
alternative to morphine and a first-line treatment for cancer pain. As a 
result, the European Association for Palliative Care recommended that oral 
oxycodone could be taken as a second-line alternative to oral morphine for 
cancer pain.(17)  
• MD Anderson Cancer Center (MDACC) performed a systematic review of 
randomized controlled trials (RCTs) of opioids for cancer pain that showed 
fair evidence for the efficacy of transdermal fentanyl and poor evidence for 
morphine, tramadol, oxycodone, methadone, and codeine.(18)  
• The International Association for the Study of Pain as well as the Canadian 
Pain Society considers venlafaxine as first line treatment for neuropathic 
pain. (19, 20) 
 
3.0 
Inclusion and Exclusion Criteria 
Individuals will be screened on presentation to the radiation medicine clinic for evaluation of 
radiotherapy. 
3.1 Inclusion Criteria 
To be included in this study, patients must meet the following criteria: 
• 
Patients who are eligible for chemoradiation therapy of the head and neck. 
• 
Patients must have adequate renal function to undergo platinum based chemotherapy. This will 
mean a baseline Cr no greater than 1.5 times the upper limit of normal. 
• 
Have a pathologic diagnosis of squamous cell carcinoma of the head and neck region. 
• 
Age ≥ 18 years of age. 
• 
Have an ECOG Performance Status of ≤ 2. 

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• 
Ability to swallow and/or retain oral or per tube medication. 
• 
Patients of child-bearing potential must agree to use adequate contraceptive methods (e.g., 
hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman 
become pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately. 
• 
Patient or legal representative must understand the investigational nature of this study and sign an 
Independent Ethics Committee/Institutional Review Board approved written informed consent 
form prior to receiving any study related procedure. 
 
3.2 Exclusion Criteria 
Patients will be excluded from this study for the following: 
• 
Patients who have previously been treated with surgery or radiation for head and neck 
cancer and/or are being treated for recurrent head and neck cancer. 
• 
Patients with known brain metastases will be excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic dysfunction 
that would confound the evaluation of neurologic and other adverse events. 
• 
Any patients prescribed medications for chronic and/or long term pain and/or neuropathy 
will be excluded, including patients under treatment of a pain specialist or substance-
abuse programs. Acute post-op medications are allowed if the patient has discontinued 
them prior to initiating study. 
• 
Any patients prescribed a Selective Serotonin Reuptake Inhibitor (SSRI), Serotonin and 
Norepinephrine Reuptake Inhibitor (SNRI), tricyclic antidepressant (TCA), monoamine 
oxidase inhibitors (MAOIs), dextromethorphan, triptan, tryptophan supplements, IV 
methylene blue, linezolid or any other medication that may increase risk of serotonin 
syndrome, as deemed by the Investigator’s opinion. 
• 
Any patients with suspected or known, current or recent (within last 5 years) use of 
cocaine, 
amphetamines, 
lysergic 
acid 
diethylamide 
(LSD), 
3,4-
methylenedioxymethamphetamine (MDMA), or any other drug of abuse that may 
increase risk of serotonin syndrome, as deemed by the Investigator’s opinion. 
• 
Any patients with history of suicide-related events, or those exhibiting a significant 
degree of suicidal ideation. 
• 
Patients with acute narrow-angle glaucoma. 
• 
Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
• 
Pregnant or nursing female patients. 
• 
Unwilling or unable to follow protocol requirements. 
• 
Any condition which in the Investigator’s opinion deems the patient an unsuitable 
candidate to receive study drug. 
• 
Received an investigational agent within 30 days prior to enrollment. 
• 
Patients on dialysis or with transplanted organs. 
• 
Patients already enrolled on other studies of systemic pain control agents. 
3.3 Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are 
eligible for this study. 
3.4 Member of the following special population will be excluded:  

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• 
Adults unable to consent 
• 
Individuals who are not yet adults (infants, children, teenagers) 
• 
Pregnant women 
• 
Prisoners 
 
 

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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM: 
INCLUSION CRITERIA 
Participant Name: ___________________________ 
Medical Record No.: _____________________________ 
Title: Efficacy and Quality of Life Analysis of Venlafaxine for Patients Treated with Concurrent 
Chemoradiation for Head and Neck Cancer 
INCLUSION CRITERIA 
Yes 
No 
N/A 
All answers must be “Yes” or “N/A” for participant enrollment. 
Date 
 
 
 
1. Patients who are eligible for chemoradiation therapy of the head and neck. 
 
 
 
 
2. Patients must have adequate renal function to undergo platinum based 
chemotherapy.  This will mean a baseline Cr no greater than 1.5 times the 
upper limit of normal. 
 
 
 
 
3. Have a pathologic diagnosis of squamous cell carcinoma of the head and 
neck region. 
 
 
 
 
4. Age ≥ 18 years of age. 
 
 
 
 
5. Have an ECOG Performance Status of ≤ 2. 
 
 
 
 
6. Ability to swallow and/or retain oral or per tube medication. 
 
 
 
 
7. Patients of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth control; 
abstinence) prior to study entry. Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately. 
 
 
 
 
8. Patient or legal representative must understand the investigational nature 
of this study and sign an Independent Ethics Committee/Institutional 
Review Board approved written informed consent form prior to receiving 
any study related procedure. 
 
Investigator Signature: ___________________________________ 
Date: ___________ 
Printed Name of Investigator: __________________________________________________ 
 
 

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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM: 
EXCLUSION CRITERIA 
Participant Name: ___________________________ 
Medical Record No.:_____________________________ 
Title: Efficacy and Quality of Life Analysis of Venlafaxine for Patients Treated with Concurrent 
Chemoradiation for Head and Neck Cancer 
EXCLUSION CRITERIA 
Yes 
No 
N/A 
All answers must be “No” or “N/A” for participant enrollment. 
Date 
 
 
 
1. Patients who have previously been treated with surgery or radiation for 
head and neck cancer and/or are being treated for recurrent head and 
neck cancer. 
 
 
 
 
2. Patients with known brain metastases will be excluded from this clinical 
trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation 
of neurologic and other adverse events. 
 
 
 
 
3. Any patients prescribed medications for chronic and/or long term pain 
and/or neuropathy will be excluded, including patients under treatment of 
a pain specialist or substance-abuse programs. Acute post-op medications 
are allowed if the patient has discontinued them prior to initiating study. 
 
 
 
 
4. Any patients prescribed a Selective Serotonin Reuptake Inhibitor (SSRI), 
Serotonin and Norepinephrine Reuptake Inhibitor (SNRI), tricyclic 
antidepressant (TCA), monoamine oxidase inhibitors (MAOIs), 
dextromethorphan, triptan, tryptophan supplements, IV methylene blue, 
linezolid or any other medication that may increase risk of serotonin 
syndrome, as deemed by the Investigator’s opinion. 
 
 
 
 
5. Any patients with suspected or known, current or recent (within last 5 
years) use of cocaine, amphetamines, lysergic acid diethylamide (LSD), 
3,4-methylenedioxymethamphetamine (MDMA), or any other drug of 
abuse that may increase risk of serotonin syndrome, as deemed by the 
Investigator’s opinion. 
 
 
 
 
6. Any patients with history of suicide-related events, or those exhibiting a 
significant degree of suicidal ideation. 
 
 
 
 
7. Patients with acute narrow-angle glaucoma. 
 
 
 
 
8. Uncontrolled concurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
 
 
 
9. Pregnant or nursing female patients. 
 
 
 
 
10. Unwilling or unable to follow protocol requirements. 
 
 
 
 
11. Any condition which in the Investigator’s opinion deems the patient an 
unsuitable candidate to receive study drug. 
 
 
 
 
12. Received an investigational agent within 30 days prior to enrollment. 
 
 
 
 
13. Patients on dialysis or with transplanted organs. 
 

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EXCLUSION CRITERIA 
Yes 
No 
N/A 
All answers must be “No” or “N/A” for participant enrollment. 
Date 
 
 
 
14. Patients already enrolled on other studies of systemic pain control agents. 
 
Participant meets all entry criteria: 
 
  Yes 
  No 
If “NO”, do not enroll participant in study. 
Investigator Signature: ___________________________________ 
Date: __________ 
Printed Name of Investigator: _________________________________________________ 

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4.0 
Local and Study-Wide Number of Subjects 
4.1 A maximum of 60 patients at Roswell Park will be enrolled. Accrual is 
expected to take up to 2 years. 
5.0 
Local and Study-Wide Recruitment Methods 
5.1 Potential subjects will be recruited at the first consultation with radiation 
medicine.  Patients will be screened by their healthcare provider in clinic.   
5.2 The source of subjects will be the population of patients with head and neck 
squamous cell carcinoma, who are evaluated in the radiation medicine clinic 
at a single institution. 
5.3 No particular materials will be used to recruit subjects.  Patients will be 
presented with details of the study during a routine consultation for 
radiotherapy in the radiation medicine clinic.   
5.4 Patients will not receive any form of payment for participation in the study. 
6.0 
Multi-Site Research 
  
 
          NA 
7.0 
Study Timelines 
7.1 Accrual is expected to take 2 years.  Data collection will be complete about 
4 years after the study opens. 
7.2 Patients may remain on study and continue to receive treatment for pain for 
up to 24 months following CRT.  
8.0 
Study Endpoints 
8.1 Primary Endpoint: 
Patient pain levels will be quantified using the Pain Scale from the EORTC Head 
and Neck Cancer Module (EORTC QLQ-H&N35).  Responses will be collected 
repeatedly during the evaluation period, as described in Section 11.  The primary 
statistical endpoint is the change in H&N35 Pain Scale score between the baseline 
and week 7 assessments. 
EORTC QLQ-H&N35 is a 35 item questionnaire designed to assess health-related 
QoL in head and neck cancer patients.  It includes seven scales (pain, swallowing, 
senses, speech, social eating, social contact, and sexuality) and 11 single items 
(problems with teeth, problems opening the mouth, dry mouth, sticky saliva, 
cough, feeling ill, pain killers, nutritional supplements, feeding tube, weight loss 
and weight gain). Items 1-30 are scored on a four-point Likert scale (1 ‘not at all’; 
2 ‘a little’; 3 ‘quite a bit’; 4 ‘very much’). Items 31-35 use a ‘yes’ (2) and ‘no’ (1) 
response format. Higher scores correspond to lower quality of life. 

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8.2 Secondary Endpoint: 
The toxicity of the pain regimen will be assessed using the CTEP NCI Common 
Terminology Criteria for Adverse Events (CTCAE Version 4.0). 
8.3 Tertiary Endpoints: 
EORTC QLQ-C30 responses will also be collected to describe the patient's global 
health, physical function, and symptoms. The Oral Mucositis Daily Questionnaire 
will be used to describe the short and long term effects of radiation on quality of 
lift.  Additional assessments will consider patient nutrition, hydration status, and 
opioid requirements during and after CRT. 
9.0 
Design 
9.1 The pain-reduction effects of adding venlafaxine to a regimen of gabapentin 
and methadone to control pain during and after chemoradiation will be 
assessed in a randomized, two arm, open-label, single institution study.  The 
treatment regimens for the two arms are described in Section 10.  Inclusion 
and exclusion criteria are detailed in Section 3. 
9.2 No interim analysis is planned. 
9.3 Patients will be randomized 1:1 to the two study arms in stratified, permuted 
blocks of six patients each.  The randomization will be stratified by location 
of the radiation treatment (unilateral or bilateral).  The randomization list 
will be provided by the study biostatistician.   
 

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On Treatment Visits (OTVs) & Follow-Ups: Oral Mucositis Daily Questionnaire (OMDQ), 
EORTC Quality of Life Survey (QLQ-C30 and H&N35), record weight loss, assess need for 
regimen or dose escalation, document treatment interruptions. 
10.0 Treatment 
10.1 ARM 1 will receive scheduled Gabapentin that will be titrated starting at 300 mg 
daily QHS by 300 mg TID increase per week, for up to 1200 mg TID, as tolerated. 
All patients will receive gabapentin regardless of initial pain and in the absence of 
pain, as is our clinical practice in order to reduce or delay subsequent opiate 
requirement. Uncontrolled, and subsequent refractory pain, will be treated with 
Methadone 2 mg TID initially to be titrated as needed up to 15 mg TID for 
analgesia. Oxycodone 5 - 10 mg Q8H prn will be available for subsequent 
breakthrough pain. No other opioid or medication for neuropathic pain will be 
allowed on protocol. Patient compliance will be assessed at weekly on-treatment 
visits. 
ARM 2 will receive scheduled Gabapentin that will be titrated starting at 300 mg 
daily QHS by 300 mg TID increase per week, for up to 1200 mg TID, as tolerated. 
Venlafaxine will also be titrated starting at 37.5mg BID by 37.5mg BID increase 
per week, up to 75mg BID per day or 150mg daily of Venlafaxine Extended 
Randomization 
All Patients 
Register 
H&N SCC -  
Any Stage 
Concurrent 
CRT 
 
Group as either 
unilateral or 
bilateral 
treatment 
 
 
Gabapentin: 
Starting at 300mg 
daily QHS and 
titrated up to 
1200mg TID 
 
Breakthrough Pain: 
Methadone 2-15mg 
TID 
Oxycodone 5-10mg 
Q8H PRN  
 
Venlafaxine: 
Starting at 37.5mg 
BID and titrated up 
to 75mg BID (or 
Venlafaxine 
Extended Release 
150mg Daily) 
No Venlafaxine 

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Release. Patients unable to tolerate Venlafaxine by mouth will be prescribed 
equivalent daily Venlafaxine of liquid suspension by mouth or through PEG tube as 
described.(21) (Appendix A) or alternatively patients will be given instructions on 
administering capsule by opening and sprinkling contents onto a spoonful of 
applesauce. This drug/food mixture should be swallowed immediately without 
chewing and followed with a glass of water to ensure complete swallowing of the 
pellets, per the package insert. Dosing in suspension form is equivalent to 
immediate release. Uncontrolled and subsequent refractory pain will be treated with 
Methadone 2 mg TID initially to be titrated as needed up to 15 mg TID for 
analgesia. Oxycodone 5 - 10 mg Q8H prn will be available for subsequent 
breakthrough pain. No other opioid or medication for neuropathic pain will be 
allowed on protocol. 
Patients will be monitored and assessed via vital signs, physical exam, weight loss, 
dysphagia, OMDQ (Appendix C), EORTC (European Organization for Research 
and Treatment of Cancer) quality-of-life scores. (22) (Appendix E and F), ECOG 
performance status (Appendix D), and opioid/morphine equianalgesic calculations. 
Opioid intake will be summated by Oral Morphine.(23-25) 
Patients will be seen at least once a week during the 7 weeks of CRT and, at 
1 month, 3 months, 6 months, 9 months (only for patients continuing on a pain 
regimen at the 6 month follow-up visit), and 12 months after the end of 
chemoradiation therapy. For patients that require prolonged analgesic therapy (i.e., 
greater than 12 months), long-term follow-up visits may be extended for up to 
24 months (as per investigator judgment). 
 
10.2 Agents 
• Gabapentin (Neurontin®): Elixir containing 50 mg/mL. Taken by 
mouth or through PEG tube.  
• Methadone: Elixir containing 10 mg/mL. Taken by mouth or through 
PEG tube. 
• Oxycodone: Elixir containing 5 mg/ 5 mL. Taken by mouth or 
through PEG tube. 
• Venlafaxine (Effexor®): Tablet containing either 37.5mg or 75mg. 
Taken by mouth. 
• Venlafaxine Extended Release (Effexor XR®): Capsule containing 
150mg taken by mouth.  
• Alternatively, patients can administer capsule by opening and 
sprinkling contents onto a spoonful of applesauce. This 
drug/food mixture should be swallowed immediately without 
chewing and followed with a glass of water to ensure complete 
swallowing of the pellets. Dosing in this form is equivalent to 
immediate release. 

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• A third option is the Elixir containing 15mg/mL(21) 
(Appendix A) taken by mouth or through PEG tube. Elixir 
dosing is equivalent to immediate release. 
• See Appendix B for oral morphine equivalent dosage. 
• Compliance will be assessed in a subjective manner via patient-
physician dialogue and electronic quality-of-life screening tools. 
10.3 Treatment is intended for an outpatient setting. However, at the 
investigator’s/physician’s discretion, the participant may receive treatment 
as an inpatient, if deemed necessary. 
If patients undergo platinum therapy and EITHER have a rise in their 
creatinine to >2 ORany symptoms of gabapentin toxicity (such as confusion, 
unsteady gait, somnolence)(26) then the CrCl will be calculated and the 
gabapentin (Neurontin®) dose modified (see Table 1).  
Creatinine clearance is difficult to measure in outpatients. In patients with 
stable renal function, creatinine clearance (CCr) can be reasonably well 
estimated using the equation of Cockcroft and Gault: 
for females CCr =(0.85)(140-age)(weight)/[(72)(SCr)]  
for males CCr =(140-age)(weight)/[(72)(SCr)] 
 
where age is in years, weight is in kilograms and SCr is serum creatinine in mg/dL. 
 
Dosage adjustment in patients ≥ 12 years of age with compromised renal 
function(27) or undergoing hemodialysis is recommended as follows: 
 
Table 1 
Gabapentin (Neurontin®) Dosage Based on Renal Function 
Renal Function 
Creatinine Clearance 
(mL/min) 
Total Daily 
Dose Range 
(mg/day) 
Dose Regimen 
(mg) 
≥ 60 
900 - 3600 
300 TID  400 TID  600 TID  800 TID  1200 TID 
> 30 - 59 
400 – 1400 
200 BIB  300 BID  400 BID  500 BID   700 BID 
> 15 - 29 
200 -700 
200 QD   300 QD   400 QD   500 QD    700 QD 
15a 
100 - 300 
100 QD   125 QD   150 QD   200 QD    300 QD 
a For patients with creatinine clearance < 15 mL/min, reduce daily dose in proportion to 
creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-
half the daily dose that patients with a creatinine clearance of 15 mL/min receive). 
 
 
For patients with GFR=10 to 70mL/min, the total daily dose of venlafaxine will be 
reduced by 50%. In patients diagnosed with hepatic cirrhosis, the starting dose will 
be reduced by 50%. 
 
  
10.4 Any patients prescribed medications for chronic and/or long term pain 
and/or neuropathy will be excluded, including patients under treatment of a 

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pain specialist or substance-abuse programs. Acute post-op medications are 
allowed if the patient has discontinued them prior to initiating study. 
Concurrent medications also will be reviewed for safety by the study 
physician and addressed, as the study physician deems appropriate. 
Patients may be pretreated for nausea and vomiting with appropriate anti-
emetics.  
10.5 The following medications will be prohibited from concomitant use: 
Selective Serotonin Reuptake Inhibitor (SSRI), Serotonin and 
Norepinephrine Reuptake Inhibitor (SNRI), tricyclic antidepressant (TCA), 
monoamine oxidase inhibitors (MAOIs), dextromethorphan, triptan, 
tryptophan supplements or any other medication that may increase risk of 
serotonin syndrome, as deemed by the Investigator’s opinion. Concomitant 
use of aforementioned medications may increase the risk of serotonin 
syndrome. Management of serotonin syndrome would be per standard of 
care with symptomatic management and/or pharmaceutical antidote (such as 
cyproheptadine).(28, 29) 
10.6 Gabapentin's most common side effects in adult patients include dizziness, 
fatigue, weight gain, drowsiness, and peripheral edema (swelling of 
extremities); these mainly occur at higher doses in the elderly. Gabapentin 
has been associated with an increased risk of suicidal acts or violent deaths. 
Gabapentin should not be discontinued abruptly after long term use. Abrupt 
or overly rapid withdrawal may provoke a withdrawal syndrome reminiscent 
to alcohol or benzodiazepine withdrawal. Gradual reduction over a period of 
weeks or months helps minimize or prevents the withdrawal syndrome. 
Informed consent contains additional details. 
10.7  Oxycodone and Methadone’s common side effects include constipation, 
fatigue, dizziness, and nausea, and vomiting, dry mouth, anxiety, itching, 
and sweating. Less common side effects include loss of appetite, 
nervousness, abdominal pain, diarrhea, urine retention, dyspnea, and 
hiccups. In high doses, overdoses, or in patients not tolerant to opiates, 
oxycodone can cause shallow breathing, bradycardia, cold-clammy skin, 
apnea, hypotension, miosis, circulatory collapse, respiratory arrest, and 
death. Concomitant use of opiates increases the risk of aforementioned side 
effects.  The risk of experiencing severe withdrawal symptoms is high if a 
patient has become physically dependent or addicted and discontinues 
treatment abruptly.(17, 18, 30, 31) Informed consent contains additional 
details. 
10.8 Venlafaxine’s common adverse side effects include headache, nausea, 
sweating, sedation, fatigue, dizziness, dry mouth, night sweats, sexual 
dysfunction, loss of appetite, and anxiousness. In high doses or overdoses, 
venlafaxine can prolong QTc, which has been implicated in a case report of 
fatal arrhythmia following suicide with intentional overdose of 
venlafaxine.(32) Combining venlafaxine with similarly acting serotonergic 
drugs and medications increases the risk of serotonin syndrome. It is a weak 

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inhibitor of CYP2D6 and thus care should be taken with concurrent use of 
medications known to interact with CYP2D6. In high doses, increases in 
blood pressure have been reported. As with all antidepressants, there is an 
increased risk of suicidality in the initial period of recovery for patients with 
a history of suicide-related events or who have exhibited a significant degree 
of suicidal ideation prior to commencement of treatment. As with all 
antidepressants, there is an increased risk of seizures. If the medication is 
abruptly stopped, a withdrawal syndrome may occur and may consist of 
dizziness, sensory disturbances, sleep disturbances, agitation or anxiety, 
tremor or headache. At completion of chemoradiation or study withdrawal, 
Venlafaxine will be tapered at 75mg per week, or at 37.5mg per if week if 
symptoms of withdrawal syndrome occur. Informed consent contains 
additional details. 
11.0 Procedures Involved 
11.1 Patient Randomization and Registration 
Informed consent MUST be completed prior to receiving any study related 
procedures.  After consent has been obtained and eligibility is confirmed, patients 
will be randomized 1:1 to the two treatment arms as described in Section 9.  
Treatment assignments will be made by the Clinical Research Coordinator.   
11.2 Baseline Evaluations  
The following will be performed within 12 weeks prior to first dose of study drug: 
• Physical examination 
• Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, body 
weight, and height) 
• Medical history (including analgesic history) 
• Pre-existing conditions 
• Pregnancy test (urine) in females of childbearing potential 
• ECOG Performance Status (Appendix D) 
• Pain Assessment: (0-10 and/or Visual Analog) 
• Quality of Life Questionnaires (EORTC QLQ-C30 and H&N35 
Survey):Appendix E and Appendix F 
• Concomitant Medications: Any medication that is ongoing within 1 week prior to 
the first dose of study drug. 
11.3 Evaluations Performed at Weekly On-Treatment Visits  
The following evaluations will be performed at the scheduled weekly on-treatment (CRT) 
visits and, as needed per patient request:  
• Body weight 
• ECOG Performance Status: Appendix D 
• Pain Assessment: (0-10 and/or Visual Analog) 

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• Oral Mucositis Daily Questionnaire (OMDQ Survey): To assess mouth and 
throat soreness: Appendix C 
 
The 2 diarrhea questions in the OMDQ will therefore be omitted and assumed to be 0 
unless noted otherwise. 
• Adverse events 
• Morphine-Equivalent Narcotic Usage: What type of pain medication are you 
using, and how much? 
 
11.4 Evaluations Performed at End of Treatment (Week 7) 
The following evaluations will be performed at the end of treatment or at time of 
treatment discontinuation: 
• Body weight 
• ECOG Performance Status: Appendix D 
• OMDQ Survey: Appendix C  
• EORTC QLQ: C30 and H&N35 Surveys: Appendix E and F 
• Pain Assessment: (0-10 and/or Visual Analog) 
• Adverse events 
• Morphine-Equivalent Narcotic Usage: What type of pain medication are 
you using, and how much 
 
11.5 Follow-Up 
The following evaluations will be performed at follow-up which will occur 4 
weeks (± 1 week) after the last dose of chemoradiation therapy and, at 3 months 
(± 1 month), 6 months (± 2 month). Study is complete after 6 months once 
patients stop pain medicine.  Study will continue for patients on pain medicine at 
9 months (± 2 month) and 12 months (± 3 month) after the initial follow-up visit 
• ECOG Performance Status: Appendix D 
• OMDQ Survey: Appendix C  
• EORTC QLQ: C30 and H&N35 Surveys: Appendix E and F 
• Pain Assessment: (0-10 and/or Visual Analog) 
Patients who are unable to make follow-up appointment(s) can be followed by 
phone/video contact for the Quality of Life assessments, OMDQ Survey and Pain 
Assessment. If a follow up visit is done via phone/ video contact, then only the Quality of 
Life Questionnaires, OMDQ Survey and Pain Assessment are required. 
11.6 Long Term Follow-Up 
The following evaluations will be performed at Long Term follow-up which is for 
patients requiring prolonged analgesic therapy (greater than 12 months). Long-
term follow-up visits may be extended for up to 24 months. Long term follow-up 
evaluations will be scheduled at 6 months intervals (± 3 months) as long as the 
patient is on a continuing pain treatment regimen 
 
• ECOG Performance Status: Appendix D 
• OMDQ Survey: Appendix C  

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• EORTC QLQ: C30 and H&N35 Surveys: Appendix E and F 
• Pain Assessment: (0-10 and/or Visual Analog) 
Patients who are unable to make follow-up appointment(s) can be followed by 
phone/video contact for the Quality of Life assessments, OMDQ Survey and Pain 
Assessment. If a follow up visit is done via phone/ video contact, then only the Quality of 
Life Questionnaires, OMDQ Survey and Pain Assessment are required. 
11.7 Schedule of Procedures and Observations 
The schedule of procedures and observations for this study is summarized in Table 2 
below. 
 
Table 2 
Schedule of Procedures and Observations 
 
Evaluation 
Baseline1 
During 
CRT 
Treatment2 
End of 
Treatment 
(Week 7) 
Follow-
Up3 
Long 
Term 
Follow-
Up4 
Physical Examination (i.e., temperature, 
heart rate, respiratory rate, blood 
pressure, weight, & height) 
X 
 
 
 
 
Body weight only 
 
X 
X 
 
 
Medical History (to include analgesic 
history) 
X 
 
 
 
 
Pre-Existing Conditions 
X 
 
 
 
 
Pregnancy Test (urine) in females of 
childbearing potential 
X 
 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
Pain Assessment: (0-10 and/or Visual 
Analog)  
X 
X 
X 
X 
X 
Modified OMDQ Survey5,7 
 
X 
X 
 
 
EORTC QLQ-C30 plus H&N35 Survey7 
X 
 
X 
X 
X 
Adverse Events 
 
X 
X 
 
 
Concomitant medications (per hospital 
EMR) 
X6 
 
 
 
 
 
 
 
 
 
 
Morphine Milligram Equivalents8 
X 
X 
 
 
 
1. To be performed within 12 weeks prior to first dose of study drug. 
2. Patient may start treatment anytime during weeks 1 through 3 of CRT.  Patient should be seen at 
least 4 weeks out of 7 to be evaluable.  
3. Follow-up evaluations will occur 4 weeks (± 1 week) after the last dose of chemoradiation therapy 
and, at 3 months (± 1 month), 6 months (± 2 month). Study is complete after 6 months once 
patients stop pain medicine.  Study will continue for patients on pain medicine at 9 months 
(± 2 month) 
and 
12 
months 
(± 3 month) 
after 
the 
initial 
follow-up 
visit. 

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Note: Patients who are unable to make follow-up appointment(s) can be followed by phone/video 
contact for the Quality of Life assessments, OMDQ Survey and Pain Assessment. If a follow up 
visit is done via phone/ video contact, then only the Quality of Life Questionnaires, OMDQ 
Survey and Pain Assessment are required. 
4. For patients requiring prolonged analgesic therapy (greater than 12 months). Long-term follow up 
visits may be extended for up to 24 months. Long term follow-up evaluations will be scheduled at 
6 month intervals (± 3 months) as long as the patient is on a continuing pain treatment regimen. 
Note: Patients who are unable to make follow-up appointment(s) can be followed by phone/video 
contact for the Quality of Life assessments, OMDQ Survey and Pain Assessment. If a follow up 
visit is done via phone/ video contact, then only the Quality of Life Questionnaires, OMDQ 
Survey and Pain Assessment are required. 
5. H&N patients rarely experience diarrhea.  The 2 diarrhea questions in the OMDQ will therefore be 
omitted and assumed to be 0 unless noted otherwise. 
6. Medications that are ongoing within 1 week prior to first dose of study drug.  The Roswell Park 
EMR will be the documentation and will not need to be repeated in notes. 
7. Captured in REDCAP. 
8. Pain Medications will be recorded in REDCAP and converted to Morphine Milligram Equivalents 
(Appendix B). 
 

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11.8  
Gabapentin is a gamma-aminobutyric acid (GABA) analogue that was originally 
formulated to treat epilepsy. The drug is known to provide significant pain relief in 
about a third of people who take it for fibromyalgia or chronic neuropathic pain; 
however, side effects result in two thirds of people. It is effective in reducing 
narcotic usage post-operatively and is helpful in neuropathic pain due to cancer. 
Oxycodone is a narcotic analgesic generally indicated for relief of moderate to 
severe pain. It was developed in 1916 in Germany as one of several new semi-
synthetic opioids in an attempt to improve on the existing opioids. Oxycodone 
15 mg taken orally is equivalent to 10 mg IV Morphine and 30 mg PO 
Hydrocodone, each with 3-5 hours average duration.(18, 30) 
Methadone is a synthetic opioid. It is used medically as an analgesic and a 
maintenance anti-addictive and reductive preparation for use by patients with opioid 
dependency. However, methadone has gained popularity among physicians for the 
treatment of other medical problems, such as an analgesic in chronic pain. Due to 
its activity at the N-Methyl-D-aspartate (NMDA) receptor it may be more effective 
against neuropathic pain, but, for the same reason, tolerance to the analgesic effects 
may be lesser compared to other opioids. The greatest benefit in this setting is that 
methadone can be dosed less frequently than shorter-acting drugs like morphine or 
hydrocodone. Another factor in the increased usage is the low cost.(17, 18, 31) 
Venlafaxine is a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) used 
medically for depression, anxiety disorders and pain. Venlafaxine and its active 
metabolite, O-desmethylvenlafaxine, are inhibitors of neuronal serotonin and 
norepinephrine reuptake and weak inhibitors of dopamine uptake. Serotonergic 
actions are present at low doses, while its noradrenergic actions are progressively 
enhanced as dose increases. It is theorized the balanced inhibition of presynaptic 
uptake in both serotonin and norepinephrine is the primary mechanism accounting 
for pain relief. (34)  
12.0 Withdrawal of Subjects 
12.1 Reasons for treatment discontinuation and withdrawal from study without 
patient consent will include the following:  
• Death 
• Patients with symptomatic deterioration: global deterioration of 
health status requiring discontinuation of treatment 
• Treatment-related toxicity 
• Toxicity unrelated to treatment that may prevent the patient from 
continuing 
• Reported or prescribed use of an opioid or neuropathic pain 
medication not listed in section 10.2 
• Investigator judgement 

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o The Investigator may withdraw a patient if, in his/her 
judgement, it is in the patient’s best interest to do so. 
• Noncompliance 
12.2 Upon treatment discontinuation all end of treatment evaluations and tests 
will be conducted.  All patients who discontinue due to an AE must be 
followed until the event resolves or stabilizes.  Appropriate medical care 
should be provided until signs and symptoms have abated or stabilized.  The 
final status of the AE will be reported in the patient’s medical records and to 
the appropriate eCRF.   
13.0 Risks to Subjects 
13.1 Please see page 16 and 17. 
The benefit to the patient in terms of improvement in pain, quality of life, 
and reduced opioid requirement likely outweigh the risks. 
13.2 Venlafaxine is a Category C teratogen. There are no adequate or well 
controlled studies in human women. Pregnant women are excluded from this 
study. A urine pregnancy test is required in women of child-bearing 
potential prior to enrollment.  
13.3 There are no known risks to others who are not subjects.  
14.0 Potential Benefits to Subjects 
14.1 Patients may benefit from this study by potentially having decreased pain, 
improved quality of life and reduced opioid requirement during 
chemoradiation treatment.  
15.0 Data and Specimen Banking 
15.1 
NA 
16.0 Measurement of Effect 
16.1 
Schedules for measuring the pain and quality of life outcomes are 
described in Section 11.   Toxicity assessments are described in Section 17. 
17.0 Safety Evaluation 
17.1 
Adverse Events 
An adverse event or adverse experience (AE) is any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related. 
Therefore, an AE can be ANY unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of ‘unrelated’, ‘unlikely’, ‘possible’, ‘probable’, or 
‘definite’). 

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An AE is considered “unexpected” if it is not listed in the investigator brochure or is not 
listed at the specificity or severity that has been observed; or if an investigator brochure is 
not required or available, is not consistent with the risk information described in the 
general investigational plan in other study-related documents. 
• Diagnosis Versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be clinically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE 
on the CRF. If a diagnosis is subsequently established, it should be reported as 
follow-up information. 
• Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade 
events or clinical sequelae) should be identified by their primary 
cause. For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on 
the CRF.  
However, clinically significant AEs occurring secondary to an 
initiating event that are separated in time should be recorded as 
independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should 
be recorded separately on the CRF. 
• Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active 
management will be recorded as AEs or SAEs on the CRF 
(e.g., abnormalities that require study drug dose modification, 
discontinuation of study treatment, more frequent follow-up 
assessments, further diagnostic investigation, etc.). 
 
If the clinically significant laboratory abnormality is a sign of a 
disease or syndrome (e.g., alkaline phosphatase and bilirubin 5 x the 
upper limit of normal associated with cholecystitis), only the diagnosis 
(e.g., cholecystitis) needs to be recorded on the Adverse Event CRF. 
 
If the clinically significant laboratory abnormality is not a sign of a 
disease or syndrome, the abnormality itself should be recorded as an 
AE or SAE on the CRF. If the laboratory abnormality can be 
characterized by a precise clinical term, the clinical term should be 
recorded as the AE or SAE. For example, an elevated serum potassium 
level of 7 mEq/L should be recorded as “hyperkalemia”. 
 
Observations of the same clinically significant laboratory 
abnormality from visit to visit should not be repeatedly recorded as 
AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes. 
• Preexisting Medical Conditions (Baseline Conditions) 
A preexisting medical condition should be recorded as an AE or SAE 
only if the frequency, severity, or character of the condition worsens 

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during the study. When recording such events on an Adverse Event 
CRF, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
17.2 
 Grading and Reporting Adverse Events 
• Grading and Relationship to Drug 
The descriptions and grading scales found in the CTEP Version 5 of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) will be utilized for 
AE reporting. CTEP Version 5 of the CTCAE is identified and located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
AEs not covered by specific terminology listed should be reported with common 
medical terminology, and documented according to the grading scales provided in 
the CTCAE Version5. 
The relationship of event to study drug will be documented by the Investigator as 
follows: 
Unrelated: The event is clearly related to other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs administered to 
the participant. 
Unlikely: The event is doubtfully related to investigational agent(s). The event 
was most likely related to other factors such as the participant’s clinical state, 
other therapeutic interventions, or concomitant drugs. 
Possible: The event follows a reasonable temporal sequence from the time of 
drug administration, but could have been produced by other factors such as the 
participant’s clinical state, other therapeutic interventions or concomitant drugs. 
Probable: The event follows a reasonable temporal sequence from the time of 
drug administration, and follows a known response pattern to the study drug. The 
event cannot be reasonably explained by other factors such as the participant’s 
clinical state, therapeutic interventions or concomitant drugs. 
Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be 
reasonably explained by other factors such as the participant’s condition, 
therapeutic interventions or concomitant drugs; AND occurs immediately 
following study drug administration, improves upon stopping the drug, or 
reappears on re-exposure. 
 

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Reporting Adverse Events: Routine AEs occurring between the start date of intervention 
until 30 days after the last intervention, or until the event has resolved, the study 
participant is lost to follow-up, the start of a new treatment, or until the study investigator 
assesses the event(s) as stable or irreversible, will be reported. New information will be 
reported after it is received. For this study, venlafaxine is the study drug. All other pain 
interventions are considered standard of care.  Attributions for AE’s will only be captured 
for the venlafaxine arm. Guidelines for Routine Adverse Event Reporting for Pilot, 
Phase 2, and Phase 3 Studies (Regardless of Expectedness) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Unrelated 
 
 
X 
X 
Unlikely 
 
 
X 
X 
Possible 
X 
X 
X 
X 
Probable 
X 
X 
X 
X 
Definite 
X 
X 
X 
X 
 
17.3 
Serious Adverse Events 
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of 
either the investigator or sponsor results in ANY of the following: 
• Death. 
• A life-threatening adverse event (experience). Any AE that places a 
participant or participants, in the view of the Investigator or sponsor, at 
immediate risk of death from the reaction as it occurred. It does NOT 
include an AE that, had it occurred in a more severe form, might have 
caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
(for > 24 hours). 
• A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• A congenital anomaly or birth defect. 
• Important Medical Event (IME) that, based upon medical judgment, 
may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Reporting Serious Adverse Events 
All new SAEs occurring from the date the participant signs the study consent until 
30 days after the last intervention or a new treatment is started, whichever comes first, 
will be reported. The Roswell Park SAE Source Form is to be completed with all 
available information, including a brief narrative describing the SAE and any other 
relevant information.  
SAEs occurring after the 30 day follow-up period that the investigator determines to be 
possibly, probably or definitely related to the study intervention should be reported. 
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please 
refer to Section 17.6 for details on reporting Unanticipated Problems. 
17.4 
Follow-Up for Serious Adverse Events 

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All related SAEs should be followed to their resolution, until the study participant is lost 
to follow-up, the start of a new treatment, or until the study investigator assesses the 
event(s) as stable or irreversible. New information will be reported when it is received. 
17.5 
Unanticipated Problems 
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of 
the following criteria: 
• Unexpected (in terms of nature, severity, or frequency) given: 
o The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of 
participant privacy or confidentiality of data. 
o The characteristics of the participant population being studied. 
• Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research). 
• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized and if in relation to an AE is also deemed Serious per 
Section 17.3. 
Reporting Unanticipated Problems: 
Unanticipated problem reporting will begin at the time of participant consent. An 
Unanticipated Problem shall be submitted to the CRS Compliance Office as “Reportable 
New Information” in the Click system within 1 business day of becoming aware of the 
Unanticipated Problem. After review, CRS Compliance will submit the UP to the IRB.  
When becoming aware of new information about an Unanticipated Problem, submit the 
updated information to CRS Compliance as “Reportable New Information” in the Click 
system..  
17.6 
FDA Reporting 
NA 
 
18.0 Data Management and Confidentiality 
18.1 Waiver of HIPPA Authorization 
HIPPA Authorization will not be waived.  In order to conduct the research, PHI 
will be accessed via the EMR in order to accurately document patient information 
including diagnosis, treatment, and medical history.  Medical record numbers, 
date of birth, date of death, and age will be necessary for the research. Each 
patient will be consented for this process including consent for investigators to 
access medical records. 
 

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Data will be entered into a secure RedCap Database on the Roswell Park server.  
This will be accessible only to investigators on the study.  For analysis, data will 
be entered into eClinical, which will only be accessible to authorized individuals 
(see section 18.2).   
 
Any paper files containing identifiers will not be taken off Roswell Park premises.  
PHI will not be reused or disclosed to any other person or entity. 
 
18.2 
Data collection and storage  
Patient data will be kept on the secure Roswell Park RedCap database, and will be 
accessible only by the PI, co-investigator, and the CRS representative. It will be 
password protected. All records will be kept in a limited access environment. All 
computer entry and networking programs will be done using PIDs only. 
Data entry into the database is to be completed in a timely fashion (within 
30 days) after the patient’s clinic visit. If an AE is considered serious it is 
captured on both the Adverse Event page and the Serious Adverse Event 
Source Form, which is handled in an expedited fashion. 
Data management activities will be performed using eClinical. eClinical is 
a suite of software tools that enables the collection, cleaning and viewing 
of clinical trial data. CRS data management will design the study-specific 
database and facilitate its development by the eClinical Information 
Technology team. Once the database design is approved by the 
Investigator, Statistician, and Clinical Research Coordinator, the database 
will be put into production and data entry can begin. Data can be entered 
and changed only by those with the rights to do so into the eCRFs (via the 
EXPeRT Module). eClinical is compliant with all relevant technical 
aspects of relevant GCP guidelines. 
• The system can generate accurate copies of stored data and audit trail 
information in human readable form. 
• System access is limited to authorized individuals through the controlled 
assignment of unique ID and password combinations. 
• The system is designed to periodically force users to change their 
passwords and verifies that user ID and password combinations remain 
unique. 
• The system automatically generates a permanent time-stamped audit trail 
of all user interactions. 
18.3  
Full build studies are managed by Roswell Park CRS Data Management 
for analysis by Roswell Park Biostatisticians. All electronic case report 
form (eCRF) data are captured for these studies. 

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Data management activities are performed using a CTMS system that 
enables the collection, cleaning and viewing of clinical trial data. CRS 
data management designs the study-specific database and facilitates 
development by the Information Technology team. Once the database 
design is approved by the Investigator, Statistician, and Clinical Research 
Coordinator, the database is put into production and data entry can begin. 
Data can be entered and changed only by those with the rights to do so 
into the eCRFs. 
 
18.4  
• Full build studies are managed by Roswell Park CRS Data Management for 
analysis by Roswell Park Biostatisticians. All electronic case report form 
(eCRF) data are captured for these studies. 
• Data management activities are performed using a CTMS system that enables 
the collection, cleaning and viewing of clinical trial data. CRS data management 
designs the study-specific database and facilitates development by the 
Information Technology team. Once the database design is approved by the 
Investigator, Statistician, and Clinical Research Coordinator, the database is put 
into production and data entry can begin. Data can be entered and changed only 
by those with the rights to do so into the eCRFs. 
19.0 Statistical Plan 
19.1 
The primary objective of the study is to assess the pain-reduction effects 
of adding venlafaxine to a regimen of gabapentin and methadone to control pain 
during and after chemoradiation.  Pain will be quantified using EORTC QLQ-
H&N35, which is measured repeatedly during the 7-week radiation treatment 
process, and periodically for as long as the patient receives pain management 
treatment, up to 24 months after enrollment (see Section 11).  
19.2 
Analysis Samples 
(1) The intent to treatment (ITT) sample includes all enrolled patients, assuming 
they treated in accordance with the randomized treatment assignment. 
(2) The Per-Protocol sample includes enrolled patients who comply with the 
prescribed pain control regimen during their radiation therapy, and complete the 
7-week follow-up EORTC QLQ-H&N35 survey. 
19.3 
Primary Analysis:  The efficacy of venlafaxine will be quantified by 
comparing the within-patient change in pain scores (EORTC QLQ-C30) between 
the baseline and week 7 assessments in the ITT sample.  The treatment effect will 
be estimated with a Generalized Linear Mixed model, describing the continuous 
EORTC QLQ-C30 outcomes as a function of a random patient effect, and fixed 
effects for treatment assignment, time (7-week vs baseline), the stratification 
factor, the treatment assignment (venlafaxine vs not) and the treatment/time 
interaction.  This modeling approach also for adjustment of other biologically 
relevant factors, such as age, gender, and disease severity.  The magnitude, 

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direction and 95% confidence interval for the adjusted interaction term estimate 
will be used to describe the effect venlafaxine in improving the pain management 
regimen.  An interaction p-value <0.05 will be considered statistically significant. 
19.4 
Power and Sample Size:  
Preliminary data from I-26314 of the end-point measured as pain score in final 
week of treatment demonstrated an effect size between 11-16% with the addition 
of gabapentin compared to the standard of care, and a 6% benefit with the 
addition of methadone compared to gabapentin alone.  Tasmuth et al (14) showed 
a 24% improvement in patient-reported pain relief for venlafaxine versus placebo.   
Simpson (16) demonstrated a 29% improvement for the addition of venlafaxine to 
gabapentin.   
Power calculations consider the simplified case where the exogenous factors 
(stratification and biologically relevant covariates) for not meaningful.  Then the 
effect of venlafaxine on the change in pain score can be assessed using a 2x2 
repeated measures ANOVA.  In both treatment arms, the baseline H&N35 pain 
scores are expected to have mean=75 and standard deviation between 14 and 20.32  
The corresponding coefficients of variation are between 0.20 and 0.30.   
Based on the data from I-26314, the week 7 follow-up Pain Scores in the control 
arm are expected to have a mean of 63, indicating 15% decline from the baseline 
mean of 75.  Correlation of 0.2 is assumed for the within-patient outcome 
measurements.  The table below shows the maximum week 7 mean in the 
venlafaxine arm that is detectable with 80% power using a 2-sided 𝛼= 0.05 F-
test for the treatment/time interaction in the model above, under different 
assumptions about the common coefficient of variation in the outcome. 
 
Coefficient 
of Variation 
Week-7 venlafaxine 
mean score 
% decline from 
Baseline=75 
0.20 
50 
33% 
0.25 
47 
37% 
0.30 
44 
41% 
 
19.5 
Toxicity Outcomes:  
Toxicities will be tabulated by treatment arm using the maximum grade observed 
by patient.  Possible differences by treatment will be described using odds ratio 
and 95% confidence interval estimates derived use Maental Hanzel methods to 
account for laterality of the radiation treatment. 
19.6 
Tertiary Outcomes:  
The frequency of rescue medication use, morphine equivalent dose, and weekly 
OMDQ scores between treatments for each group individually and the combined 
cohort.  The effect of venlafaxine on other quality of life outcomes will be 
quantified using the methods described for the primary outcome. 

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20.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
20.1 The Roswell Park Data and Safety Monitoring Board will assess the 
progress of the study, the safety data, and critical efficacy endpoints. The 
DSMB will review the study annually and will make recommendations that 
include but not limited to; (a) continuation of the study, (b) modifications to 
the design (c) or termination of the study. 
21.0 Vulnerable Populations 
NA 
 
22.0 Community-Based Participatory Research 
22.1 NA 
23.0 Sharing of Results with Subjects 
23.1 NA- due to the nature of the study, there are no expected incidental findings 
or tests that would need to be conveyed to patients or primary care 
physicians. 
24.0 Setting 
24.1 Patients will be recruited from the Radiation Oncology clinic at Roswell 
Park, or from the Roswell Park satellite facility.  All research procedures 
will be performed within Roswell Park. . 
25.0 Provisions to Protect the Privacy Interests of Subjects 
25.1 All discussion regarding the study including recruitment, consent process, 
and follow up visits will be conducted in a quiet, private environment.  Any 
Investigator working with the patient will be introduced and an attempt will 
be made to ensure that the same Investigator is available to see the patient at 
the next visit. Subjects will be free to request an alternate provider should 
they feel more comfortable with someone else. 
25.2 All procedures will be thoroughly explained to each patient, both during the 
consent process, and during the baseline visit and follow ups.  Ample 
opportunity will be provided for questions to be asked and answered.  
Subjects will be provided with a number to call should they have any further 
concerns following their visits. 
25.3 The Investigators are responsible for retention of the patient log and patient 
records; although personal information may be reviewed by authorized 
persons, that information will be treated as strictly confidential and will not 
be made publicly available.  The Investigators are also responsible for 
obtaining patient authorization to access medical records and other 
applicable study specific information according to the Health Insurance 

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Portability and Accountability Act regulations (where applicable).  Records 
and personal information will be accessed only through the Roswell Park 
network on a password protected server. 
26.0 Resources Available 
26.1 All Investigators on the study have been trained in human subject research 
as per requirements at Roswell Park.  Dr. Singh is currently overseeing 
several other clinical trials in human subjects.  All Investigators that will be 
working with subjects have experience working with patients in a clinical 
setting, and are familiar with the resources available at Roswell Park.  
Specifically, Dr. Singh is the PI for Clinical Trial I 262314, which included 
the same patient population of head and neck cancer patients undergoing 
chemoradiotherapy and a similar analgesia regimen with Gabapentin and 
Methadone.  
26.2 Recruitment of new subjects is feasible based on the volume of new patients 
seen in the radiation medicine clinic on a weekly basis.  On average, there 
are at least 4 new consultations per week, and if all patients are screened, 
approximately half will be eligible for the study based on need for 
chemotherapy.  Clinical Trial I 262314 accrued 60 patients in 18 months, 
which has similar inclusion criteria as the current study. Therefore, we 
anticipate completion of accrual to be within 24 months.  
Time devoted to conducting and completing the research will include 
subject recruitment, consent process, fielding patient phone calls, and 
arranging follow up visits. Each visit with a patient will require 
approximately 30 minutes of devoted time from the Investigator.  Additional 
time will be spent ensuring patient compliance, entering data into the 
electronic system, and analyzing data. 
The facilities at Roswell Park include a medical oncology clinic, radiation 
oncology clinic, chemotherapy infusion clinic, and various support staff for 
patients.  This includes a social work department as well as psychologists 
who will be available to meet with patients should the need arise.   
All persons assisting with the research will be fully informed regarding 
research procedures and protocols prior to starting work on the study.  A 
clinical research coordinator assigned to the study will be available to assist 
with ensuring compliance with all protocol requirements. 
27.0 Prior Approvals 
NA 
28.0 Compensation for Research-Related Injury 
NA 
29.0 Economic Burden to Subjects 

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29.1 All medications will be covered by insurance. There should therefore be no 
additional costs to patients who have insurance. 
 
30.0 Consent Process 
30.1 Informed consent will take place in the radiation medicine clinic at Roswell 
Park.  The Investigator (or IRB approved designee) is responsible for 
obtaining written consent from each patient or the patient's legally 
authorized representative in accordance with “SOP: Informed Consent 
Process for Research (HRP-090)” using the approved informed consent 
form, before any study specific procedures (including screening procedures) 
are performed. The informed consent form acknowledges all information 
that must be given to the patient, including the purpose and nature of the 
study, the expected efficacy and possible side effects of the treatment(s), and 
specifying that refusal to participate will not influence further options for 
therapy. Any additional information that is applicable to the study must also 
be included. Additional national or institutionally mandated requirements 
for informed consent must also be adhered to. The patient should also be 
made aware that by signing the consent form, processing of sensitive 
clinical trial data and transfer to other countries for further processing is 
allowed. 
The Investigator shall provide a copy of the signed consent form to the 
patient and the signed original shall be maintained in the Investigator File. A 
copy of the signed consent form must be filed in the patient file. At any 
stage, the patient may withdraw from the study and such a decision will not 
affect any further treatment options. 
Non-English Speaking Subjects 
• 
The population of potential subjects may include those that speak 
languages other than English.  During screening for the study, the 
patient will be asked their preferred language.  If a non-native English 
speaker is enrolled, translator services will be required at the first visit, 
during the consent process, and during each follow up evaluation.  The 
translator will be medically qualified and fluent in both English and 
the patient’s primary language. The consent for itself will be in 
English, however, a translator will be present to read and explain the 
consent to the subject in the subject’s native language.  In addition to 
scheduled visits, phone translators will always be available should the 
subjects have questions.  
 

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Subjects who are not yet adults (infants, children, teenagers) 
• Subjects less than 18 years of age will not be enrolled in the study. 
 
Cognitively Impaired Adults 
• Subjects with cognitive impairment will not be enrolled in the study. 
 
Adults Unable to Consent 
• Adults unable to consent will not be enrolled in the study. 
 
31.0 Process to Document Consent in Writing 
31.1 Written documentation of consent will be completed in accordance with 
“SOP: Written Documentation of Consent (HRP-091).”  
32.0 Drugs or Devices 
• 
Drugs will not be supplied by the study. 
 
33.0 REFERENCES 
 
1. 
Kramer S, Newcomb M, Hessler J, Siddiqui F. Prophylactic versus reactive PEG tube 
placement in head and neck cancer. Otolaryngol Head Neck Surg. 2014;150(3):407-12. doi: 
10.1177/0194599813517081. PubMed PMID: 24381015. 
2. 
Strom T, Trotti AM, Kish J, Rao NG, McCaffrey J, Padhya TA, Lin HY, Fulp W, 
Caudell JJ. Risk factors for percutaneous endoscopic gastrostomy tube placement during 
chemoradiotherapy for oropharyngeal cancer. JAMA Otolaryngol Head Neck Surg. 
2013;139(11):1242-6. doi: 10.1001/jamaoto.2013.5193. PubMed PMID: 24136493. 
3. 
Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L, 
Garofalo E. Gabapentin for the symptomatic treatment of painful neuropathy in patients with 
diabetes mellitus: a randomized controlled trial. JAMA. 1998;280(21):1831-6. PubMed PMID: 
9846777. 
4. 
Sharp H, Morris JC, Van Waes C, Gius D, Cooley-Zgela T, Singh AK. High incidence of 
oral dysesthesias on a trial of gefitinib, Paclitaxel, and concurrent external beam radiation for 
locally advanced head and neck cancers. Am J Clin Oncol. 2008;31(6):557-60. doi: 
10.1097/COC.0b013e318172d5de. PubMed PMID: 19060587. 
5. 
Bar Ad V, Weinstein G, Dutta PR, Chalian A, Both S, Quon H. Gabapentin for the 
treatment of pain related to radiation-induced mucositis in patients with head and neck tumors 
treated with intensity-modulated radiation therapy. Head Neck. 2010;32(2):173-7. doi: 
10.1002/hed.21165. PubMed PMID: 19572284. 
6. 
Bar Ad V, Weinstein G, Dutta PR, Dosoretz A, Chalian A, Both S, Quon H. Gabapentin 
for the treatment of pain syndrome related to radiation-induced mucositis in patients with head 

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and neck cancer treated with concurrent chemoradiotherapy. Cancer. 2010;116(17):4206-13. 
Epub 2010/06/22. doi: 10.1002/cncr.25274. PubMed PMID: 20564146. 
7. 
Starmer HM, Riley LH, 3rd, Hillel AT, Akst LM, Best SR, Gourin CG. Dysphagia, short-
term outcomes, and cost of care after anterior cervical disc surgery. Dysphagia. 2014;29(1):68-
77. Epub 2013/08/15. doi: 10.1007/s00455-013-9482-9. PubMed PMID: 23943072. 
8. 
Dong T RA, Jones G.C, Scoble D, Deeken J, Bajaj G.K. Retrospective Analysis of 
Prophylactic Gabapentin on Pain and Weight Loss in Patients Undergoing Radiation Therapy for 
Oropharyngeal Cancer. Int J Radiat Oncol Biol Phys. 2016;94(4):893-4. 
9. 
Bar Ad V. Gabapentin for the treatment of cancer-related pain syndromes. Reviews on 
recent clinical trials. 2010;5(3):174-8. PubMed PMID: 20482492. 
10. 
Hearn L, Derry S, Phillips T, Moore RA, Wiffen PJ. Imipramine for neuropathic pain in 
adults. Cochrane Database Syst Rev. 2014(5):CD010769. doi: 
10.1002/14651858.CD010769.pub2. PubMed PMID: 24838845. 
11. 
Derry S, Wiffen PJ, Aldington D, Moore RA. Nortriptyline for neuropathic pain in adults. 
Cochrane Database Syst Rev. 2015;1:CD011209. doi: 10.1002/14651858.CD011209.pub2. 
PubMed PMID: 25569864. 
12. 
Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain 
in adults. Cochrane Database Syst Rev. 2015(7):CD008242. doi: 
10.1002/14651858.CD008242.pub3. PubMed PMID: 26146793. 
13. 
Sindrup SH, Bach FW, Madsen C, Gram LF, Jensen TS. Venlafaxine versus imipramine 
in painful polyneuropathy: a randomized, controlled trial. Neurology. 2003;60(8):1284-9. 
PubMed PMID: 12707430. 
14. 
Tasmuth T, Hartel B, Kalso E. Venlafaxine in neuropathic pain following treatment of 
breast cancer. Eur J Pain. 2002;6(1):17-24. doi: 10.1053/eujp.2001.0266. PubMed PMID: 
11888224. 
15. 
Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment 
of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110(3):697-
706. doi: 10.1016/j.pain.2004.05.010. PubMed PMID: 15288411. 
16. 
Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic 
neuropathy. J Clin Neuromuscul Dis. 2001;3(2):53-62. PubMed PMID: 19078655. 
17. 
Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, Mercadante S, 
Meynadier J, Poulain P, Ripamonti C, Radbruch L, Casas JR, Sawe J, Twycross RG, Ventafridda 
V, Expert Working Group of the Research Network of the European Association for Palliative C. 
Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer. 
2001;84(5):587-93. doi: 10.1054/bjoc.2001.1680. PubMed PMID: 11237376; PMCID: 
PMC2363790. 
18. 
Koyyalagunta D, Bruera E, Solanki DR, Nouri KH, Burton AW, Toro MP, Bruel BM, 
Manchikanti L. A systematic review of randomized trials on the effectiveness of opioids for 
cancer pain. Pain Physician. 2012;15(3 Suppl):ES39-58. PubMed PMID: 22786461. 
19. 
Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, 
Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, 
Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain 
in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-73. doi: 
10.1016/S1474-4422(14)70251-0. PubMed PMID: 25575710; PMCID: PMC4493167. 
20. 
Moulin D, Boulanger A, Clark AJ, Clarke H, Dao T, Finley GA, Furlan A, Gilron I, 
Gordon A, Morley-Forster PK, Sessle BJ, Squire P, Stinson J, Taenzer P, Velly A, Ware MA, 

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Weinberg EL, Williamson OD, Canadian Pain S. Pharmacological management of chronic 
neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 
2014;19(6):328-35. PubMed PMID: 25479151; PMCID: PMC4273712. 
21. 
Donnelly RF, Wong K, Goddard R, Johanson C. Stability of venlafaxine immediate-
release suspensions. Int J Pharm Compd. 2011;15(1):81-4. PubMed PMID: 23696051. 
22. 
Fayers P, Bottomley A, Group EQoL, Quality of Life U. Quality of life research within 
the EORTC-the EORTC QLQ-C30. European Organisation for Research and Treatment of 
Cancer. Eur J Cancer. 2002;38 Suppl 4:S125-33. PubMed PMID: 11858978. 
23. 
Abrahm JL. Management of pain and spinal cord compression in patients with advanced 
cancer. ACP-ASIM End-of-life Care Consensus Panel. American College of Physicians-
American Society of Internal Medicine. Ann Intern Med. 1999;131(1):37-46. PubMed PMID: 
10391814. 
24. 
Litrivis L. How Should Common Symptoms at the End of Life be Managed? The 
Hospitalist. 2013 May  
25. 
Looke TD, Kluth CT. Effect of preoperative intravenous methocarbamol and intravenous 
acetaminophen on opioid use after primary total hip and knee replacement. Orthopedics. 
2013;36(2 Suppl):25-32. doi: 10.3928/01477447-20130122-54. PubMed PMID: 23379573. 
26. 
Beydoun A, Uthman BM, Sackellares JC. Gabapentin: pharmacokinetics, efficacy, and 
safety. Clin Neuropharmacol. 1995;18(6):469-81. PubMed PMID: 8681309. 
27. 
Lal R, Sukbuntherng J, Luo W, Chen D, Blumenthal R, Ho J, Cundy KC. Clinical 
pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release 
tablets in patients with varying degrees of renal function using data from an open-label, single-
dose pharmacokinetic study. Clinical therapeutics. 2012;34(1):201-13. doi: 
10.1016/j.clinthera.2011.12.004. PubMed PMID: 22206794. 
28. 
Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol. 
1999;13(1):100-9. doi: 10.1177/026988119901300111. PubMed PMID: 10221364. 
29. 
Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with 
cyproheptadine. J Emerg Med. 1998;16(4):615-9. PubMed PMID: 9696181. 
30. 
Biancofiore G. Oxycodone controlled release in cancer pain management. Ther Clin Risk 
Manag. 2006;2(3):229-34. PubMed PMID: 18360598; PMCID: PMC1936259. 
31. 
Leppert W. The role of methadone in cancer pain treatment--a review. Int J Clin Pract. 
2009;63(7):1095-109. doi: 10.1111/j.1742-1241.2008.01990.x. PubMed PMID: 19570126. 
32. 
Bosse GM, Spiller HA, Collins AM. A fatal case of venlafaxine overdose. J Med 
Toxicol. 2008;4(1):18-20. PubMed PMID: 18338306; PMCID: PMC3550100. 
33. 
Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM. Efficacy of 
duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain 
models in rats. J Pharmacol Exp Ther. 2004;311(2):576-84. doi: 10.1124/jpet.104.070656. 
PubMed PMID: 15254142. 
34. 
Breitbart W, Chandler S, Eagel B, Ellison N, Enck RE, Lefkowitz M, Payne R. An 
alternative algorithm for dosing transdermal fentanyl for cancer-related pain. Oncology 
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34.0 APPENDICES/SUPPLEMENTS 
Appendix A Oral Suspension Recipe(21) 
 
 
Appendix B Oral Morphine Equivalence Ratios(35) 
 

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Appendix C Oral Mucositis Daily Questionnaire (OMDQ) 
 
 
 
 

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Appendix D ECOG Performance Status Scores 
Description 
Status 
Fully active, able to carry on all pre-disease performance without restriction. 
0 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work. 
1 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
4 
Dead 
5 
 
 
 

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Appendix E EORTC QLQ-C30 Questionnaire 
 
Not at 
All 
A 
Little 
Quite 
A Bit 
Very 
Much 
1. Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase?  
 
 
2. Do you have any trouble taking a long walk?  
 
3. Do you have any trouble taking a short walk outside of the 
house? 
 
4. Do you need to stay in bed or a chair during the day? 
 
5. Do you need help with eating, dressing, washing yourself 
or using the toilet?  
 
1 
 
 
1 
 
1 
 
 
1 
 
1 
2 
 
 
2 
 
2 
 
 
2 
 
2 
3 
 
 
3 
 
3 
 
 
3 
 
3 
4 
 
 
4 
 
4 
 
 
4 
 
4 
During the past week: 
 
Not at 
All 
A 
Little 
Quite 
A Bit 
Very 
Much 
6. Were you limited in doing either your work or other daily 
activities? 
 
7. Were you limited in pursuing your hobbies or other leisure 
time activities? 
 
8. Were you short of breath? 
 
9. Have you had pain?  
 
10. Did you need to rest? 
 
11. Have you had trouble sleeping? 
 
12. Have you felt weak? 
 
13. Have you lacked appetite? 
 
14. Have you felt nauseated? 
 
15. Have you vomited? 
 
1 
 
 
1 
 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
2 
 
 
2 
 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
3 
 
 
3 
 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
4 
 
 
4 
 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
 
 
Not at 
All 
A 
Little 
Quite 
A Bit 
Very 
Much 
16. Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase?  
 
 
17. Do you have any trouble taking a long walk?  
1 
 
 
1 
2 
 
 
2 
3 
 
 
3 
4 
 
 
4 

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18. Do you have any trouble taking a short walk outside of the 
house? 
 
19. Do you need to stay in bed or a chair during the day? 
 
20. Do you need help with eating, dressing, washing yourself 
or using the toilet?  
 
 
1 
 
 
1 
 
1 
 
2 
 
 
2 
 
2 
 
3 
 
 
3 
 
3 
 
4 
 
 
4 
 
4 
During the past week: 
 
Not at 
All 
A 
Little 
Quite 
A Bit 
Very 
Much 
21. Were you limited in doing either your work or other daily 
activities? 
 
22. Were you limited in pursuing your hobbies or other leisure 
time activities? 
 
23. Were you short of breath? 
 
24. Have you had pain?  
 
25. Did you need to rest? 
 
26. Have you had trouble sleeping? 
 
27. Have you felt weak? 
 
28. Have you lacked appetite? 
 
29. Have you felt nauseated? 
 
30. Have you vomited? 
 
1 
 
 
1 
 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
2 
 
 
2 
 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
3 
 
 
3 
 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
4 
 
 
4 
 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
 
 
 

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Appendix F EORTC QLQ-H&N35 Questionnaire 
 
During the past week: 
 
Not at 
All 
A 
Little 
Quite 
A Bit 
Very 
Much 
31. Have you had pain in your mouth? 
 
32. Have you had pain in your jaw? 
 
33. Have you had soreness in your mouth? 
 
34. Have you had a painful throat? 
 
35. Have you had problems swallowing liquids?  
 
36. Have you had problems swallowing pureed food?  
 
37. Have you had problems swallowing solid food?  
 
38. Have you choked when swallowing?  
 
39. Have you had problems with your teeth?  
 
40. Have you had problems opening your mouth wide?  
 
41. Have you had a dry mouth?  
 
42. Have you had sticky saliva?  
 
43. Have you had problems with your sense of smell? 
 
44. Have you had problems with your sense of taste?  
 
45. Have you coughed?  
 
46. Have you been hoarse?  
 
47. Have you felt ill?  
 
48. Has your appearance bothered you?  
 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
 
 
 
 
 
 
During the past week: 
 
Not at 
All 
A 
Little 
Quite 
A Bit 
Very 
Much 

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49. Have you had trouble eating?  
 
50. Have you had trouble eating in front of your family?  
 
51. Have you had trouble eating in front of other people?  
 
52. Have you had trouble enjoying your meals?  
 
53. Have you had trouble talking to other people?  
 
54. Have you had trouble talking on the telephone?  
 
55. Have you had trouble having social contact with your 
family?  
 
56. Have you had trouble having social contact with friends?   
 
57. Have you had trouble going out in public?  
 
58. Have you had trouble having physical contact with family 
or friends?  
 
59. Have you felt less interest in sex?  
 
60. Have you felt less sexual enjoyment?  
 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
During the past week: 
 
 
No 
 
Yes 
61. Have you used pain-killers? 
 
62. Have you taken any nutritional supplements (excluding 
vitamins)? 
 
63. Have you used a feeding tube? 
 
64. Have you lost weight? 
 
65. Have you gained weight?  
1 
 
1 
 
1 
 
1 
 
1 
2 
 
2 
 
2 
 
2 
 
2 
 
Scoring for the EORTC QLQ-C30 and HN35 modules: Global Health Status (QoL), 
Functional Scales, and Symptom Scales are scored from combining items. The methodology and 
process is outlined on the EORTC website: http://www.eortc.be/qol/files/SCManualQLQ-
C30.pdf