Conditions: Cancer-related Pain
Keywords: Pain Cancer Lidocaine Sodium Channel Blockers
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 33
Healthy volunteers: no

Brief summary:
This study's primary objective is to test the hypothesis that a single infusion of subcutaneous lidocaine can cause a clinically useful reduction in cancer pain within 48 hours of infusion and lasting a minimum of 7 days. A clinically useful reduction in pain is defined by either a 2-point reduction (on a 0-10 scale) in the worst pain experienced over a 24-hour period, or a ≥30% reduction in 24-hour opioid requirement. We will use a composite endpoint of reduction in pain without increase in 24-hr opioid requirement or no decrease in pain with a ≥30% reduction in 24-hour opioid requirement.Subjects will receive either lidocaine or placebo, followed at least 1 week later by the alternate agent.

Detailed description:
Ten mg/kg of lidocaine will be infused subcutaneously via a Baxter infusor over a 5.5 hour period in ambulatory adult cancer patients with a worst pain score of at least 4 out of 10 despite therapy with at least one opioid plus appropriate oral adjuvant analgesic(s).

A clinically useful reduction in pain is defined by either a 2-point reduction (on a 0-10 scale) in the worst pain experienced over a 24-hour period, or a ≥30% reduction in 24-hour opioid requirement.

The secondary objectives are 1) to determine whether any significant toxicities occur as a result of the infusion. For this study significant toxicity is considered as any adverse event which either leads to the infusion being terminated, or which leads to medical intervention, such as prescribing of another medication or equivalent treatment, 2) to determine the effect of Lidocaine infusion on QOL parameters as measured by the Patient Outcome Scale (POS) Questionnaire and 3) to determine the duration of response to lidocaine infusion.

Subjects will fill out Brief Pain Inventory (BPI), Patient Outcome Scale (POS) periodically and medication logs daily while on study.

On Days of treatment the subjects will have vital sign monitoring every 15 minutes for the 1st hour and then periodically as set out in the protocol.

Arms:
arm 1: Lidocaine arm 2: Placebo first as compared with lidocaine first

Interventions: intervention 1: Lidocaine intervention 2: Placebo (D5W)
Intervention descriptions: intervention 1: 10mg/kg by subcutaneous infusion over 5.5 hours intervention 2: Same volume as for lidocaine infusion, identical clear liquid in appearance, given in same device over same time period (5.5 hrs)

Protocol document:
Prot_SAP_000.pdf: 
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Study Protocol 
 
Title of Project: A Randomized Double Blind Placebo Controlled Crossover Trial 
of the Use of Subcutaneous Lidocaine Infusion (SCLI) for Chronic Cancer-
related Pain.  
 
 
Principal Investigators:   S. Jefferys and P. Hawley 
Co-Investigators:    
G. Fyles  
 
 
Background and Rationale 
 
Pain related to cancer can be controlled by conventional pharmacologic 
treatment in the majority of cases.  However there are circumstances in which 
our attempts to gain analgesia are thwarted either by therapeutic failure or 
intolerable side effects. Even when satisfactory analgesia is obtained, the 
need for daily exposure to medications (particularly opioids) can lead to side 
effects which can compromise quality of life.  The concept of the use of 
parenteral lidocaine is mechanistically radically different. Here the drug is 
administered over a relatively short period of time and yet the potential relief 
extends both beyond the infusion time and the plasma half-life of this agent. 
An infusion lasting several hours can produce pain relief lasting weeks.  
 
Mechanisms of action 
Lidocaine blocks impulses travelling along nerves by inhibiting sodium 
channels. In high doses, complete neural blockade is seen. At low doses, 
lidocaine does not cause any change in conduction in normal nerves but 
prevents pain from being generated in damaged nerves. Lidocaine can also 
prevent damaged dorsal root ganglia from sprouting. Lidocaine is thought to 
suppress central sensitization thereby producing a clinically relevant effect 
which persists well beyond the presence of the drug in the blood (1-6). 
 
Animal studies have allowed further investigation of the mechanism(s) of 
action of lidocaine. Small doses of systemic lidocaine decrease allodynia in 
the animal paw withdrawal test, and larger doses produce a reduction in 
allodynia still measurable at 21 days after the infusion, consistent with the 
human data (7-12). 
 
Human studies 
Lidocaine has been found to be safe in multiple controlled clinical trials for 
neuropathic pain; better than placebo and as effective as other analgesics (13-
19). Subcutaneous lidocaine levels were measured by Linchitz (20) during long-
term lidocaine infusion (26-56 days). The infusion rate varied between 100 
and 180 mg/hr and the serum levels varied between 3.03 and 4.67mcg/ml 
with an average of 3.69 mcg/ml.  Another study using a computer-controlled 


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Sept 22nd 2017 Page 2 of 17 
intravenous infusion was able to demonstrate a relationship between blood-
level and both analgesia and side-effects (21).  
 
Intravenous and subcutaneous lidocaine infusions have been found to be 
helpful in cancer pain control in descriptive studies (22-26) and there have been 
at least 3 reviews, including a 2007 Cochrane review which conclude that 
lidocaine is an indispensable part of the armamentarium for treating 
intractable severe pain, particularly neuropathic pain(27-30). Though it was 
made clear that further placebo-controlled testing of lidocaine infusion was 
required, this treatment modality has been recognised as having the potential 
to significantly alter clinical practice in the care of cancer patients who suffer 
from opioid-refractory cancer pain.  
 
There has since  been one double-blind randomized placebo-controlled 
crossover study of 4mg/kg intravenous lidocaine for opioid-refractory pain in 
cancer patients, which demonstrated a dramatic 75% reduction in pain 
intensity as compared with 26% for placebo, 82% of patients reporting a more 
than 50% reduction in pain scores as compared with 16% after placebo, and 
duration of benefit averaging 9.3 days, with associated reduction in opioid 
requirements, and no serious side-effects (31). Though it is reasonable to 
assume that the subcutaneous route would have the same beneficial effects 
as a slow intravenous infusion, this has not yet been studied in controlled 
trials. 
 
The clinical picture of lidocaine toxicity closely follows the blood level: 1-
3mcg/ml is therapeutic, and is free of toxicity. This is the level seen in slow 
lidocaine infusions. Mild toxicity (light-headedness, dizziness, sedation) is 
seen at 4-6mcg/ml. At this level, stopping the infusion prevents further 
toxicity.  
 
Cardiovascular Monitoring  
Lidocaine infusion is rarely used in the palliative care setting. Informal 
communication with a variety of institutions suggests that this is because of 
the belief that cardiac monitoring would be required. When using lidocaine for 
treatment of cardiac arrhythmias it is usual to have electrocardiographic 
(ECG) monitoring, however cancer patients with severe intractable pain are 
often admitted to palliative care units (PCUs) or hospices. Equipment for 
resuscitation is often not available. The requirement for cardiac monitoring is 
appropriate if the patient is at high risk for arrhythmias (such as following 
cardiac arrest), or if the patient is unable to complain of side effects, however 
cancer patients without cardiac problems would have neither of these 
concerns.  
 
Two large retrospective reports (24,25) of lidocaine infusions being used in 
substantial numbers of American hospitalized hospice patients (“over 100” in 
one report, and 82 in another), reporting promising effects in uncontrolled 


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settings. In neither of these reports was electrocardiographic monitoring a 
part of the treatment protocol, and no significant adverse effects attributed to 
lidocaine occurred, despite some of the patients in the latter study having 
known cardiac disease. In the prospective cancer pain study (31) all patients 
were monitored with 3-lead ECG during and for 2 hours after their 4mg/kg 
infusion (2mg/kg bolus, then 2mg/kg over 1 hour), and blood pressure was 
taken every 10 minutes. No cardiovascular toxicity was observed. Other 
studies have reported the same lack of toxicity when lidocaine is given in this 
way to non-cardiac patients (32). 
 
Clinical Experience  
The finding that a single bolus of lidocaine could produce an analgesic effect 
of three weeks or more, has led one of the investigators (SJ) and a colleague 
to use single bolus lidocaine therapy for chronic, largely non-cancer pain in 
Kelowna.  Intermittent intravenous lidocaine infusions of 5-9mg/kg over 1-2 
hours have also been used routinely for severe opioid-resistant cancer pain at 
the Vancouver Centre by another investigator (PH) for approximately 8 years. 
In Kelowna we have a considerable body of experience of over 10 years with 
over 3000 Subcutaneous Lidocaine Infusions (SCLI). Our clinical experience 
suggested a useful analgesic response in approximately half the patients, 
lasting from days to several weeks.  We did not encounter toxicity-related 
problems and did not feel that ECG monitoring was required. In our early 
experience in the Kelowna General Hospital (KGH) non-cancer pain 
population we converted 60 patients receiving Intravenous Lidocaine Infusion 
(IVLI) over 1-3 hours, to SCLI over 4-10 hours. We found that these patients 
experienced pain relief as good as, or better than, that obtained by IVLI. We 
saw no toxicity. We now use IVLI only for our cancer pain patients and about 
10 non-cancer patients who have refused to change the route of 
administration. SCLI starting with 8-12mg/kg (less in the elderly) at 
1.5mg/kg/hr has not been associated with side effects other than some mild 
somnolence. All patients go home with the infusion and we have had minimal 
calls because of adverse effects. We believe that SCLI is the appropriate 
route to investigate for the reasons outlined above i.e. decreased cost, 
complexity and toxicity.  At the KGH Pain Clinic we administer about 15-18 
SCLIs weekly and find that most of such patients experience 15-21 days of 
pain relief following each SCLI.  
 
Despite our positive experience, there are no published studies of SCLI, and 
access to this treatment in BC is limited to the Kelowna area. We believe that 
a randomized placebo controlled trial of the use of SCLI in cancer patients 
with inadequately controlled pain would be of significant value and may lead 
to improved access to this potentially very useful treatment modality.  
 
 
 
Study Objectives 


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This study’s primary objective is to test the hypothesis that a single 
infusion of subcutaneous lidocaine can cause a clinically useful reduction 
in cancer pain within 48 hours of infusion and lasting a minimum of 7 days 
A clinically useful reduction in pain is defined by either a 2-point reduction 
(on a 0-10 scale) in the worst pain experienced over a 24-hour period, or a 
≥30% reduction in 24-hour opioid requirement.  We will use a composite 
endpoint of reduction in pain without increase in 24-hr opioid requirement 
or no decrease in pain with a ≥30% reduction in 24-hour opioid 
requirement. 
 
The secondary objectives are 1) to determine whether any significant 
toxicities occur as a result of the infusion. For this study significant toxicity 
is considered as any adverse event which either leads to the infusion 
being terminated, or which leads to medical intervention, such as 
prescribing of another medication or equivalent treatment, 2) to determine 
the effect of Lidocaine infusion on QOL parameters as measured by the 
Patient Outcome Scale (POS) Questionnaire and 3) to determine the 
duration of response to lidocaine infusion.    
 
    
Eligibility criteria: 
 
Male or female patients 18 years of age or older 
In or outpatients referred to the BCCA PSMPC Clinics with a diagnosis of 
cancer  
Subjects must have somatic, visceral or neuropathic pain related to cancer 
Pain intensity, measured by a worst pain score over the last 72 hours of 
≥4 on a 0-10 numerical rating scale 
Must have tried at least one opioid medication without adequate response 
or with significant side-effects for at least one week 
For those with neuropathic pain, must have also tried at least one adjuvant 
analgesic, such as a tricyclic (unless contraindicated) or an anticonvulsant 
without adequate response or with significant side-effects for at least one 
week 
Life expectancy of > 3 months 
Must be able to communicate symptoms indicating potential toxicity of 
Lidocaine 
Must have a competent caregiver in the home overnight after each 
infusion 
Must be willing to remain within 30 minutes of the Cancer Centre during 
each infusion 
 
 
 
Exclusion criteria: 
Clinically significant cardiac disease, i.e, cardiac failure, atrial fibrillation 
with slow ventricular rate (<60), any degree of heart block 


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New analgesic treatment initiated in time frame which might have effect 
within one week of study drug. 
Hyper or hypokalemia. 
 
Liver failure (bilirubin ≥ 25 umol/L). 
 
Renal failure (eGFR <50% of normal) 
 
Uncontrolled hypertension (>160/90). 
 
Hypotension (systolic < 90). 
Uncontrolled seizures. 
Planned initiation of chemotherapy, radiotherapy or bisphosphonates 
within 30 days prior to treatment with study drug. 
 
Received an investigational drug within 30 days prior to study. 
 
History of allergy to lidocaine or other topical, local or infusional 
anesthetics. 
 
 
Methods 
Recruitment 
Subjects will be recruited from the BCCA Pain and Symptom 
Management/ Palliative Care (PSMPC) clinics at 5 sites - Vancouver, 
Kelowna, Abbotsford, Centre for the North and Fraser Valley. All patients 
attending BCCA PSMPC clinics complete a detailed pain and symptom 
and palliative care assessment. This includes worst pain intensity over the 
last 3 days as well as pain impact on function, and a body map to indicate 
location of pain. All patients attending the PSMPC clinics at the Vancouver 
and Kelowna Centres will be screened for eligibility by the research nurse 
and attending physician and then approached either by the attending 
physician or the clinic nurse as to whether or not they would like to hear 
about the study. If they would, the physician or research nurse will give the 
subject the consent form. The subject will be given the opportunity to 
thoroughly review and ask any questions they may have. Potential 
subjects from the Abbotsford and Fraser Valley sites will be approached 
by a Pain and Symptom Management/Palliative Care Team physician or 
nurse at those sites and referred to Vancouver for completion of study 
procedures, including consent and treatment. Once the consent is signed 
blood will be drawn for creatinine/GFR, bilirubin level, electrolytes if not 
already done in the 30 days prior to recruitment.  
 
Baseline Visit 
The baseline visit will include: documenting of age, gender, weight, history 
and physical, cancer diagnosis, (PPS), Edmonton Classification System 
for Cancer Pain (ECS-CP), medication and allergy history, blood pressure, 
pulse rate and ECG result, and physician assessment of cause(s) of 
pain(s). Patients will complete BPI, POS questionnaires and will be given 
a Medication Use Log to record their pain medication use for 3 days prior 
to their treatment day. Subjects will be introduced to the Brief Pain 
Inventory (BPI) at this time. This is a widely accepted and validated pain 


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assessment tool which asks for pain severity over the 24 hours prior to 
completion, which makes it very suitable for repeated use in assessing 
response to lidocaine. It takes only a few minutes to complete. The pain 
assessment on the morning of the infusion will be the baseline point for 
determination of response in the study, but subjects will need to be 
familiar with it in order for repeated scoring throughout the study. 
Introducing the BPI at the baseline visit will allow it to be explained without 
the time pressure of needing to start the infusion.  
 
At the baseline visit the subjects will be instructed as to discontinuation of 
their long-acting opioid on the morning of treatment as appropriate for the 
pharmacokinetics of the particular opioid:For those on Morphine, 
Oxycodone or Hydromorphone their long-acting dose will be omitted on 
the morning of the treatment, and the dose divided into three 4-hourly 
doses of the short-acting preparation of the same drug. In the absence of 
a response to treatment, the long-acting dose will be re-assessed at the 
end of the treatment day. If the subject does experience analgesia from 
the study drug then the dosing of the long-acting opioid will be adjusted as 
needed according to that response by telephone advice from the study 
physician.   
 
For those using the Fentanyl patch, without supplemental short-acting 
opioid equivalent to 25% of their total daily oral morphine equivalent 
(OME) dose,the patch will be removed at bedtime of the night prior to the 
treatment, and a short-acting opioid substituted at a dose based on a 
current equianalgesic table; the choice of opioid being expected to be the 
subject’s prior breakthrough opioid. In the absence of a response to 
treatment, the Fentanyl patch will be put back on by the end of the 
treatment day. For patients on methadone, without supplemental short-
acting opioid equivalent to 25% of their total daily OME dose, their 
morning dose will be held and a short-acting opioid will be substituted 
following the same process as described above for the Fentanyl patch. 
The second methadone dose of the day will be given if no analgesic 
response is noted by the end of the infusion, so a maximum of one dose 
will be missed in the absence of response to the study drug. If the subject 
does experience analgesia from the study drug then the fentanyl patch or 
methadone dosing will be adjusted as needed according to that response 
by telephone advice from the study physician. The same breakthrough 
dose as per the subject’s usual prescription will be available, so if patients 
derive no pain relief from the treatment they will not have any opioid dose 
reduction.  
 
Those on the Fentanyl patch or methadone with at least 25% of their total 
daily  OME taken as supplemental short-acting opioid, will continue their 
patch or oral methadone unchanged, as a response to the lidocaine 
leading to no need for breakthrough opioid doses would allow a 25% 


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reduction in OME, thereby protecting the patient from relative opioid over-
treatment in the post-infusion period. 
 
Prescriptions required for both treatment days will be provided at the 
baseline visit so that subjects have adequate supplies of short-acting 
opioid. The subjects will fill these prescriptions at their regular outside 
pharmacy. Those subjects not taking a long-acting opioid will not be 
instructed to make any changes to their opioid dosing prior to the 
treatments. Subjects will be instructed to bring all their medications to their 
treatments. 
 
After the baseline visit, subjects will be scheduled for their first treatment 
within 14 days, and instructions sent to pharmacy accordingly. On the day 
prior to first treatment the subject will be randomized according to a 
predetermined schedule held in the dispensing pharmacy in a double-blind 
fashion to either placebo (D5W) or active drug (10 mg/kg preservative-free 
lidocaine). Both products will be administered subcutaneously via a Baxter 
infusor. All infusions will be made up to the same volume with D5W by a 
licensed pharmacist. The infusors are designed to deliver the whole 
contents at a constant rate over 5.5 hours, so the actual dose rate will vary 
depending on the subject’s body weight.  
           Prior to the First Scheduled Treatment: 
Subjects will be asked to complete a Medication Use Log for three days 
prior to the first treatment visit  
 
First Treatment Day 
On the day of infusion any long-acting opioid medication will be switched 
to short-acting as described above, because a dramatic response to 
lidocaine could theoretically reduce pain such that symptoms of opioid 
toxicity such as sedation could arise if the opioid dose was large. If this 
does occur the short-acting opioid dose can be reduced. It should be 
noted that this problem has only been seen in in-patients on high dose 
opioids and has not been observed in our experience with intravenous 
lidocaine infusions in ambulatory patients.  
 
Subjects will be met by the study nurse who will complete the Day 1 
assessment, including the Brief Pain Inventory, POS and Medication Use 
Log and a Holter monitor will be attached by a cardiology technician. The 
preferred location of insertion of the subcutaneous catheter (usually the 
abdomen) will be injected with 1ml of 1% lidocaine subcutaneously at 
least 2 minutes before insertion of the subcutaneous catheter in order both 
that the catheter insertion will be painless, and also for blinding, as the 
lidocaine infusion will produce a degree of numbness in the area once the 
infusion is started, whereas the placebo infusion (D5W) will not. The 
amount of lidocaine in 1ml of 1% solution is only 10mg, and will not cause 


Version 13 Lidocaine RCT Protocol 
Sept 22nd 2017 Page 8 of 17 
any systemic analgesia.  The infusion (lidocaine or D5W placebo) will start 
between 0900 - 0930hrs.   
 
Subjects will be monitored for pre infusion vital signs and then clinically for 
the 1st hour,  with vital signs (blood pressure, pulse oximetry, pulse rate) 
measured every 15 minutes, and physican to be contacted if the vital 
signs fall outside of the defined parameters. The infusor will be inspected 
every 15 minutes during this first hour to ensure that it appears to be 
emptying at the expected rate. Adverse events will be documented. After 
the 1st hour, if stable, subjects will be allowed to leave the clinic with their 
caregiver but will be required to stay within 30 mins from the cancer centre 
and to return for infusor inspection and vital signs measuring halfway 
through the infusion (+/- 30 mins) and again within 1 hour of completion of 
the infusion (total 5.5 hours). They will be required to have a cell phone 
(one will be provided if they do not already have one) in order to be able to 
contact the study nurse/physician if they experience any adverse effects, 
and be able to return for assessment quickly. A patient lounge area will be 
available at the cancer centre if the patient wishes to stay in the building. 
Subjects will be provided with the telephone numbers for the study nurse 
and the physician. A physician will be at the cancer centre throughout all 
infusions and in the event of a serious adverse reaction will assess the 
patient immediately. Subjects and companions will be reimbursed 
reasonable expenses for lunch and parking at the Cancer Centre if 
needed.  
 
Regular opioid dosing during the treatment day will be determined by 
discussion with the study nurse/physician, considering the subjects’ pain 
levels. If the subject is responding sufficiently that sedation could result 
from relief of pain, the subject will be instructed by the nurse/physician to 
reduce their regular opioid dose. The magnitude of dose reduction will be 
individually determined according to pain levels and any sedation 
experienced.  
 
Blood will be drawn for lidocaine level during the hour before the infusion 
is completed, and the infusor removed once empty ( approximately 5.5 
hours post)End of infusion outcomes, including BPI, POS, Medication Use 
Log and Adverse Events Log, vital signs will be collected and the patient 
will resume their normal or reduced dose of opioid at the time of their next 
scheduled dose, reduced as needed. 
 
Subjects will remove their Holter monitor 4 hours after completion of 
infusion and will return the monitor as instructed according to site, for 
analysis the following day. The monitor tracings will be reviewed 
independently. The Holter monitors will be made available from the 
Cardiology Depts. at Vancouver General Hospital and Kelowna General 
Hospital, as well as Lifelabs in Prince George.  


Version 13 Lidocaine RCT Protocol 
Sept 22nd 2017 Page 9 of 17 
 
Subjects will be allowed to use breakthrough pain medications as needed 
during the study period. These doses will be documented.  
 
Between Visits 
Subjects’ short-acting opioid consumption will be assessed by telephone 
after the infusions, and those who respond will re-start their long-acting 
opioid at a dose determined by their use of short-acting opioid and current 
pain experience. Those who have not responded will resume their prior 
long-acting and breakthrough opioid doses as prior to the infusion and 
have their next treatment within a minimum of 48 hours and maximum of 
three weeks of the pain returning to baseline... Pain control will be 
maintained between the infusions by the same opioid consumption as at 
baseline, including breakthrough as needed, and returning to the subject’s 
prior opioid dosing regimen as soon as any effect of the infusion is 
perceived to have worn off. Long-acting opioid dosing will only be reduced 
if the patient feels they have sufficiently improved pain control following an 
infusion, so there will be no risk of confounding the study results or making 
pain worse. As noted in the eligibility/exclusion criteria, no new adjuvant 
analgesic (non-opioid medication) or procedure which may have an 
analgesic effect will be started or stopped during the study. 
 
At 1000 am on Day 2 and Day 3, the BPI and POS will be completed. If   
there is a reduction in pain scores, the BPI and POS will continue to be 
completed on Day  7, 14 and 21 post each infusion, or until the worst pain 
score on the BPI #3 has returned to baseline.  If there is no change, the 
questionnaires for  Day 7 will be completed and the patient will be 
scheduled for the next follow up visit and treatment within a minimum of 
48 hours and maximum ofthree weeks of the pain returning to  baseline.  
The Medication Use Log is to be completed daily, and the Adverse Events 
Log completed if an adverse event occurs. Telephone contact will be 
made at a minimum twice a week until the pain is back to the pre-
treatment level by the research nurse or physician and to adjust 
medications if necessary, and, once pain returned to baseline,  once 
weekly telephone contact will be done til the 2nd treatment visit to review 
any condition or medication changes Subjects will also be encouraged to 
call the physician at any time if they experience any adverse event or to 
report return to baseline pain score.  
 
Once the worst pain score on the BPI (question #3) has returned to 
baseline and at least 48 hours have elapsed, the second treatment will be 
arranged. If there is a response the patient will continue with diaries and 
questionnaires weekly until the BPI score returns to baseline  
 
Second Treatment Visit 


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This will be arranged within a minimum of 48 hours and maximum of three 
weeks of the pain returning to baseline  but will be no earlier than 48 hours 
after the 1st treatment.  The baseline weight will be used to determine the 
dose for the second treatment.  At 1000 am on Day 2 and Day 3 post 
second treatment, the BPI and POS will be completed. If there is a 
reduction in pain scores, the BPI and POS will continue to be completed 
on Day  7, 14 and 21 post each infusion, or until the worst pain score on 
the BPI #3 has returned to baseline, at which time the end of study visit 
will be arranged within a minimum of 48 hours and a maximum of  three 
weeks of  the pain  returning to baseline . If there is no change, the 
questionnaires for Day 7 will be completed and the patient will be 
scheduled for the end of study visit within a minimum of 48 hours and 
maximum of three weeks of the pain returning to baseline . The 
Medication Use Log is to be completed daily, and the Adverse Events Log 
completed if an adverse event occurs. Telephone contact will be made at 
a minimum twice a week until the pain is back to the pre-treatment level. 
Subjects will also be encouraged to call the physician at any time if they 
experience any adverse event or to report return to baseline pain score.  
 
Final Visit Post Second Infusion (once the worst pain score on the BPI 
(question #3) has returned to baseline by phone assessment and at least 
48 hours or a maximum of three weeks of the pain returning to baseline.,  
At this visit subjects will again complete the Brief Pain Inventory and POS 
and their Medication Use Log and Adverse Events Log will be reviewed. 
This will be the end of the study.  
 
 
Outcome measures:  
 
Primary:  
The primary outcomes measure is a binary variable indicating whether 
lidocaine caused a reduction in cancer pain within 48 hours of infusion and 
lasting a minimum of 7 days. Lidocaine will be considered to have caused 
reduction in cancer pain if the subject had either one of the following 
episodes lasting a minimum of 7 days:  
 
1)  A 2-point reduction in severity of pain as assessed by the worst 
pain score in the last 24 hours (question 3) of the Brief Pain 
Inventory – Short Form (BPI), compared to the BPI pain score at 
baseline. 
 
Or: 
 
2) ≥30% reduction in 24-hour opioid dose.  
 


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The duration of the pain reduction is measured by weekly BPI pain 
scores.,  
 
Secondary: 
 
1) Incidence and severity of adverse events.  
 
2) Effect of Lidocaine infusion on QOL parameters as measured by 
the Patient Outcome Scale (POS) Questionnaire 
 
3) Duration of response to lidocaine infusion.    
 
 
Notes on Outcome Measures 
 
The BPI refers to “worst pain over the last 24 hours” rated between 0 and 10, and 
a 2 points difference has been determined in multiple studies to be clinically 
useful. Based on our experience with lidocaine infusions already we know that a 
response to lidocaine occurs within the first 3 days (actually usually within the 
first 24 hours), so the daily BPI for the first 3 days will capture whether or not a 
clinically significant improvement in pain has been achieved.  
 
Because some patients may accept similar levels of pain but reduce their opioid 
analgesics significantly, with consequent reduction in side-effects, the 30% 
reduction in analgesic use is also included as indicative of a positive response, to 
ensure that clinically meaningful benefits are not missed by relying just on the 
pain scores. 
 
For this study significant toxicity is considered as any adverse event which either 
leads to the infusion being terminated, or which leads to medical intervention, 
such as prescribing of another medication or equivalent treatment.   
 
The Patient Outcome Scale (POS) is a QOL tool used routinely in the BCCA 
PSMPC clinics that addresses physical, psychological, spiritual, practical, 
psychosocial and emotional concerns and consists of 12 questions in 9 domains: 
pain, other symptoms, anxiety, information, support, depression, self-worth, 
wasted time and personal affairs. It was used in the Subcutaneous Lidocaine 
Feasibility Study. 
 
The duration of response is a descriptive outcome which will be determined by 
the time to return of the BPI question #3 worst pain in 24 hours pain rating to the 
same as at that provided on the morning of the infusion, before the infusion 
started. The duration of benefit will be reported in descriptive terms only and is 
not an endpoint which will be subject to statistical analysis. This data will be 
useful for planning subsequent clinical implementation, if the study shows the 
treatment to be effective.  


Version 13 Lidocaine RCT Protocol 
Sept 22nd 2017 Page 12 of 17 
 
 
 
Schedule of Assessments:  
 
Baseline:  
Age, gender, weight, history and physical, cancer diagnosis, Palliative 
Performance Scale (PPS), and Edmonton Classification System for 
Cancer Pain (ECS-CP), physician assessment of cause(s) of pain(s), 
medication and allergy history, blood pressure, pulse rate and ECG, BPI, 
POS and blood draw if needed. 
 
           Prior to the First Scheduled Treatment: 
Medication Use Log use for three days prior to the first  treatment visit  
 
Day 1 pre each infusion:  
BPI, POS, and Medication Use Log, review of Adverse Events Log,vital 
signs, attach Holter Monitor. The Holter Monitor will record for the duration 
of each infusion plus 4 hours subsequently, and will be removed by the 
patient. 
 
During each infusion:  
Vital signs will be measured and the infusor will be inspected every 15 
minutes for the 1st hour, halfway through the infusion and on completion; 
the physician will be contacted ASAP if the pulse drops to less than 60 
beats per minute or increases to over 100 beats per minute, or the PaO2 
falls below 90%; systolic BP changes by 25mm from pre-treatment BP. 
Patients will be given a Medicaton Log and an Adverse Event Log to keep 
track of any A/Es they experience. 
  
In the hour prior to completion of each infusion (i.e. 4.5 to 5.5 hours since 
started:no later than between 2.00 and 3.00pm): 
A lidocaine blood level will be drawn at the appropriate BCCA laboratory 
and the subject’s vital signs will be taken. Blood will be analysed at the 
Provincial Toxicology Lab, Vancouver  
 
At the end of each infusion on Day 1: 
BPI, POS, Medication Use Log, assessment of toxicity via Adverse Events 
Log and vital signs.  
 
At each of the intervals where the vital signs are to be taken, the patient’s 
pain score will be assessed and recorded and the infusion site will be 
assessed to ensure the medication is infusing properly 
 
Daily During Study: 
Medication Use Log 


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Subjects encouraged to call study physician if any concerns  
On day 2 and 3 after each Infusion and at least twice a week  
or until pain is back to pre-treatment level  
Phone call by physician or study nurse to review opioid dosing, adverse 
events and subject’s perception of pain relief 
 
Once pain returned to baseline, once weekly telephone contact will be 
done til the 2nd treatment visit to review any condition or medication 
changes  
 
At 10.00am on Day 2 and Day 3 post each infusion, BPI and POS 
Questionnaires to be completed. 
If there is a response to the treatment, the patient will also complete them 
on Day, 7,14 and 21, or until the worst pain score on the BPI #3 has 
returned to baseline . If there is not a response , the BPI and POS 
Questionnaires will only be required for Day 2, 3 and 7. 
Daily  
Medication Use Log to be completed and Adverse Events Log if subject 
experiences symptoms or side-effects  
 
 
Final Visit: (post 2nd infusion, once the worst pain score on the BPI 
(question #3) has returned to baseline by phone assessment and 
minimum 48 hours  and a maximum of three weeks since the return to 
baseline., At the final visit, the ,BPI, POS, Medication Use Log. Adverse 
Events Log and  PPS will be reviewed 
 
A positive response re: pain relief would be defined as any of the following: 
 A 2-point reduction in worst pain intensity (#3 on the BPI) 
within 48 hours of infusion and lasting a minimum of 7 days  
 Reduction in analgesic dose by greater or equal to 30% will 
also be considered an indicator of positive response.  
 
 
 
Statistical Considerations: 
Objective 
 
To compute the power and sample size calculation for the study  
 
Assumptions  
- 
Probability of response in the placebo group = 30% 
- 
There is no carry-over effect, no period effect and no sequence effect in 
the study 


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Sept 22nd 2017 Page 14 of 17 
- 
0.01% of the patients who did not respond to the lidocaine will respond to 
the placebo  
 
Null Hypothesis: There is no difference between a single infusion of 
subcutaneous lidocaine and the placebo  
Alternative Hypothesis: A single infusion of subcutaneous lidocaine can cause 
a reduction in cancer pain 
 
Sample Size / Interim Analysis 
 
A sample size of 40 patients achieves 84% power to detect a 20% 
difference at a 2.5% significance level using a one-sided McNemar’s Test, 
under the assumptions that 30% of the patients respond to the placebo 
and 0.01% of the patients who do not respond to the lidocaine will respond 
to the placebo. This sample size is increased to 50 patients to account for 
a 20% drop-out rate. This drop-out rate is based on our experience 
accruing similar patients to studies. The sample size methodology is 
based on the methodology described in Lachenbruch 1992. 
 
We have demonstrated in the completed Feasibility Study for a 
Randomized Double Blind Placebo Controlled Crossover Trial of the Use 
of Subcutaneous Lidocaine Infusion for Chronic Cancer-related Pain that 
recruitment to such a study is feasible, and that we should expect this 
study to take 6 months for accrual. 
 
An interim analysis will be carried out after 20 patients have completed the 
study to allow the trial to be stopped early for demonstrated efficacy. One-
sided McNemar’s tests will be carried out to test whether a single infusion 
of subcutaneous lidocaine will cause a reduction in cancer pain for both 
the interim and final analyses at the p-values of 0.00153 and 0.02347 
respectively.  
 
The assumptions of no carry-over effect, no period effect and no 
sequence effect are made under this study. To check these assumptions, 
a repeated measures logistic regression model will be fitted to model the 
probability of pain reduction by treatment type (placebo versus lidocaine), 
stratifying by the treatment order (first or second treatment). This model 
accounts for inter-subject variation and within-subject correlation. Score 
tests will be used to test whether the treatment order estimate equals to 
zero at a 5% significance level. Rejection of this null hypothesis implies a 
carry-over effect, period effect and sequence effect.  
 
 
Safety Considerations: 
Any subject with unrecognized allergy to lidocaine would be expected to 
react within the first hour, and subjects will be closely observed during that 


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time. Any later side-effect will be able to be addressed promptly by the 
patient returning to the Cancer Centre for assessment by the nurse and/or 
physician. There is an emergency response team in the cancer centre 
during working hours and the study physician will be available for the 
duration of all infusions. 
 
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