Clinical trial NCT04254679
Conditions: Outpatient Surgery Abdominal Surgery Breast Surgery
Keywords: Opioids Surgery Postoperative Period Postoperative Pain Analgesia Pain Management
Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Start date: 2020-01-29; Completion date: 2020-12-03
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
North America is facing an opioid epidemic fueled by surgeons, who are the second largest subgroup of physicians involved in opioid prescribing. Surgery often serves as the initial event for opioid-naïve patients to obtain a prescription for opioids and spiral into misuse and addiction. From the perspective of perioperative care clinicians, the answer to the opioid crisis may be using opioid-free analgesia. However, the number of comparative studies in this field is limited and existing small trials do not reflect current standards of care in North America. Lack of evidence means that the decision to prescribe opioids after outpatient surgery largely depends on surgeon preference and healthcare culture. Hence, there is an urgent need for a robust randomized controlled trial (RCT) to guide clinical decision-making. The feasibility and optimal design of this RCT should be informed by a pilot trial. The overarching goal of this pilot RCT is to investigate the feasibility of conducting a full-scale RCT to assess the comparative-effectiveness of opioid versus opioid-free analgesia after outpatient general surgery.

Detailed description:
This study will be a pragmatic, parallel, two-group, assessor-blind, pilot RCT. The investigators aim to recruit 80 adult patients at two tertiary hospitals in Montreal. Eligibility criteria will span outpatient procedures in abdominal and breast surgery. Patients are randomized on a 1:1 ratio to treatment with either opioid (standard care) or without opioid (only non-opioid analgesics). Patients will be followed up for 3 months after surgery; postoperative day (POD) 1 to POD 7 and at 2, 3 and 4 weeks after surgery, and at 3 months. Assessments will include postoperative pain, physical and mental function, adverse drug events, prolonged opioid use and opioid misuse. Feasibility outcomes will include the number of patients screened, consented and randomized, adherence with treatment and completion of follow-up. Data from this pilot study will inform the calculation of sample size requirements for the full-scale RCT. An embedded qualitative study will be conducted to help optimize trial design based on clinicians' and patients' perspective.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Opioid analgesics intervention 2: Non-opioid analgesics
Intervention descriptions: intervention 1: Current standard of care in the participating centers Prescription of around-the-clock non-opioid analgesics (acetaminophen and/or NSAIDs/COX-2) and a supply of opioids to be used as a rescue in case of breakthrough pain.

The specific round-the-clock analgesia and rescue opioid regimens will be determined by the patient's primary surgeon considering the surgical procedure, comorbidities and patient's preference. intervention 2: Prescription of around-the-clock non-opioid analgesics (acetaminophen alone or combined with NSAIDs/COX-2).

The specific non-opioid analgesia regimens will be determined by the patient's primary surgeon considering the surgical procedure, comorbidities and patient's preference.

Protocol documents:
Prot_SAP_000.pdf: 
Study Protocol 
 
 
 
 
Opioid-free analgesia after outpatient general surgery: A 
pilot randomized controlled trial 
 
 
 
NCT04254679 
Publication date (As supplementary material for the trial manuscript):  
July 18, 2022 


Supplement 1. Study protocol as approved by ethics  
1 
 
2 
Project title: Opioid-free analgesia after outpatient general surgery: A pilot randomized 
3 
controlled trial 
4 
RATIONALE 
5 
Canada is in the midst of an epidemic of opioid use and abuse fueled by increased 
6 
prescriptions by physicians. Overprescription has been implicated as a driving force 
7 
behind the growing number of overdoses and deaths caused by opioids. Canada has 
8 
the second highest rate of opioid prescription per-capita in the world after the United 
9 
States1. Physicians wrote on average one opioid prescription for every two Canadians 
10 
in 20172. In the same year, at least 4100 opioid-related deaths occurred across 
11 
Canada3. This death toll increased to 4460 in 2018, which represents an average of 12 
12 
Canadians dying  from opioid overdoses every day3. The estimated economic cost of 
13 
opioid misuse in Canada, accounting for health, justice, lost productivity and other direct 
14 
costs, tops $3.5 billion per year4. As a response to this grim statistic, the federal Minister 
15 
of Health has made combatting the 8opioid crisis9 a top priority5. 
16 
Surgery often serves as the initial event for opioid-naïve patients to obtain a prescription 
17 
for opioids and spiral into misuse and addiction6,7. Those undergoing outpatient surgery 
18 
(i.e., with same day discharge), which represent nearly 80% of all surgeries performed 
19 
in Canada and the United States8, are particularly vulnerable as they invariably require 
20 
some form of analgesia to be taken at home during the first postoperative days. In North 
21 
America, analgesia for these patients often includes over-the-counter non-opioid drugs 
22 
[e.g., acetaminophen and/or non-steroid anti-inflammatory drugs (NSAIDs)/Cox-2 
23 
inhibitors (COX-2)] and prescription opioid tablets to be taken 8as needed9 in case of 
24 
breakthrough pain. With this current prescription pattern, up to 1-in-10 patients become 
25 
persistent opioid users postoperatively, i.e., they continue to take the drug for more than 
26 
three months after surgery6,9,10. Those who do not become persistent users may also 
27 
contribute to the opioid epidemic by diverting unused tablets for nonmedical use by 
28 
others. A recent systematic review suggests that of all opioid tablets obtained by 
29 
surgical patients 42% to 71% go unused11. In other words, they are prescribed 
30 


unnecessarily and become a readily available source for diversion. It is estimated that 
31 
over 50% of people who abuse opioids obtain the drug via diversion from friends or 
32 
relatives with unused prescriptions12. Although the prescription of opioids after 
33 
outpatient surgery seems harmless to many, postoperative overprescription is an urgent 
34 
element of the opioid crisis given how commonly it may contribute to misuse, diversion, 
35 
addiction and death. 
36 
From the perspective of surgeons and other perioperative care clinicians, the answer to 
37 
the opioid crisis may be preventing opioid prescriptions whenever possible using opioid-
38 
free analgesia. In European countries, postoperative discharge prescriptions commonly 
39 
include only non-opioid drugs while, interestingly, pain-related outcomes (i.e., 
40 
satisfaction with pain treatment) are often superior to North America13-15. Moreover, 
41 
evidence regarding the benefits of postoperative opioids has largely relied on unimodal, 
42 
single-dose studies conducted for regulatory purposes under strict experimental 
43 
conditions16. Arguably, a more appropriate approach to guide clinical practice is to 
44 
examine the impact of postoperative opioids in 8real-world9 conditions, where analgesia 
45 
strategies are often multimodal and pain treatment span several days. Data from a 
46 
scoping review recently completed by our research group (currently under peer-review 
47 
for publication) supports that the number of comparative studies in this field is limited, 
48 
while existing small trials often challenge the value of adding opioids to multimodal 
49 
analgesia regimens17-19. Lack of evidence in this field means that the decision to 
50 
prescribe opioids after outpatient surgery largely depends on healthcare culture and 
51 
surgeon preference. Hence, there is an urgent need for robust randomized clinical trials 
52 
(RCTs) to guide clinical decision-making.  
53 
Due to the complexity inherent to well-designed RCTs, pilot studies are critical to 
54 
assess acceptability, test logistical aspects, optimize design and build the capacities 
55 
required for a full-scale trial20. Undertaking an RCT of opioid-free analgesia raises 
56 
important practical concerns including: surgeon and patient hesitation about pain 
57 
treatment without opioids, decision regarding participation under preoperative stress, 
58 
treatment adherence and optimal measurement strategies. Thus, the overarching 
59 
objective of the proposed pilot study is to investigate the feasibility of conducting a full-
60 
scale, pragmatic RCT aimed to estimate the extent to which analgesia regimens 
61 


including opioids (opioid analgesia, OA) impact postoperative outcomes after outpatient 
62 
general surgery in comparison to regimens that are opioid-free (opioid-free analgesia, 
63 
OFA). By addressing the prevention of opioid prescription after outpatient surgery, this 
64 
proposal tackles the first pillar of the New Canadian Drugs and Substances Strategy 
65 
(CDSS), i.e., preventing problematic drug and substance use supported by a strong 
66 
evidence base21.   
67 
SPECIFIC RESEARCH OBJECTIVES 
68 
PART 1. Main study (Pilot RCT) 
69 
1.1. To estimate the proportion of screened patients who meet eligibility criteria. 
70 
1.2. To assess the willingness of surgeons to recruit/randomize patients undergoing 
71 
different surgical procedures. 
72 
1.3. To estimate the proportion of eligible patients who consent to randomization. 
73 
1.4. To estimate the proportion of patients who adhere to the interventions proposed. 
74 
1.5. To estimate follow-up completion rates. 
75 
1.6. To inform the calculation of sample size requirements for a full-scale RCT. 
76 
PART 2. Embedded qualitative study 
77 
2.1. To inform, via qualitative research methods, optimal study design of a full-scale 
78 
RCT by assessing patient and clinician perspectives on trial conduct, participation, 
79 
interventions and measurement strategy. 
80 
 
81 
METHODS  
82 
PART 1. Main study (Pilot RCT) 
83 
This study will be a parallel, two-group, assessor-blind, pilot randomized trial with 
84 
participants individually allocated on a 1:1 ratio to treatment with either OA or OFA. To 
85 
maximize applicability of the study to current perioperative care settings, the trial was 
86 
designed to be pragmatic; i.e. it will be undertaken in routine clinical practice under <real 
87 
world= conditions. Eligibility criteria will facilitate enrollment of diverse patients 
88 


undergoing outpatient surgery (day surgery) and interventions will be delivered with 
89 
flexibility in medication selection. An embedded qualitative study will be conducted to 
90 
help optimize trial design based on clinicians9 and patients9 perspective22. The study 
91 
protocol will be reviewed by the McGill University Health Centre (MUHC) Research 
92 
Ethics Board and patient recruitment will start after ethics approval. All participants will 
93 
sign a written consent form and a paper copy of the form will be attached to the patient 
94 
medical chart. Trial registration and protocol information will be made available at the 
95 
ClinicalTrials.gov website. The planned flow of participants through the study is 
96 
summarized in Figure 1. A trial management team (TMT), composed by trial leaders 
97 
(Drs. Fiore, Baldini and Feldman) and trial managers (Ms Pepa Kaneva, Ms Uyen Do 
98 
and Mr Charbel El Kefraoui) will meet weekly to discuss the progress of the trial and 
99 
address any issues that may arise. 
100 
 
101 


Figure 1. Flow of participants through the study. POD = postoperative day 
102 
Patients 
103 
Adult patients (over 18 years old) undergoing elective outpatient surgery (with planned 
104 
discharge same day on the day of the operation) in two sites of the McGill University 
105 
Health Centre (MUHC) in Montreal, Canada (Montreal General Hospital and Royal 
106 
Victoria Hospital) will be considered for inclusion. Eligibility will span a wide range of 
107 
general surgery procedures that are routinely conducted with same day discharge, 
108 
including procedures in abdominal (i.e., cholecystectomies, hernia repairs) and breast 
109 
surgery (i.e., lumpectomies, partial and complete mastectomies, axillary node 
110 
dissections).  
111 
As a pragmatic trial, we will keep exclusion criteria to the minimum necessary to ensure 
112 
both patient safety and internal validity. Patients with intraoperative or early 
113 
postoperative complications (i.e., diagnosed in the Post-Anesthesia Care Unit (PACU)) 
114 
that require postoperative hospital stay will be excluded. Other reasons for exclusion 
115 
are: contraindications to any of the drugs used in the trial according to Health Canada 
116 
Monographs (i.e. active substance use disorder, pregnancy, severe heart failure, 
117 
allergy, active symptomatic peptic ulcer or gastrointestinal bleeding, bleeding disorders, 
118 
severe renal or liver impairment)23-25, conditions that could interfere with outcome 
119 
assessment [e.g., cognitive impairment, inability to speak English or French, difficulty to 
120 
be reached after surgery (e.g., limited access to a telephone or a computer)].  
121 
Overview of recruitment and consent procedures 
122 
 (1) Eligible patients scheduled for elective outpatient general surgery will be informed 
123 
about the study by their primary surgeon during the preoperative surgical consultation, 
124 
(2) those who are interested in the study will be advised by the treating clinician that a 
125 
member of the study group will contact them to discuss the study in detail during their 
126 
subsequent standard visit to the preoperative assessment clinic or by telephone (if the 
127 
clinic is bypassed), (3) patients who are eligible and interested in participating will be 
128 
asked to sign the consent form and complete the study9s preoperative questionnaires in 
129 
the preoperative clinic or at home. In the latter case, consent will be obtained via pre-
130 


paid mail and preoperative questionnaires will be completed online or by phone. It will 
131 
be up to patients to choose the preferred method of completing the questionnaires. 
132 
Trial posters will be displayed in waiting areas of the MGH and RVH preoperative clinics 
133 
to raise awareness of the study for both patients and clinicians. Study promotional 
134 
materials are attached to this application (Figure 5-6). 
135 
Randomization and blinding 
136 
Treatment allocations will be concealed until patients are deemed ready to be 
137 
discharged home from the PACU – i.e., when a discharge order is signed by the primary 
138 
surgeon, or a delegated clinician member of his/her team. Randomization will be 
139 
conducted via a secure web-based randomization service (www.sealedenvelope.com). 
140 
Research staff will have password-protected access to the randomization website by 
141 
means of a computer or smart phone. No personal information about participants will be 
142 
entered in this platform. To yield balanced yet unpredictable groups, randomization will 
143 
use computer-generated, permuted, balanced blocks of randomly varying size (2, 4 or 
144 
6).  To achieve group balance for important covariates, randomization will be stratified 
145 
by procedure type (abdominal, breast). Participants and clinicians will be informed 
146 
verbally of the treatment allocation at the point of randomization. The primary surgeon, 
147 
or a delegated clinician member of his/her team, will be responsible for signing a pre-
148 
written analgesia discharge prescription in accordance with the treatment that patients 
149 
have been allocated to.  
150 
Participants and treating clinicians (i.e., surgeons, anesthetists, and nurses) will not be 
151 
blinded to treatment allocation due to the complexity of the medication prescribing 
152 
strategies. To reduce potential risk of detection bias (systematic differences between 
153 
groups in how outcomes are determined), outcome assessors will be blinded to 
154 
treatment allocation. Patient-reported outcomes and treatment adherence data will be 
155 
collected via self-administered electronic questionnaires distributed using REDCap 
156 
(http://project-redcap.org/) and completed by patients via smartphone, tablet or personal 
157 
computer. Electronic outcome data will be transmitted directly to the REDCap database 
158 
and verified by a blinded assessor. Adherence data will be verified by unblinded study 
159 
staff. Patients who are not computer savvy, have limited access, or prefer non-
160 


electronic assessment will complete the questionnaires via telephone interviews with a 
161 
blinded assessor; in this case, data will be recorded in paper forms and subsequently 
162 
transferred to the REDCap database. Prior to every telephone interview, patients will be 
163 
reminded not to disclose their allocation status or information about pain medications. 
164 
To prevent unblinding, telephone follow-ups to monitor treatment adherence will be 
165 
done by a team member not involved in outcome assessment.  
166 
Outcome data that are not patient-reported (e.g., postoperative complications, 
167 
unplanned healthcare utilization, chronic opioid use) will be obtained from medical 
168 
records by a blinded assessor. Any inadvertent unblinding will be reported. 
169 
Effectiveness of blinding will be estimated by asking assessors to guess patients9 group 
170 
allocation at one month after surgery (after the last patient questionnaire is responded). 
171 
Statistical analysis will also be blinded with information regarding allocation protected by 
172 
codes that will be revealed only after all analyses are completed.  
173 
Interventions 
174 
Opioid analgesia (OA) group 
175 
Patients randomized to the OA group will receive the current standard of care in the 
176 
participating centers, which includes the prescription of around-the-clock non-opioid 
177 
analgesics (acetaminophen and/or NSAIDs/COX-2) and a supply of opioids to be used 
178 
as a rescue in case of breakthrough pain (i.e., pain that erupts while a patient is already 
179 
medicated with painkillers). Prior to hospital discharge, patients will undergo a 
180 
medication education session with the PACU nurse and be advised to fill their 
181 
prescription at a pharmacy of their preference. Medication education sessions with a 
182 
nurse prior to discharge are part of standard care at MUHC. In light of the pragmatic 
183 
nature of this trial, the specific round-the-clock analgesia and rescue opioid regimens 
184 
will be determined by the patient9s primary surgeon considering the surgical procedure, 
185 
comorbidities and patient9s preference. Postoperative pain management strategies 
186 
currently used at the MUHC are set with input from pain specialists (Alan Edwards Pain 
187 
Management Unit) and follow Health Canada standards for safety and efficacy26. 
188 
Examples are included in eFigure1. 
189 


To confirm if patients randomized to this group are treated according to current 
190 
standards of care, we will conduct a retrospective chart review of post-discharge 
191 
analgesics prescribed to patients who underwent the eligible surgeries between 
192 
September 01 to October 31, 2019. We estimate that, within this 2-month period, the 
193 
electronic medical charts of approximately 100 patients will be reviewed. Only data 
194 
regarding the surgical procedure conducted and analgesia regimen prescribed (pain 
195 
medication received, dosage, frequency of administration, treatment duration) will be 
196 
collected by the research team.  
197 
Opioid-free (OF) analgesia group 
198 
Patients randomized to the OFA group will receive a prescription of around-the-clock 
199 
non-opioid analgesics (Acetaminophen alone or combined with NSAIDs/COX-2). In 
200 
case of breakthrough pain, rescue analgesia may be provided by (1) increasing doses 
201 
of non-opioid analgesics, (2) adding non-opioid drugs that were not included in the initial 
202 
regimen or (3) switching drugs according to single-dose efficacy evidence27,28 targeting 
203 
individual variances in analgesia response29. As per standard care, prior to hospital 
204 
discharge, patients will undergo a medication education session with the PACU nurse 
205 
and be advised to fill their prescription at a pharmacy of their preference. Considering 
206 
the pragmatic nature of this trial, the specific non-opioid analgesia regimens will be 
207 
determined by the patient9s primary surgeon considering the surgical procedure, 
208 
comorbidities and patient9s preference. The pain specialists involved in this trial [Dr. 
209 
Gabriele Baldini (Anesthesia), Dr. Avinash Sinha (Anesthesia), Dr. Suzanne Morin 
210 
(Internal Medicine), and Ms Krista Brecht (Alan Edwards Pain Management Unit)] have 
211 
set potential analgesia strategies for the OFA group, according to Health Canada 
212 
standards for safety and efficacy 26 (eFigure 2). 
213 
Management of persistent pain  
214 
As opioid-free analgesia is new to our setting, specific strategies will be implemented to 
215 
ensure that patients are receiving adequate pain management during the pilot trial. A 
216 
8hotline9 (dedicated mobile phone that will be kept with study staff in shifts) will be 
217 
available 24/7 in case patients experience persistent pain despite the use of rescue 
218 
analgesia. When this line is called, study staff will inform patients about the 
219 


management options available according to their treatment allocation. An information 
220 
sheet containing the 8hotline9 contact details will be provided to patients prior to PACU 
221 
discharge (see Discharge Information Sheet – Opioid-free Group). 
222 
Patients in the opioid-free group will have a back-up prescription of opioids (regimen 
223 
decided by the primary surgeon) faxed to the 24h pharmacy closest to their residence. 
224 
This prescription will be faxed upon patient discharge from the hospital, with a brief 
225 
letter informing the study and ethics approval (see Information Sheet for Pharmacy). 
226 
When a patient calls the study staff reporting persistent pain, they will be informed about 
227 
the availability of the prescription and the pharmacy address. To prevent patients to fill 
228 
their opioid prescription 8just in case9, they will not be informed about the availability of 
229 
the prescription unless they report persistent pain. When the prescription is filled, 
230 
education about the use of opioids will be given by the pharmacist as per routine 
231 
pharmacy services. If pain persists despite the use of opioids, patients will be advised to 
232 
proceed according to the management of persistent pain in the opioid group, as 
233 
described below.  
234 
As per the institutions9 current practice, patients in the opioid group who experience 
235 
persistent pain will be advised to call their primary surgeon9s office/clinic during working 
236 
hours (weekdays, 8AM to 4PM) or visit a hospital emergency room (ER) for further 
237 
evaluation (after-hours and weekends). If an ER visit is required, patients will be asked 
238 
to give preference to visiting the ER of the hospital where his/her surgery had been 
239 
performed. An information sheet containing specific instruction will be provided to 
240 
patients prior to PACU discharge (see Discharge Information Sheet – Opioid Group). 
241 
Changes of initial prescription will be entirely up to the patients9 surgical team and/or ER 
242 
physician. 
243 
Adherence and study discontinuation  
244 
Treatment adherence (i.e., patients in each group taking their pain medications as 
245 
prescribed) will be monitored via self-administered electronic questionnaires distributed 
246 
using REDCap (http://project-redcap.org/) and completed by patients via smartphone, 
247 
tablet or personal computer from postoperative day (POD) 1 to POD 7 and at 2, 3 and 4 
248 
weeks after surgery. Electronic adherence data will be transmitted directly to the 
249 


REDCap database and verified by unblinded study staff. Patients will also be offered the 
250 
option to respond to adherence questionnaires via telephone; in this case, data will be 
251 
recorded in paper forms by unblinded staff and subsequently transferred to the REDCap 
252 
database. Patients will be instructed to take medications for postoperative pain only in 
253 
accordance with the initial discharge prescription or based on prescriptions given by 
254 
healthcare providers after hospital discharge. If patients desire discontinuation of any of 
255 
the study medications, they will be advised to discuss other medication options with the 
256 
surgical team and/or their outpatient care provider. Surgeons may change pain 
257 
medications or put an end to a patient participation in the trial at any time if he/she 
258 
considers this to be in the best interest of the patient. 
259 
Other aspects of perioperative care 
260 
Surgical techniques, anesthesia procedures, or preoperative/intraoperative analgesia 
261 
protocols will be left to the discretion of the attending surgeon and anesthesiologist to 
262 
best reflect routine clinical practice. However, technical details about the surgery, 
263 
anesthesia and perioperative analgesia interventions (including preoperative use of 
264 
analgesics in preparation for surgery, e.g., gabapentin, and intraoperative use of local 
265 
anesthetics infiltration or blocks) will be obtained from electronic medical records and 
266 
recorded for study purpose. Any nonpharmacological therapies for pain recommended 
267 
by the surgical team or outpatient healthcare providers (e.g., heat or ice compress, 
268 
acupuncture, massage therapy) will be permitted and recorded during follow-up 
269 
assessments. Considering the pragmatic nature of this trial, medication education 
270 
provided by nurses and all other aspects of perioperative care will be according to the 
271 
institutions9 routine practice, which include detailed care pathways for selected surgical 
272 
procedures (http://www.muhcpatienteducation.ca/surgery-guides.html).   
273 
Measurement Strategy 
274 
As a pilot RCT, this study will primarily focus on feasibility outcomes. Clinical outcomes 
275 
will be assessed secondarily to inform the measurement strategy and sample size 
276 
requirements for a future full-scale RCT.    
277 
Assessment of feasibility outcomes (primary) 
278 


A full-scale RCT be deemed feasible if, during the pilot study period (4 months): 
279 
• 
At least 70% of patient undergoing the outpatient general surgery procedures of 
280 
interest are eligible to be randomized. 
281 
• 
At least 90% of the surgeons who agreed to have their patients randomized will 
282 
comply with the agreement, i.e., not change their minds (see section 8pilot study 
283 
sample size and feasibility9 below).   
284 
• 
At least 50% of eligible patients agree to participate in the study and are 
285 
randomized.  
286 
• 
At least 80% of the randomized patients comply with their allocated treatment (i.e. 
287 
will take their pain medications as prescribed).  
288 
• 
At least 80% of the patients randomized complete outcome assessment at 30-days 
289 
after surgery. 
290 
• 
Among patients who complete outcome assessments, the proportion of missing 
291 
data is less than 10% (i.e., non-response to questionnaires or specific questionnaire 
292 
items). 
293 
To determine recruitment rates, study staff will keep a screening log of patients 
294 
approached, patients who fulfill eligibility criteria and those who do not fulfill eligibility 
295 
criteria. Reasons for ineligibility will be recorded. This log will also record information 
296 
about eligible patients who were successfully recruited, and those who were not 
297 
recruited despite being eligible. In the event of surgeons opting for not recruiting 
298 
patients despite eligibility, rates and reasons will be recorded. Adherence to treatment 
299 
will be assessed by comparing patients9 analgesia prescription at discharge to self-
300 
reported analgesic intake at each time-point of assessment. Follow-up completion rates 
301 
and missing outcome data will be computed based on REDCap entries (date- and time-
302 
stamped). Patients will be considered to have withdrawn from the trial if they miss three 
303 
consecutive assessments and then permanently stop responding the questionnaires. 
304 
Reasons for patients not consenting participation, not completing follow-ups or 
305 
withdrawing from the trial will be recorded whenever possible. 
306 
Assessment of clinical outcomes (secondary) 
307 


Our clinical outcome measurement strategy was informed by the World Health 
308 
Organization (WHO)9s International Classification of Functioning and Disability (ICF) 
309 
and will cover constructs in the domains of impairment, activity limitation and 
310 
participation restriction30. A range of outcome measures were identified as being 
311 
potentially useful for a full-scale trial on OA versus OFA. One of the main goals for this 
312 
pilot study is to determine their appropriateness and usability. Due to the subjective 
313 
nature of pain and response to analgesia, we placed special focus on PROMs, i.e., 
314 
reports of health status coming directly from the patient. Preference was given to 
315 
measures that (1) have validity evidence supporting their use in surgical 
316 
populations31,32, (2) have been recommended by surgery, anesthesia and pain 
317 
societies32-34, (3) use scoring systems based on modern psychometric methods (Item-
318 
Response Theory, Rasch analysis)35, (4) have been used in previous literature on 
319 
postoperative/opioid analgesia, (5) have short recall periods (preferably 24 hours, no 
320 
more than 7 days) and (6) have low response burden (i.e. are brief). Author-generated 
321 
questions will be used to assess constructs that have not been addressed by existing 
322 
measures or that have been addressed in a context that is not applicable to the current 
323 
study. The outcome measures addressed in this study include: the Brief Pain Inventory 
324 
Short-Form36-38, time to stopping pain medication37, Patient-Reported Outcomes 
325 
Measurement Information System 29 Profile (PROMIS-29); domains: physical function, 
326 
anxiety, depression, fatigue, sleep disturbance, social roles and activities, pain intensity 
327 
and pain interference)33,38,39, Perioperative Opioid-Related Symptom Distress Scale40, 
328 
Prescription Opioid Misuse Index41, recovery from surgery (author-generated question), 
329 
return to work or normal activities (author-generated question), impression of treatment 
330 
effectiveness (author-generated question), satisfaction with the pain treatment received 
331 
(author-generated question), 30-day postoperative complications42,43, 30-day unplanned 
332 
healthcare utilization, 30-day adverse drug events44-46, and prolonged opioid use (3-
333 
month follow-up). See eTable 3 for a complete description of these measures.  
334 
Patient-reported outcome data will be obtained via (1) electronic questionnaires or (2) 
335 
telephone interviews, according to the patient9s preference. Electronic questionnaires 
336 
will be completed remotely (via smartphone, tablet or personal computer) using our 
337 
REDCap platform. A link to the daily questionnaires will be distributed to patients via 
338 


text message or email (according to the patient9s preference) in the morning, with up to 
339 
3 reminders sent in case of no response. Participants will be asked to, preferably, 
340 
complete the questionnaires in the morning to prevent bias associated to 
341 
chronobiological variations in pain47. Patients who opt for non-electronic assessment will 
342 
complete the questionnaires via telephone interviews, preferably conducted before 
343 
12PM. Information regarding postoperative complications and unplanned healthcare 
344 
utilization will be obtained via patient self-report (week 4) and verified using electronic 
345 
medical records. Information regarding opioid prescription dispensing will be obtained 
346 
using Dossier Santé Québec (DSQ), accessed by a physician-collaborator (Dr. Mohsen 
347 
Alhashemi, Minimally Invasive Surgery Fellow) upon patient authorization via study 
348 
consent form. Details of our follow-up schedule are summarized in Figure 4. 
349 
350 
Figure 2. Patient follow-up schedule, POD = Postoperative day 
351 
Preoperative screening measures  
352 
These measures focus on potential prognostic factors for difficult pain control, need for 
353 
opioid analgesia and opioid seeking behavior after surgery. In a future full-scale RCT, 
354 
they may help refining inclusion and exclusion criteria, as well as setting stratification 
355 
strategies to balance important covariates between treatment groups. Screening 
356 
measures addressed in this pilot study include: demographic and operative information 
357 
(data also used to characterize the patient population), the Pain Catastrophizing 
358 


Scale48,49, the Pain Anxiety Symptoms Scale (short version)19,50, the Screener and 
359 
Opioid Assessment for Patients with Pain (SOAPP)51, preferred treatment group (author 
360 
generated question) and expectations for treatment effectiveness (author generated 
361 
question). See eTable 2 for a complete description of these screening measures.  
362 
Data management plan and analysis  
363 
Data collection and storage will be according to the MUHC9s Regulatory Framework in 
364 
Health Research, which is in line with provincial and federal legislations. All data will be 
365 
entered and stored in a password-protected system of electronic data capture 
366 
(REDCap, http://project-redcap.org/) and quality will be ensured via in-built validation 
367 
checks (i.e., missing data, out-of-range values and invalid responses). Data analysis will 
368 
be conducted using Stata version 14 software (StataCorp). Analysis and trial reporting 
369 
will be according to the Consolidated Standards of Reporting Trials (CONSORT) 
370 
Guidelines extension for Pilot and Feasibility Trials52.  
371 
Data generated from the pilot study will help inform a full-scale RCT by testing the study 
372 
procedures; therefore, no inferential statistical analyses will be performed to compare 
373 
groups. Continuous variables will be summarised using means, standard deviations 
374 
(SDs), medians, lower and upper quartiles, minimum, maximum and number of 
375 
observations. Categorical variables will be summarised using frequencies and 
376 
percentages. To address feasibility, descriptive statistics of patients approached, 
377 
screened, eligible, consented and randomised, treatment adherence and follow-up 
378 
completion rates will be computed. Completeness of follow-up will be compared 
379 
between trial arms. Reasons for non-consent, exclusion and trial withdraw will be 
380 
recorded and reported. Baseline data will be summarized descriptively to assess 
381 
comparability between treatment arms and to highlight any differences between patients 
382 
who were randomized, who withheld consent and who did not meet eligibility criteria. 
383 
Analyses of postoperative outcomes will be exploratory, descriptive and follow the 
384 
intention-to-treat principle, with all patients analyzed in their assigned treatment group.  
385 
The primary outcome measure to be addressed in the full-scale RCT will be informed by 
386 
data from this pilot trial. Decision will be based on acceptability and relevance to 
387 
patients and clinicians (qualitative study described below), completion rates, evidence of 
388 


measurement properties according to previous literature, effect sizes and sample size 
389 
requirements. There are no planned interim data analyses; however, if the TMT 
390 
identifies that recruitment, randomization and data collection are below target, strategies 
391 
will be implemented to improve progress. Any changes to methods after trial 
392 
commencement will be documented and reported. Any future revisions to protocol and 
393 
consent forms will be implemented only after IRB approval. 
394 
Pilot study sample size and feasibility 
395 
This pilot trial is not confirmatory; therefore, a formal sample size calculation was not 
396 
conducted. In accordance to previous recommendation that at least 70 measured 
397 
participants are required for estimating SDs of continuous measures53, we aim to recruit 
398 
and obtain outcome data from 80 patients (40 per group), allowing for a ~15% attrition 
399 
rate. This sample size is also in line with recommendations regarding the minimal 
400 
number of participants required to identify feasibility issues54. 
401 
This pilot study will be conducted in two high volume centres where approximately 1000 
402 
eligible outpatient abdominal and breast surgeries are performed every year. In May 
403 
2019, we circulated our study protocol (draft) and conducted an electronic survey of 
404 
surgeons across the two institution; 10 surgeons (7 General, 3 Breast) agreed to have 
405 
their patients recruited for this pilot trial. Based on previous trial experience, 
406 
approximately 60% of the patients approached during the trial period will be eligible and 
407 
agree to participate. Therefore, we estimate that 80 participants could be feasibly 
408 
enrolled in 4 months. With additional 3 months required to finalize patient follow-up and 
409 
the time required for data analyses and report/manuscript preparation, we anticipate 
410 
that the time required to complete this study is approximately one year. Specific details 
411 
about our timeline are presented in. 
412 
PART II. Embedded qualitative study  
413 
A qualitative study involving patients and clinicians will be integrated within this pilot trial 
414 
to provide further fundamental insights into the design of a future full-scale RCT.  
415 
Study objective: 
416 


The objective of this study is to inform, via qualitative research methods, optimal study 
417 
design of a full-scale RCT by assessing patient and clinician perspectives on trial 
418 
conduct, participation, interventions and measurement strategy. 
419 
Research questions: 
420 
1. What are participants and non-participants9 perspectives on the pilot trial conduct, 
421 
participation (or non-participation), interventions, and measurement strategy? 
422 
2. What are clinicians9 perspectives on the acceptability of the pilot trial, experience 
423 
operationalizing the study in practice, treatment effectiveness, challenges that may 
424 
impact on the feasibility of a full-scale RCT, and areas for improvement in the future 
425 
trial design? 
426 
Interviews will be conducted until thematic saturation is reached (i.e., the point in data 
427 
collection after which no new themes emerge), accounting for a minimal targeted 
428 
sample of five patients and five clinicians. Our methodological approach will follow 
429 
Braun and Clarke9s guideline for the use of thematic analysis in qualitative studies 55. As 
430 
demonstrated by O9Cathain et al. (2013), qualitative analysis is a valuable tool to 
431 
optimize interventions in comparative-effectiveness research. Reporting of this 
432 
qualitative study will be in line with the Consolidated Criteria for Reporting Qualitative 
433 
Studies (COREQ) guidelines 56. 
434 
Interviews with patients 
435 
A sub-sample of patients who participated in the recruitment process for the pilot trial 
436 
will be invited to participate in one-on-one qualitative interviews. Patients who do not 
437 
consent to randomization in the trial will also be invited to participate in the interviews as 
438 
they may provide relevant insights regarding the consent process and study 
439 
acceptability. In order to capture the heterogeneity of outpatient general surgery 
440 
procedures and improve sample representativeness, we will use a quota sampling 
441 
method 57 targeting patients representing a broad spectrum of demographic, clinical and 
442 
surgical characteristics (Table 1). Patients will be offered the opportunity to be 
443 
interviewed face-to-face or by telephone. Patients will be informed about the qualitative 
444 
interviews during preoperative recruitment and those who are interested will be 
445 


contacted after their involvement with the trial. A consent form specific to the qualitative 
446 
study will be signed prior to the interviews. To ensure accurate recall, patients will be 
447 
interviewed no later than 6 weeks after their surgery. Interviews will focus on (1) 
448 
acceptability of the study, (2) personal experience with the process of recruitment and 
449 
randomization, (3) reasons for not accepting randomization (where appropriate), (4) 
450 
perceived value and experiences with the intervention, (5) perceived value and 
451 
experienced with the outcome assessments, (6) reasons for not completing outcome 
452 
assessment (where appropriate), and (7) areas for improvement in trial design.  
453 
Table 1. Qualitative study interviews: Target sampling quotas for patients 
454 
Characteristic 
Targeted quota 
Age  
 
 < 30 years 
>20% 
 > 65 years 
>20% 
Gender 
 
 Male 
>40% 
 Female 
>40% 
Surgery 
 
 Abdominal 
>20% 
 Breast 
>20% 
Education 
 
 Low (less than high school) 
>20% 
 High (university degree or above) 
>20% 
Employment status 
 
 Working/studying 
>30% 
 Retired 
>30% 
Postoperative complications after hospital 
 
 Yes 
>10% 
 No 
>60% 
Consented randomization 
 
 Yes 
>70% 
 No 
>20% 
 
455 
Patient recruitment process 
456 


Subsequent contact for participation in the qualitative study will be made upon patient 
457 
authorization. Patients will be approached as follows, depending on whether they 
458 
agreed or not to participate in the pilot RCT: 
459 
(1) Patients who agreed to participate in the pilot RCT and signed the informed consent 
460 
form: In the consent form for the Pilot RCT (see " Informed consent form - Pilot RCT 
461 
"), we will ask whether we have permission to contact the patient to inquire about 
462 
participation in the qualitative part of this project (check "YES" or "NO"). Those who 
463 
checked <YES= will be contacted after their participation in the Pilot RCT. A separate 
464 
informed consent form (See "Informed consent form - Interview with patients") will 
465 
be signed prior to the qualitative interview.  
466 
(2) Patients who refused to participate in the Pilot RCT: Those who refused to 
467 
participate in the Pilot RCT will be informed about the qualitative study and be offered to 
468 
sign a "Permission to contact form" if they agree to be contacted regarding 
469 
participation in the qualitative study. Patient who agree to participate will sign separate 
470 
informed consent form prior to the qualitative interview (See "Informed consent form - 
471 
Interview with patients"). 
472 
Interviews with clinicians 
473 
A sample of clinicians (surgeons, nurses, anesthesiologists) involved in the 
474 
perioperative care (i.e., prescription, education about postoperative analgesia) of 
475 
patients undergoing the surgeries of interest in this trial will be invited to participate in 
476 
one-on-one qualitative interviews. Interviews will be conducted face-to-face or by 
477 
telephone after informed consent is obtained. In order to improve sample 
478 
representativeness, we will use a quota sampling method 57 targeting clinicians 
479 
representing a broad spectrum of demographic and professional characteristics (Table 
480 
2). Interviews will be conducted within the period of patient recruitment to ensure 
481 
accurate recall.  Interviews with clinicians will focus on (1) acceptability of the study, (2) 
482 
experience operationalizing the study in practice (i.e., recruiting patients and providing 
483 
interventions), (3) reasons for not recruiting patients (where appropriate), (4) 
484 
perspectives on treatment effectiveness, (5) local issues that may impact on the 
485 
feasibility of a full-scale RCT and (6) areas for improvement in trial design.  
486 


Table 2. Qualitative study interviews: Target sampling quotas for clinicians 
487 
Characteristic 
Targeted quota 
Years of clinical experience (after residency) 
 
 < 5 years 
>20% 
 > 15 years 
>20% 
Practice location 
 
 Montreal General Hospital 
>40% 
 Royal Victoria Hospital 
>40% 
Training background 
 
 Surgery 
>60% 
 Anesthesia 
>20% 
 Nursing 
>20% 
Received formal research training (Masters, PhD) 
 
 Yes  
>40% 
 No 
>20% 
(For surgeons) Specialty  
 
        General (abdominal) 
>20% 
        Breast Surgery 
>20% 
(For surgeons) Had patients involved in the trial 
 
 Yes 
>40% 
 No (or low randomization rate, <3 patients) 
>20% 
 
488 
Clinician recruitment process 
489 
All clinicians (surgeons, nurses, anesthesiologists) who care for patients undergoing the 
490 
surgeries eligible for this study will be informed about the qualitative study by their 
491 
respective Division Chiefs (see team of collaborators in "Expertise and Resources 
492 
Available"). Clinicians who meet eligibility criteria will be contacted via email by a 
493 
member of the study team. Their contact information will be obtained via the McGill 
494 
and/or MUHC website. Those who agree to participate will sign a consent form (See 
495 
"Informed consent form – Interview with Clinicians") prior to the qualitative interview.  
496 
Interview procedures, data management and analysis 
497 
Interviews will follow semi-structured guides designed with open-ended questions to 
498 
elicit patients9 and clinicians9 personal perspectives about the trial. Initial guides will be 
499 


drafted by the trial steering committee and pilot tested for terminology, flow and 
500 
redundancy. All interviews will be digitally recorded using high quality audio equipment 
501 
and transcribed verbatim by a third-party ISO certified transcription company. Analysis 
502 
of interview data will be conducted via inductive thematic analysis informed by Braun 
503 
and Clarke (2006)55. Thematic analysis is a method used to identify, analyze, and report 
504 
themes and subthemes within the interviews to provide a rich description of the 
505 
qualitative data. The inductive approach to thematic analysis is data-driven, where the 
506 
themes will be derived from within the data themselves and no pre-existing coding 
507 
framework will be applied during analysis. Based on data obtained from the first 
508 
interviews, two independent researchers (coders) will code each interview transcription 
509 
and search for recurring themes. The coding process will be conducted using the 
510 
software MAXQDA 12 (VERBI GmbH, Berlin, Germany). For every two transcripts 
511 
coded, coders will meet to (1) compare the codes assigned, (2) revise the codes 
512 
iteratively as new information emerges, (3) cluster the codes (via thematic mapping) into 
513 
initial themes and sub-themes to inform the subsequent development and refinement of 
514 
themes, and 4) generate a clear definition and name for each of the theme. Assessment 
515 
of saturation will be conducted iteratively (after every 2 interviews) using a saturation 
516 
grid58.  
517 
The findings from this qualitative study will be regularly fed back to the trial steering 
518 
committee so that aspects of the pilot study conduct can be reviewed iteratively where 
519 
appropriate. Themes for which saturation is reached will be classified as meaningful 
520 
issues to inform the optimal design of the full-scale RCT. 
521 
Summary of sample size estimates 
522 
PART I. Main study (Pilot RCT) 
80 participants (40 per group). 
PART II. Embedded qualitative study  
20 participants (estimate) - A minimal of 10 participants (5 patients, 5 clinicians) will be 
recruited but the total sample may vary according to data saturation.  


Total sample size 
100 participants (estimate). 
 
523 
EXPERTISE AND RESOURCES AVAILABLE 
524 
This project builds on the expertise of scientists and clinicians with extensive experience 
525 
and knowledge in the fields of surgery and postoperative analgesia. Dr. Julio Fiore Jr 
526 
(Outcomes Researcher) is the principal investigator and primarily responsible for writing 
527 
the study protocol. He will be in charge of the overall coordination and supervision of all 
528 
aspects of this pilot RCT, including recruitment, randomization and data management. 
529 
He has substantial experience with the design and conduct of pilot and full-scale RCTs. 
530 
Dr. Gabriele Baldini (Anesthetist) and Dr. Liane Feldman (Surgeon) are co-investigators 
531 
and knowledge users (i.e. prescribers of postoperative pain medications). They will be 
532 
responsible for supervising all clinical aspects of the study (i.e. analgesia interventions) 
533 
and for liaising with clinicians across both study sites. Our team of collaborators bring in 
534 
a wide range of clinical and research expertise to this project: RCTs (Dr. Kaberi 
535 
Dasgupta, Physician/Epidemiologist), acute pain assessment and management (Dr. 
536 
Suzanne Morin, Physician/Epidemiologist), postoperative analgesia (Dr. Avinash Sinha, 
537 
Anesthetist; Ms Krista Brecht, Pain Nurse), surgery (Dr. Sarkis Meterissian, Breast 
538 
Clinic Director; Dr. Mohsen Alhashemi, Minimally Invasive Surgery Fellow), opioid 
539 
misuse (Dr. Marc Martel, Psychologist) and qualitative research (Dr. Fatemeh 
540 
Rajabiyazdi, Postdoctoral Fellow/Qualitative Researcher). Statistical support from the 
541 
RI-MUHC Biostatistics Support Unit has been sought and incorporated in this pilot trial 
542 
in preparation for a full-scale RCT. 
543 
The project will be coordinated by the Steinberg-Bernstein Centre for Minimally Invasive 
544 
Surgery, based at the Montreal General Hospital. The centre offers dedicated office 
545 
space (100m2) with computer facilities for data collection and warehousing and employs 
546 
a full-time research coordinator (Ms. Pepa Keneva, MSc). Two master9s students (Ms 
547 
Uyen Do and Mr Charbel El Kefraoui) will coordinate the day-to-day management of the 
548 
project at the two sites under the supervision of Drs. Fiore, Baldini and Feldman. Our 
549 


experienced multidisciplinary team has all the necessary elements (i.e. infrastructure, 
550 
methodological and context expertise) to successfully conclude this project. 
551 
ANTICIPATED CHALLENGES AND MITIGATION STRATEGIES  
552 
Prescription of opioids to treat breakthrough pain after surgery is imbedded in Canada9 
553 
healthcare culture. For this reason, we cannot exclude that (1) certain clinicians may be 
554 
wary of discharging patients without an opioid prescription and (2) ethical issues may be 
555 
raised anticipating a negative impact on pain outcomes. However, considering the 
556 
current opioid crisis, changes have been observed in the paradigm of 8mandatory opioid 
557 
prescription9 as some surgeons across the MUHC began managing pain after outpatient 
558 
general surgery using only non-opioid drugs. According to their personal experience, 
559 
this practice did not increase unplanned healthcare visits due to uncontrolled pain and, 
560 
importantly, satisfaction with pain control reported during scheduled postoperative visits 
561 
seems unchanged in comparison to when opioids were regularly prescribed. Besides 
562 
this anecdotal data, preliminary results from our scoping review suggest that previous 
563 
comparative studies do not support the value of prescribing opioids after outpatient 
564 
surgery17-19 – these results, however, must be confirmed in a formal systematic 
565 
review/meta-analysis. In other patient populations such as chronic musculoskeletal pain 
566 
and acute extremity pain, the role of opioid analgesia has also recently been questioned 
567 
in large RCTs showing non-superiority38,59 and increased adverse events38. In light of 
568 
this evidence and considering the ongoing paradigm change at a local level, this pilot 
569 
trial gained support from key stakeholders in our surgical departments and divisions 
570 
who are committed to encouraging recruitment across both study sites.  
571 
As certain surgeons may heavily rely on opioids to treat postoperative pain, we 
572 
anticipate that some may refuse to recruit selected patients or refuse to recruit patients 
573 
altogether. Similarly, some patients may be doubtful about the efficacy of pain treatment 
574 
without opioids and refuse randomization. This issue will be addressed by comparing 
575 
demographic and surgical data of randomized patients versus non-randomized patients. 
576 
Differences may suggest that our results are not generalizable to certain surgical 
577 
populations, indicating venues to improve our patient selection criteria and/or 
578 
recruitment process. Our integrated qualitative study including interviews with patients 
579 


who refused randomization and surgeons with low recruitment rates will provide 
580 
fundamental insights into the strategies to mitigate these potential issues. The 
581 
qualitative study will also provide relevant information to optimize our measurement 
582 
strategy, which currently includes daily follow-up in the first 7 days after surgery. The 
583 
use of daily outpatient follow-up assessment has been successful in a recent RCT on 
584 
postoperative analgesia37 but, if proven unfeasible in our setting, strategies will be 
585 
implemented to reduce patient burden (e.g., reducing follow-up frequency).  
586 
Finally, surgeons from different specialities may give preference to different non-opioid 
587 
drugs, e.g. NSAIDs/COX-2 may be avoided by some surgeons due to potential risk of 
588 
bleeding60, while others may be concerned about risk of liver failure when using 
589 
acetaminophen61. In line with the pragmatic nature of this trial, surgeons will have the 
590 
freedom to, within the analgesia principles of each intervention group, choose the 
591 
regimen that they find most appropriate according to surgical procedure, comorbidities 
592 
and individual preference. To ensure safety, analgesia prescriptions will follow Health 
593 
Canada monographs for maximum dosages and length of treatment26. Potential 
594 
treatment adverse events will be identified and reported according to internationally 
595 
accepted standards supported by Health Canada44-46,62.   
596 
DATA COLLECTION AND CONFIDENTIALITY 
597 
Retrospective chart review: All the information collected during our preliminary chart 
598 
review will remain confidential to the extent required and provided by law. A study ID 
599 
number will be assigned to each patient9s chart. No code linking patient identifiers to 
600 
patient data will be kept and it will not be possible to identify patients.   
601 
Pilot Trial: All data collected in our pilot trial will be entered and stored in a password-
602 
protected system of electronic data capture (REDCap; Research Electronic Data 
603 
Capture, hosted at Research Institute of MUHC), and subsequently transferred to the 
604 
statistical program for analysis. A study ID number will be assigned to each participant. 
605 
Information collected in paper-based forms will be kept in locked cabinets within a 
606 
locked office (R2-111). Participants will be identified by a code to protect their identity. A 
607 
document linking the codes to the participants9 identity will be kept separately in a 
608 
password protected file, which can only be accessed by the study staff. 
609 


All data will be kept under safe storage for 7 years and then deleted, shredded or 
610 
incinerated. Only investigators will have access to the data.  Furthermore, the results 
611 
and the project may be published, but patients9 identity will not be revealed.   
612 
KNOWLEDGE TRANSLATION (KT) PLAN 
613 
Results from this pilot trial will inform the planning and commissioning of a future full-
614 
scale RCT on opioid-free analgesia after outpatient general surgery. If proven feasible, 
615 
this full-scale RCT will inform guidelines targeting sustainable changes in surgical care 
616 
to mitigate the negative downstream effects of postoperative opioid overprescription. 
617 
Our findings will be disseminated according to CIHR9s Guide to Knowledge Translation 
618 
(KT) Planning63 and target a broad audience of surgeons, anesthetists, nurses, 
619 
pharmacists, surgical outcomes scientists and research funders. Our KT strategies 
620 
include, but are not limited to, conference presentations (local, national and 
621 
international), publication of a peer-reviewed paper, and diffusion of findings in 
622 
websites, newsletters and social media platforms. As opioids are part of standard 
623 
postoperative care in North America, we believe that our study will contribute feasibility 
624 
data to support and encourage further opioid-free analgesia research beyond our 
625 
immediate research setting in Canada and internationally (i.e., the United States). 
626 
SIGNIFICANCE 
627 
The overprescription of opioids to surgical patients is recognized as one of the driving 
628 
forces behind the current opioid crisis. Patients undergoing outpatient general surgery 
629 
are frequently prescribed opioids to be taken at home postoperatively, but this practice 
630 
is not supported by evidence. Alternatives to opioids are often overlooked by Canadian 
631 
surgeons, while they should be incorporated as the foundation of postoperative 
632 
analgesia whenever possible. If proven effective in a future full-scale RCT, the use of 
633 
opioid-free analgesia after outpatient surgery may ultimately contribute to preventing 
634 
opioid-related harms. Hence, the pilot study described in this protocol is an essential 
635 
first step for building a strong body of evidence to mitigate the negative downstream 
636 
effects of postoperative opioid overprescription in Canada.  
 
637 


AMENDMENTS TO THE PROTOCOL AFTER INITIAL ETHICS APPROVAL 
638 
 
639 
Change 
Reason 
October 2019. Prior to patient 
recruitment  
Retrospective chart review 
• To confirm that patients randomized to 
OA group are treated according to 
current standards of care, a 
retrospective chart review was 
conducted to collect data on post-
discharge analgesics prescribed to 
patients who underwent the eligible 
surgeries in 2019 [period of January 01 
to December 31, 2019]. This data (not 
reported in the manuscript) supported 
that patients in the OA group were 
treated according to standard care. 
October 2019. Prior to patient 
recruitment  
Randomization strategy 
• After discussion with surgeons, the 
team realized that the randomization of 
patients in the PACU (with discharge 
prescriptions written right before 
hospital discharge) would be 
impractical as surgeons often write 
their prescriptions in the OR after skin 
closure. For this reason, 
randomizations were conducted in the 
OR. 
September 2020. After patient 
recruitment  
Knowledge translation plan 
• After discussion, the team decided that 
the two components of this pilot study 
(quantitative and qualitative) would be 
reported in separate manuscripts.  
June 2021. After patient recruitment 
Outcome measure/data analysis 
Data on overall impression of treatment 
effectiveness at each postoperative 
timepoint.  
• We noticed that this author-generated 
question was accidently excluded from 
the final version of the Redcap 
questionnaire distributed to patients. 
Therefore, these data were not 
analyzed or reported in the manuscript. 
Impressions about treatment 
effectiveness were detected via other 
patient-reported questionnaires.   
June 2021. After patient recruitment 
and data analysis 
Outcome measure/data analysis 
Data regarding satisfaction with pain 
management at postoperative week 4 
• After data analyses, the team realized 
that findings regarding satisfaction with 
pain management at postoperative 
week 4 were redundant (did not add 
relevant information in comparison to 
the data reported by patients on week 
1). For this reason, this information was 


not reported in the manuscript. This 
data would not be useful as it is subject 
to recall bias given that most patients 
do not use pain medications beyond 
week 1.  
 
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