Signs and Symptoms of Opioid-associated Iatrogenic Withdrawal in Critically Ill Adults
Conditions: Substance Withdrawal Syndrome
Sponsor: Marc M. Perreault

 
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SOWA-ICU 
Signs and symptoms of opioid-associated iatrogenic withdrawal in critically ill adults 
RESEARCH PROTOCOL 
 
 
Pharmacy Residents: 
Laura Delucilla, PharmD, MSc Candidate 
Jean-François Cabot, PharmD, MSc candidate 
Qian Li, PharmD, MSc candidate 
Karima Zerrouki, PharmD, MSc candidate 
 
McGill University Health Centre 
 
Research Director/Investigator: 
Marc Perreault, PharmD, MSc, FCSHP 
 
Clinical Directors: 
Marie-Soleil Delisle, PharmD, MSc 
Marc Alexandre Duceppe, PharmD, MSc 
 
Collaborators 
Leon Tourian, MD, Psychiatrist, MGH 
Dev Jayaraman, MD, Intensivist, MGH 
Sulaiman Khadadah, ICU Fellow 
Celine Gélinas, RN, PhD, JGH 
Lisa Burry, PharmD, Mount Sinai, Toronto  
 
PHA6220 – Research in Pharmacy 
Master in Advanced Pharmacotherapy  
Faculty of Pharmacy 
December 1st, 2017 

 
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Table of Contents 
 
1. Introduction ............................................................................................................................ 1 
2. Literature review .................................................................................................................... 1 
3. Research objectives ............................................................................................................. 3 
4. Methods ................................................................................................................................... 3 
4.1 Study design...................................................................................................................................3 
4.2 Populations .....................................................................................................................................4 
4.3 Subject selection mode ..............................................................................................................4 
4.3.1 Inclusion criteria .....................................................................................................................4 
4.3.2 Exclusion criteria .....................................................................................................................4 
4.4 Definition of variables ..................................................................................................................5 
4.4.1 Primary outcome variables .................................................................................................5 
4.4.2 Secondary outcome variables ...........................................................................................8 
4.5 Data collection and study procedure (Appendix II) ............................................................9 
4.6 Measurement tools ..................................................................................................................... 10 
5. Data analysis ........................................................................................................................ 11 
5.1 Statistical analysis ....................................................................................................................... 11 
5.1.1 Descriptive statistics ............................................................................................................ 11 
5.1.2 Statistical inference ............................................................................................................. 11 
5.2 Sample size .................................................................................................................................. 11 
6. Advantages and limitations .............................................................................................. 11 
6.1 Advantages.................................................................................................................................. 11 
6.2 Limitations ..................................................................................................................................... 12 
7. Relevance of study ............................................................................................................. 12 
8. Ethical considerations and patient consent .................................................................. 12 
9. References ............................................................................................................................ 14 
10. Time frame and budget ................................................................................................... 18 
11. Appendices ........................................................................................................................ 19 
Appendix I. Research strategy in Medline................................................................................... 19 
Appendix II. Study procedure ........................................................................................................ 21 
Appendix III. Dependent variables: signs and symptoms of OIWS ........................................ 22 
Appendix IV. Diagnostic and Statistical Manual of Mental Diagnosis-V (DSM-5): “Opioid 
Withdrawal” criteria. ......................................................................................................................... 27 
Appendix V. Acute Physiology and Chronic Health Evaluation II (APACHE II) developed 
by Knaus et al. ................................................................................................................................... 28 
Appendix VI. Glasgow Coma Scale (GCS) developed by Jennett et al. ............................. 29 
Appendix VII. Child-Turcotte-Pugh score developed by Pugh et al. .................................... 30 
Appendix VIII. Confusion Assessment Method in the Intensive Care Unit (CAM-ICU) 
developed by Ely et al. .................................................................................................................... 31 
Appendix IX. Confusion Assessment Method (CAM) developed by Inouye et al. ............. 32 
Appendix X. Richmond Agitation-Sedation Scale (RASS) developed by Sessler et al. ..... 33 

 
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Appendix XI. Agitated Behavior Scale (ABS) developed by Carrigan et al. ....................... 34 
Appendix XII. Critical-Care Pain Observation Tool (CPOT) developed by Gelinas et al. . 35 
Appendix XIII. Numeric Rating Scale (NRS)................................................................................. 36 
 
 
 
Abbreviation list 
 
ICU 
  
Intensive care unit 
IWS 
  
Iatrogenic withdrawal syndrome 
MGH   
Montreal General Hospital 
MUHC  
McGill University Health Centre 
OIWS   
Opioid-associated iatrogenic withdrawal syndrome 
PICU   
Pediatric intensive care unit 
RVH  
 
Royal Victoria Hospital 

 
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1. Introduction 
Adult medical, surgical and trauma intensive care unit (ICU) patients routinely experience pain, 
agitation, delirium and anxiety (1). Opioids and benzodiazepines are the primary medications to 
relieve pain, facilitate mechanical ventilation and decrease physiological and psychological stress 
in the critically ill (1). In a prospective, observational study in 51 Canadian ICUs, 92% of patients 
received opioids and sedatives at least once during mechanical ventilation (2). Upon repeated and 
prolonged administration, opioid tolerance may develop as a result of receptor desensitization and 
upregulation of excitatory intracellular pathways (2, 3). When these drugs are abruptly discontinued 
or rapidly tapered, patients may develop a cluster of signs and symptoms known as the acute 
iatrogenic withdrawal syndrome (IWS). While this phenomenon is well described in the pediatric 
critical care population, there is a paucity of data in critically ill adults (4-7). IWS has been associated 
with negative clinical outcomes such as increased length of hospital stays, prolonged duration of 
mechanical ventilation and higher cost of hospitalization (4-7).  
 
In one prospective, observational study, the reported incidence of IWS in the adult ICU population 
was 16.7% (8). In prospective studies done in the pediatric ICU (PICU), observed incidence was 7.5 to 
100% (9). Two assessment tools have been validated in children: The Withdrawal Assessment Tool-
Version 1 (WAT-1) and the Sophia Observation Withdrawal Symptoms-scale (SOS) (10). No such tool 
currently exists in the adult ICU (9). 
   
Identifying IWS can be challenging in the critically ill. Several confounding factors (delirium, 
worsening of critical illness, presence of multiple agents with potential to cause withdrawal, 
comorbidities) may mimic symptoms similar to opioid or benzodiazepine withdrawal (6, 11). To our 
knowledge, no study on the symptomatology of IWS has been conducted to describe opioid or 
benzodiazepine withdrawal exclusively. This is most likely due to the presentation similarities of both 
syndromes and frequent concomitant use of these drugs in the ICU setting (4, 9). 
 
No physiological markers have been identified to correlate with IWS. In outpatients with chronic 
opioid addiction, several studies have shown a significant association between increased cortisol 
and catecholamine levels and acute withdrawal following naloxone reversal. Cortisol and 
catecholamines are two stress markers that reflect the state of distress and adrenergic 
hyperstimulation characteristic of opioid withdrawal (12). 
 
To date, the clinical presentation of opioid withdrawal in the adult ICU has not been characterized 
in a prospective setting. The present study thus aims to describe the symptomatology of opioid-
associated iatrogenic withdrawal in two adult tertiary care centers in Montréal, Québec, Canada 
and explore the potential of using serum cortisol as a biomarker (4, 9). 
 
2. Literature review 
Research strategy can be found in Appendix I. 
 
Epidemiology  
A systematic review on the epidemiology, risk factors and symptomatology of IWS was recently 
conducted and identified only one prospective study on IWS in the adult ICU population, which 
reported an incidence of 16.7% (8, 9). In retrospective trials, incidence ranged from 19.7 to 100% (9). 
These heterogeneous results are likely attributed to the lack of standardized definition and 
evaluation of IWS (9). 
 
Risk factors 
There is significant overlap in the IWS risk factors identified in pediatric and adult populations such as 
younger age (3, 4, 7, 9) duration of continuous opioid therapy (i.e. more than three to five days) and 
prolonged benzodiazepine exposure (4, 5, 7, 9, 13-17). Additional risk factors identified specifically in 
the adult ICU include higher daily doses of opioids and benzodiazepines, as well as the presence of 
acute respiratory distress syndrome (ARDS) (7, 9). In the PICU, prolonged exposure prior to weaning 

 
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and total cumulative opioid and benzodiazepine doses have been associated with an increased 
risk of IWS (4, 5, 14, 15). The onset of withdrawal symptoms can occur within 12 hours following opioid 
discontinuation and may be precipitated by an abrupt taper or the administration of opioid 
antagonists (1, 18). 
 
Clinical presentation  
Most literature is extracted from PICU studies designed with the objective of developing or validating 
IWS assessment tools (16). Ista et al. compiled a list of 26 symptoms of mixed withdrawal as reported 
in the literature and evaluated the co-occurrence of IWS symptoms in low and high risk patients (19). 
An expert panel identified 15 symptoms encompassing the central nervous system (anxiety, 
agitation, inconsolable crying, grimacing, sleep disturbance, hallucinations), autonomic dysfunction 
(increased muscle tension, muscle twitching, tremors, tachycardia, tachypnea, fever, sweating) and 
gastrointestinal problems (vomiting, diarrhea) (19, 20). However, the investigators did not control for 
potential confounders of IWS diagnosis such as inadequate pain management or delirium. A review 
by Chiu et al. identified symptoms of opioid withdrawal specific to the neonatal and PICU 
populations such as inconsolable crying, irritability, grimacing, tremors, increased muscle tone, poor 
feeding, vomiting, diarrhea, sleep disturbance, hyperactive Moro reflex, fever, nasal stuffiness, 
sweating and yawning (4). However, evaluation of symptoms and outcomes were done by the 
same practitioner in select studies, which may have confounded the results (4, 21). 
 
Opioid withdrawal appears to present differently in adults (4). In a prospective study evaluating the 
validity of the WAT-1 in the adult ICU, commonly observed symptoms in the PICU such as diarrhea, 
vomiting and fever did not correlate with a diagnosis of IWS (8, 22). Chiu et al. reports that 
withdrawal symptoms in adults tend to begin with anxiety, irritability, agitation and dysphoria, 
followed by sweating, rhinorrhea, tachypnea, insomnia and yawning in the acute phase. Symptoms 
such as mydriasis, tachycardia, hypertension, nausea, vomiting, piloerection and fever manifest 
during subsequent phases of withdrawal (4). In the retrospective study by Cammarano et al., IWS 
was diagnosed using a modified Himmelsbach scale, which assesses the severity of opioid 
withdrawal in chronic users only (7, 23). Thus, the symptoms identified in this study may not be 
applicable to opioid-naive patients. It is currently unclear whether all these symptoms can be 
identified in opioid-naive critically ill patients 
 
The distinction between opioid and benzodiazepine withdrawal remains unclear because both 
drugs are often used simultaneously in the ICU setting. Duceppe et al. reports that there are currently 
no adult or pediatric ICU studies that evaluated the incidence of isolated opioid or benzodiazepine 
withdrawal symptoms (9). The 2002 adult critical care guidelines, updated in 2013, identifies nausea, 
vomiting, sweating, agitation, restlessness, irritability, anxiety and muscle cramps as common 
symptoms to both acute opioid and benzodiazepine withdrawal (1, 18). Benzodiazepine and opioid 
withdrawal symptoms largely overlap, which contributes to the difficulty in describing both 
syndromes adequately (20, 24).  
 
Assessment tools 
As stated previously, in the PICU, two validated tools are commonly used to assess IWS: the WAT-1 
and the SOS. Both are included in the 2016 European clinical guidelines for pain, sedation, 
withdrawal and delirium assessment in critically ill infants and children (10). However, they were 
validated in a manner that could potentially affect the results’ reliability – in the psychometric 
evaluation studies, the same nurse scored both the tool and withdrawal severity. The lack of blinding 
to the presence of IWS and the lack of independent evaluation thus make those studies susceptible 
to observer bias. The WAT-1 performed poorly in the adult ICU, suggesting that the presentation of 
IWS is different in adults as compared to children (4). 
 
Biomarkers 
The literature on opioid dependence has consistently demonstrated elevated levels of cortisol (12, 
25-38) and catecholamines (12, 39-43) during the acute withdrawal phase. Human and animal 

 
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models postulate that long-term use of opioids induces hypoadrenalism through impairment of the 
hypothalamic-pituitary-adrenal (HPA) axis. Opioid withdrawal leads to marked elevations of cortisol 
as a result of excess ACTH secretion (26, 32, 35). This HPA activation persists following normalization of 
the adrenergic system, which led some authors to conclude that cortisol is a more sensitive indicator 
of opioid withdrawal than catecholamines (30, 32). A small study by Higgins et al. on 5 non-
dependent subjects assessed acute opioid withdrawal after a single dose of morphine and 
observed a dose-dependent increase in cortisol levels when subjects were subsequently injected 
with naloxone (28). Despite the clinical relevance, several limitations reduce the applicability of 
those results to our study population, mainly the selection of opioid-dependent subjects and rapid 
induction of withdrawal – through injection of naloxone or abrupt cessation of opioid with support 
medications such as alpha2-agonists. Since our subjects are mostly opioid-naive prior to 
hospitalization and will be gradually weaned off their opioids, the magnitude of increase in cortisol 
levels will likely be lower. 
 
As for catecholamines, serum epinephrine and norepinephrine appear to increase rapidly following 
opioid withdrawal in numerous animal and human studies (12, 39-43). However, in contrast with 
cortisol, catecholamine levels decrease shortly following acute withdrawal. In a study of subjects 
undergoing rapid opioid detoxification, catecholamine levels peaked two hours following naloxone 
administration (12). A gradual opioid weaning as often seen in clinical practice is unlikely to be 
recognized through measurement of serum catecholamines. 
 
3. Research objectives 
Research question 
What are the signs and symptoms of opioid-associated iatrogenic withdrawal syndrome (OIWS) in 
the adult ICU population? 
 
Primary objective 
To identify specific signs and symptoms of OIWS in mechanically ventilated adult ICU patients 
receiving at least 72 hours of regular opioids at the Montreal General Hospital (MGH) and the Royal 
Victoria Hospital (RVH) from February to October 2018 
 
Secondary objective 
To determine if the presence of OIWS is associated with an increase in serum cortisol. 
 
4. Methods 
4.1 Study design 
Multicenter Prospective Observational Open Cohort Study 
The clinical presentation of OIWS is poorly described in the adult ICU population. The descriptive 
study design aims to identify signs and symptoms of OIWS in the prospect of developing a validated 
bedside screening tool. The prospective approach will enable collection of all relevant information 
while limiting missing data and assessing for potential confounding variables. 
 
Throughout the study, investigators will be blinded to the diagnosis of OIWS to reduce evaluation 
bias and increase internal validity. Additionally, on one occasion for each patient, OIWS evaluation 
will be performed by two physicians, allowing for inter-rater reliability. This will ensure accurate OIWS 
diagnosis and reduce information bias. Following transfer to the ward, one additional data 
collection will be performed to optimize OIWS detection. 
 
The study will be conducted in two hospitals of the McGill University Health Centre (MUHC) with 
different ICU populations, hereby increasing the external validity of the results. The MGH is a Level I 
trauma center, whereas the RVH treats surgical and medical patients. Furthermore, a multicentric 
approach will increase the sample size and the likelihood of describing the syndrome adequately. 

 
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4.2 Populations 
Target population  
Mechanically ventilated adult ICU patients receiving continuous or regular intermittent opioids for 
more than 72 hours 
 
Source population 
Mechanically ventilated adult ICU patients admitted to the MGH and the RVH from February to 
October 2018 receiving continuous or regular intermittent opioids for more than 72 hours and 
meeting the inclusion and none of the exclusion criteria of the study 
 
Study population 
Mechanically ventilated adult ICU patients admitted to the MGH and the RVH from February to 
October 2018 receiving at least 72 hours of continuous or intermittent opioids, meeting the inclusion 
and none of the exclusion criteria and consenting to participate in the study 
 
4.3 Subject selection mode 
4.3.1 Inclusion criteria 
- 
Patients 18 years of age or older 
- 
Admitted to the RVH and MGH intensive care units from February to October 2018 
- 
Patients requiring mechanical ventilation and receiving continuous or regular intermittent 
opioids for at least 72 hours (calculated from the hour of administration of the first opioid 
dose) 
o 
Recent prospective observational studies in the PICU and adult ICU populations have 
demonstrated that iatrogenic withdrawal symptoms may develop following 3-5 days 
of continuous opioid therapy (5, 8) 
o 
Patient will be considered as receiving regular intermittent opioids if more than half of 
the scheduled  “as-needed” doses within 24 hours were administered.  
§ 
In the event that only prn narcotics are prescribed on a q1h prn or q2h prn 
basis, patients will be eligible if ≥ 4 prn doses are required per day. 
- 
Weaning of at least 10% from previous stable opioid dose 
○ 
A weaning episode is defined as a ≥ 10% decrease in the total stable opioid dose 
received over 4 hours for opioid infusions and over 12 hours for intermittent opioid 
administration (22) 
○ 
According to our previous experience (i.e. WAAICUP-1), the weaning definition of ≥ 
10% was chosen for practical reasons (8) 
4.3.2 Exclusion criteria 
- 
Patient for whom consent cannot be obtained 
- 
Patient and/or family unable to communicate in French or English 
○ 
May interfere with obtaining informed consent and OIWS assessment 
- 
Patient who is deaf without appropriate hearing aid 
○ 
Hearing impairment may interfere with patient communication and assessment of 
signs and symptoms 
- 
Imminent and predictable death (< 72 hours) according to medical team 
- 
Patients receiving opioids for the purposes of palliative care or prescribed by the palliative 
care team.  
- 
Severe brain injury, defined as Glasgow Coma Scale (GCS) score of 8 or less at ICU admission 
- 
Moderate brain injury, defined as GCS between 9 and 12, with elevated intracranial pressure 
(ICP > 20 mmHg) which requires ICP monitoring and osmotherapy 
○ 
Major confounding factors for withdrawal syndrome by causing shivering, 
sympathetic drive and autonomic disorders 
- 
Acute neurological condition (e.g. status epilepticus, encephalopathy, stroke)  
○ 
Potential confounders of OIWS assessment 

 
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○ 
If the acute neurological condition resolves within 72 hours, the patient may be 
included in the study 
- 
Substance abuse prior to ICU admission 
○ 
Chronic alcohol use defined as alcohol consumption of more than 2 drinks/day 
and/or more than 14 drinks/week for men and 9 drinks/week for women (44)  
○ 
Chronic use of illicit drugs and amphetamines (except amphetamines taken for 
therapeutic purposes) defined as a consumption of at least 3 times per week 
○ 
Chronic use of opioids (e.g. transdermal fentanyl, methadone, hydromorphone, etc.) 
defined as a consumption of at least 3 times per week 
○ 
May induce withdrawal and confound OIWS assessment (45)  
○ 
Chronic consumption of these substances will be confirmed by the patient, family, or 
medical chart 
- 
Admission to the ICU with substance overdose or alcohol withdrawal syndrome. 
- 
Readmission to the MGH or RVH ICU during the recruitment period (limit of one study entry 
per patient) 
- 
Spinal cord injury above the lumbar region 
○ 
Sympathetic response to withdrawal absent depending on site/level of injury 
○ 
Assessment tools not validated in these patients (DSM-5, RASS, CAM-ICU, CPOT) 
- 
Opioid tolerance prior to ICU admission, defined as regular daily use of opioids for a chronic 
medical condition or continuous opioid administration for > 7 days prior to ICU admission (46) 
Does not include patients who take opioids infrequently. 
○ 
The FDA defines opioid tolerance as patients receiving at least 60 mg/day of oral 
morphine equivalents (600 mcg IV fentanyl IV equivalents/day) for ≥ 1 week (46)   
4.4 Definition of variables 
4.4.1 Primary outcome variables 
Dependent variables 
- 
Presence of signs and symptoms of OIWS 
o 
According to daily evaluation by investigator after an episode of opioid weaning has 
begun (See Appendix III) 
Independent variables 
- 
Presence of OIWS (qualitative nominal - dichotomous) 
o 
According to DSM-5 evaluation completed daily by physician after an episode of 
opioid weaning has begun 
- 
Demographic and clinical variables 
o 
Age (quantitative continuous): Age in years at ICU admission 
o 
Sex (qualitative nominal - dichotomous) 
o 
Weight (quantitative continuous): Weight in kg at ICU admission 
o 
Height (quantitative continuous): Height in cm at ICU admission 
o 
Body mass index (BMI) (quantitative continuous): In kg/m2 at ICU admission 
o 
Ethnicity (qualitative nominal) 
o 
Site of ICU admission (qualitative nominal - dichotomous) 
o 
Smoking status (qualitative nominal - dichotomous) 
- 
Number of cigarettes per day according to medical chart, patient or family at 
ICU admission (quantitative discrete)  
- 
Number of pack-years according to medical chart, patient or family at ICU 
admission (quantitative continuous) 
o 
Principal diagnosis at ICU admission (qualitative nominal) 
- 
Definite diagnosis according to medical chart at ICU admission using ICD-10 
classification 
o 
Length of stay in the ICU (quantitative continuous) 
- 
Time in hours from ICU admission to ICU discharge, transfer to ward or patient 
death, according to medical chart 
- 
Opioid withdrawal has been associated with longer ICU stays (4-6) 
o 
Duration of mechanical ventilation (quantitative continuous) 

 
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- 
Time in hours according to medical chart 
- 
Longer duration of mechanical ventilation has been associated with 
increased risk of IWS in ICU patients (7)  
o 
Acute Physiology and Chronic Health Evaluation II Score (APACHE II) (qualitative 
ordinal) 
- 
To assess severity of disease and ICU mortality on a scale of 0 to 71 (47)  
- 
As reported by an archivist based on data from the first 24 hours of ICU 
admission 
o 
Glasgow Coma Scale (GCS) (qualitative ordinal) 
- 
To assess mental status and severity of brain injury on a scale of 3 to 15 (48)  
- 
As reported by nurse on patient flow sheet at ICU admission 
o 
Renal function 
- 
Daily serum creatinine in µmol/L according to medical chart (quantitative 
continuous) 
- 
Presence of renal replacement therapy according to medical chart 
(qualitative nominal - dichotomous) 
- 
Drug accumulation may occur when renal excretion is decreased, minimizing 
OIWS 
o 
Level of hepatic dysfunction upon ICU admission 
- 
Severity of hepatic dysfunction as calculated by the Child-Turcotte-Pugh 
score at ICU admission (qualitative ordinal) 
- 
Drug accumulation may occur when hepatic metabolism is decreased 
o 
Presence of ECMO (qualitative nominal - dichotomous) 
- 
Collected daily according to medical chart  
- 
Patients on ECMO may require higher fentanyl doses due to sequestration of 
lipophilic drugs and increased volume of distribution (49)  
o 
Cumulative opioid dose preweaning (quantitative continuous) 
- 
Cumulative opioid dose in fentanyl equivalents (µg/kg) according to 
medication administration record (MAR) from time of start of opioids during 
ICU admission 
- 
Higher cumulative opioid doses have been associated with increased risk of 
IWS in ICU patients (8)  
o 
Duration of continuous opioid administration preweaning (quantitative continuous) 
- 
Time in hours according to MAR or patient flow sheet 
- 
Prolonged opioid exposure has been associated with an increased risk of IWS 
in ICU patients (4, 8, 13-15)   
o 
Rate of opioid weaning > 10% from previous stable dose (quantitative continuous) 
- 
Calculated in % according to MAR or patient flow sheet 
- 
Continuous infusion: perfusion rate over previous 4h 
- 
Continuous intermittent administration: total dose over previous 12h 
- 
Rapid tapering or abrupt discontinuation of opioids has been associated with 
increased risk of IWS in ICU patients (7, 20)  
o 
Presence of clonidine, beta-blockers or antidepressants prior to ICU admission 
(qualitative nominal - dichotomous) 
- 
The agent and whether it was represcribed in ICU will be noted according to 
the medication reconciliation chart at admission 
- 
These medications may cause withdrawal when discontinued 
o 
Occasional use of prescribed opioids prior to ICU admission (qualitative nominal - 
dichotomous) 
- 
Agent (qualitative nominal) and daily doses in fentanyl equivalents 
(µg/kg/day) (quantitative continuous) will be noted according to medication 
reconciliation chart at admission 
- 
Chronic opioid users are excluded from the present study (as indicated in 
exclusion criteria) 

 
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o 
Prior history of substance abuse (qualitative nominal - dichotomous) 
- 
Agent (qualitative nominal) will be noted according to patient, family or 
medical chart 
- 
A prior history of substance abuse may render those patients more susceptible 
to CNS depressants (e.g. opioids and benzodiazepines) 
Confounding variables 
- 
Chronic or occasional use of benzodiazepines prior to ICU admission (qualitative nominal - 
dichotomous) 
- 
Agent (qualitative nominal) and total daily doses in lorazepam equivalents 
(mg/kg/day) (quantitative continuous) will be noted according to medication 
reconciliation chart at admission 
- 
Withdrawal due to benzodiazepines may overlap with OIWS assessment (6, 24) 
- 
Concomitant administration of benzodiazepines during ICU stay (qualitative nominal - 
dichotomous) 
- 
Agent and total daily dose (mg/kg) will be noted daily (qualitative nominal and 
quantitative continuous, respectively), as well as total cumulative benzodiazepine 
dose received since ICU admission in lorazepam equivalents (mg/kg) (quantitative 
continuous), according to MAR.  
- 
Higher mean daily doses of benzodiazepines have been associated with an 
increased risk of IWS in ICU patients (7)  
- 
Withdrawal due to benzodiazepines may overlap with OIWS assessment (6, 24)  
- 
Administration of medication that may influence severity of OIWS (e.g. clonidine, 
dexmedetomidine, methadone, buprenorphine, propofol, beta-blockers and antipsychotics) 
(qualitative nominal - dichotomous) 
- 
Agent,  total daily dose will be noted daily according to MAR (qualitative nominal) 
- 
Clonidine, dexmedetomidine, methadone, buprenorphine and antipsychotics can 
be used to treat or attenuate symptoms of opioid withdrawal and therefore may 
confound OIWS assessment (4, 50) 
- 
Presence of chronic neurological conditions (e.g. dementia, Parkinson’s disease, essential 
tremor) (qualitative nominal - dichotomous) 
- 
According to past medical history in medical chart 
- 
Symptoms of dementia and Parkinson’s disease may confound OIWS assessment 
- 
Presence of delirium (qualitative nominal - dichotomous) 
- 
During ICU stay: according to the Confusion Assessment Method for the ICU (CAM-
ICU) as measured by investigators during evaluation and/or nursing staff, collected 
daily once opioid weaning is initiated and until transfer 
- 
After transfer to ward: according to the Confusion Assessment Method (CAM) 
measured once by investigators within 24-96 hours of transfer 
- 
Symptoms of delirium may overlap with OIWS assessment (10, 20, 51)  
- 
Presence of agitation due to a condition other than OIWS (qualitative nominal - dichotomous) 
(10)  
- 
During ICU stay: according to the Richmond Agitation-Sedation Scale (RASS) as 
measured by investigators and/or nursing staff, collected daily once opioid weaning 
is initiated (qualitative ordinal) and until transfer 
- 
After transfer to ward: according to the Agitated Behavior Scale (ABS), measured 
once by investigators within 24-96 hours of transfer (qualitative ordinal) 
- 
Presence of pain (qualitative nominal - dichotomous)  
- 
In patients unable to self-report: Critical-Care Pain Observation Tool (CPOT) score > 2, 
as measured by investigator or medical staff, collected daily once opioid weaning is 
initiated  
- 
In patients able to self-report: Numeric Rating Scale (NRS) ≥ 4, collected daily once 
opioid weaning is initiated 
- 
The symptoms of uncontrolled pain may confound OIWS assessment (20)  

 
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- 
Administration of co-analgesia during ICU hospitalization (e.g. acetaminophen, non-steroidal 
anti-inflammatory drugs, anticonvulsants, antidepressants, corticosteroids) (qualitative 
nominal) 
- 
Agent and total daily dose will be noted daily according to MAR 
- 
Co-analgesia is used to treat or attenuate pain, which may confound OIWS 
assessment 
- 
Anti-inflammatory drugs also act as antipyretics, which may confound OIWS 
assessment 
- 
Presence of nicotine replacement therapy during ICU admission (qualitative nominal - 
dichotomous)  
- 
Nicotine consumption in mg (qualitative continuous) prior to ICU admission (e.g. 
cigarettes, nicotine replacement therapy) and whether nicotine replacement 
therapy was prescribed in ICU will be noted according to medication reconciliation 
chart at admission (qualitative nominal) 
- 
Nicotine withdrawal or nicotine-induced delirium may confound OIWS assessment 
(45)  
- 
Factors which may confound specific signs and symptoms of OIWS (qualitative nominal - 
dichotomous) 
- 
Fever secondary to documented or suspected infection 
- 
According to diagnosis documented in medical chart 
- 
Diarrhea due to Clostridium difficile infection or enteral feeds 
- 
According to positive C. difficile antigen detection test in medical chart or 
presence of enteral feeds in patient flow sheet 
- 
Use of physical restraints (qualitative nominal - dichotomous) (52)  
- 
Collected daily according to medical chart 
- 
Patients with restraints are more likely to be given supplemental sedative and 
analgesic agents which may confound OIWS assessment 
 
4.4.2 Secondary outcome variables 
Both serum cortisol levels will only be measured in patients not receiving exogenous corticosteroids. 
 
Independent variables 
- 
Basal serum cortisol level (quantitative continuous) 
- 
Measured ± 2 hours from the start of opioid weaning  
- 
Weaning serum cortisol level (quantitative continuous) 
- 
Measured on the day of transfer to ward or after a maximum of 72 hours after start of 
weaning, at the same time of day as the first measure, whichever occurs first. 
- 
 Change in serum cortisol levels (quantitative continuous) 
- 
Difference between weaning and basal serum cortisol levels 
 
Confounding variables 
- 
Timing of sample in hh:mm (quantitative continuous) 
- 
Cortisol is secreted in a diurnal pattern (53)  
- 
Serum cortisol samples will be taken at the same time of day 
- 
Presence of primary adrenal insufficiency (qualitative nominal - dichotomous) 
- 
According to past medical history in medical chart 
- 
Patients with this condition may present with hypocortisolemia and receive 
exogenous corticosteroids, which may confound serum cortisol assays 
- 
Presence of acute illness (infection, trauma, surgery, illness) (qualitative nominal) 
- 
According to APACHE II score at ICU admission 
- 
Cortisol has been studied as a marker of severity of disease, with higher levels 
associated with worse prognosis. This association appears to be stronger during the 
first two days of admission (54)  
- 
May thus increase cortisol levels depending on severity of disease (53)  

 
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- 
May also provoke transient adrenal insufficiency (53)  
- 
Presence of septicemia or septic shock (qualitative nominal - dichotomous) 
- 
Diagnosis of sepsis will be noted according to medical chart 
- 
Sepsis causes relative adrenal insufficiency in up to 30 to 70% of patients, which may 
confound results (55-57)  
- 
Medications (ketoconazole, spironolactone, dopamine agonists, etc.) (qualitative nominal) 
- 
May reduce cortisol production (53) 
  
4.5 Data collection and study procedure (Appendix II) 
From February to October 2018, patients from the MGH and RVH critical care units will be screened 
daily from unit patient lists generated through Oasis for eligibility. The investigators will be transiting 
daily between both centers. Once a patient is approaching 72 hours of mechanical ventilation and 
regular opioid administration, subjects will be evaluated for inclusion and exclusion criteria 
according to medical chart, and data will be recorded in the “Patient Screen Log”. Once a patient 
fits our entry criteria, here are the steps for obtaining consent: 
 
1- A member of the treating team (ICU physician or patient nurse) will inform the patient about this 
research project. If the patient is deemed unfit to provide informed consent, the patient’s  decision 
maker will be approached.  
2- If patient/decision maker shows interest, a member of the research team, independent of the 
clinical care of the patient will meet with the patient/decision maker and explain the research and 
seek informed consent.  
3- If the intubated patient verbally agrees but is unable to sign the consent, then a witness will sign 
the consent and the discussion will be documented on the consent form. 
4- If the consent is obtained from a decision maker, then we will further seek direct patient consent 
as soon as patient is deemed apt to consent.  
In this case, we would ask the patient to sign a new consent form and a copy will be provided to the 
patient and the newly signed consent will be kept in our files. 
 
 Once recruitment is completed, the patient will be given a subject number and placed on the 
“Enrollment List”, which includes medical record numbers, admission dates, screen dates and 
enrollment dates. 
 
After enrollment, demographic, reason for admission, lifestyle and medical data will be collected 
retrospectively from the medical chart, the patient's family and the medical team, and will be noted 
in the “Enrollment and Outcomes Form”. The reasons for exclusion and the number of patients who 
refused consent will be collected. Temporarily excluded patients will be re-evaluated daily for 
possible inclusion into the study.  
 
Once the patient begins the targeted opioid weaning of ≥ 10%, investigators will perform evaluations 
daily between 10am and 2pm. These evaluations will consist of using pre-tested data collection 
sheets to record signs and symptoms of possible OIWS, opioid doses, administered medications, 
laboratory values and other clinical data such as the RASS, CPOT and CAM-ICU scores. Data 
collection will be based on subject observation and interview when possible, nurse assessments, 
medical charts and laboratory results. Serum cortisol levels will be measured on the first day of opioid 
weaning (± 2 hours from dose decrease) and on the day patient is transferred to the ward or 72 
hours from start of weaning whichever occurs first. 
 
Once a weaning episode is identified, the physician collaborator will be contacted to perform daily 
DSM-5 evaluations. DSM-5 evaluations will be placed in opaque envelopes and investigators will be 
blinded to the results throughout the study. Additionally, for each patient, at least one inter-rater 
DSM-5 evaluation between 2 physician collaborators will be performed in order to assess interrater 
reliability. The two evaluations will be done within 2 hours of each other to minimize time-related 
discrepancies. 

 
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If opioid weaning is unsuccessful and opioid dose is re-increased, the subject will continue to be 
observed, however daily evaluations will only resume at the next weaning episode. Daily follow-up 
ends on day of transfer to the ward. One additional data collection and DSM-5 evaluation will be 
performed on the same day within 24 to 96 hours following transfer. Follow up ends 14 days after 
initial opioid weaning if patient remains in the ICU or if patient dies.  
 
4.6 Measurement tools  
 
DSM-5 
(Appendix IV) 
- No validated diagnostic tools for OIWS currently exist in the adult ICU 
- DSM-5 is the gold standard for diagnosing opioid withdrawal in numerous settings  
- Although not validated in the ICU population, it remains the most appropriate OIWS 
diagnostic tool for the study (9, 58) 
APACHE II score 
(Appendix V) 
- Validated tool to predict the risk of mortality in ICU patients (47, 59)  
- Calculated by an archivist using data collected in the first 24h of ICU admission 
- In this study: to assess patient disease severity at enrollment 
Glasgow Coma 
Scale (GCS) 
(Appendix VI) 
- Validated in ICU and trauma patients to assess the severity of head trauma based on 
ocular, verbal and motor criteria (48)  
- GCS score ≤ 8: comatose patient with no evidence of eye or verbal response 
- GCS score 9-15: presence of eye and verbal response (60)  
- In this study: to assess the level of consciousness of trauma patients and to verify 
exclusion criteria at ICU admission 
Child-Turcotte-
Pugh score 
(Appendix VII) 
- Extensively studied in critically ill patients to assess liver function (61)  
- In the ICU, CTP scores at admission correlate with 12-month mortality (62)  
- In this study: to assess severity of hepatic dysfunction at ICU admission 
Confusion 
Assessment 
Method (CAM)  
(Appendix IX) 
- Validated tool to identify delirium in patients on general medicine hospital wards 
- Enables non-psychiatrist clinicians to quickly determine if delirium is present (63)  
- In this study: performed by the investigator within 24-96 hours of ICU transfer to ward  
CAM-ICU 
(Appendix VIII) 
- Validated tool to identify presence of delirium in a dichotomous manner in the ICU (64)  
- In this study: collected daily by investigators or according to nurse assessment 
Richmond 
Agitation 
Assessment 
Scale (RASS) 
(Appendix X) 
- To assess level of agitation and sedation, and to prevent under or over sedation in ICU 
- Scale ranges from -5 (unarousable sedation) to +4 (combative) 
- RASS score ≤ -3 indicates a deeply sedated state (65)  
- In this study: collected daily by investigator and according to nurse assessment 
- RASS + 1 defines restlessness and RASS ≥ 2 defines agitation 
Agitated 
Behaviour Scale 
(ABS) (Appendix 
XI) 
- Originally designed to assess agitation in patients with traumatic brain injury (66)  
- Validated in numerous settings, including long-term care facility (67)  
- ABS score ≥ 22: Agitation, ≤ 21: No agitation (68) 
- In this study: performed once by the investigator within 24-96h of ICU transfer 
Critical-Care 
Pain Observation 
Tool (CPOT) 
(Appendix XII) 
- To assess pain in critically ill mechanically ventilated patients based on facial 
expressions, body movements and muscle tension during nociceptive procedures 
- To qualify pain in patients unable to verbalize; in patients able to communicate, self-
reporting of pain remains the gold standard 
-  CPOT > 2: unacceptably high level of pain, ≤ 2: minimal to no pain (68)  
- In this study: measured daily by investigators and according to nurse assessment  
Numeric Rating 
- To assess pain intensity on a numerical scale, most commonly ranging from 0 to 10 

 
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Scale (NRS) 
(Appendix XIII) 
(NRS-11); only the scale extremities are detailed (69)  
- In this study: to assess pain during daily evaluations once patients can self-report. 
Investigators will ask patients to rate their pain on a scale from 0 (absence of pain) to 10 
(worst pain imaginable). An NRS ≥ 4 represents an unacceptable level of pain. 
 
5. Data analysis 
5.1 Statistical analysis 
5.1.1 Descriptive statistics 
Demographic and clinical characteristics of patients who developed OIWS will be compared to 
those who did not. Categorical variables will be presented as proportions. For continuous variables, 
means and standard deviations will be computed for normal distributions whereas medians 
(interquartile range) will be used for non-normal distributions. 
 
For the primary outcome, episodes will be compared between the withdrawal positive (W+) group 
and the withdrawal negative (W–) group. Every day on which the DSM-5 is positive is equivalent to 
an episode of withdrawal, whereas a negative DSM-5 counts as an episode in which no withdrawal 
was observed. Patients who are positive for at least one episode of withdrawal make up the W+ 
group, whereas those who did not have a single episode of withdrawal make up the W– group, thus 
eliminating crossover. If a single patient experiences multiple days of withdrawal, s/he will account 
for multiple episodes in the study. Signs and symptoms will be tallied per episode and compared 
between the two groups. The results will be presented as proportions (i.e. incidence of symptom per 
total episodes). In the event of a discordant inter-rater evaluation, only the positive result will be 
taken into account. 
 
For the secondary outcome, serum cortisol levels and changes in serum cortisol levels are continuous 
variables and therefore descriptive statistics will be used as stated above, depending on the 
distribution. 
 
5.1.2 Statistical inference 
To gauge for presence of evaluation bias, inter-rater agreement will be determined using Cohen’s 
kappa. This test measures the extent to which physicians concur when assessing for presence of 
OIWS using the DSM-5 criteria. A kappa of ≥ 0.61 is indicative of good inter-rater agreement (70).  
 
For secondary outcomes, baseline, weaning and change in cortisol levels will be compared 
between patients positive and negative for OIWS. A Student’s t-test or a Wilcoxon signed rank test 
will be used. The test will be determined based on distribution and sample size. 
 
5.2 Sample size 
Based on our experience with the WAAICUP studies, 88 patients were eligible to participate in the 
study in an 8-month period, of which around 50 consented (22). We thus aim to recruit 50 patients 
based on the feasibility of these previous studies. 
 
6. Advantages and limitations 
6.1 Advantages  
As stated previously, a prospective approach will limit missing data and enable assessment of 
potential confounders. The multicentric design enables study of different ICU populations, thereby 
increasing external validity and sample size. 
 
There is currently no validated tool for OIWS diagnosis in the adult ICU population. Use of the DSM-5 is 
adequate in this study since it standardizes physician evaluation and is considered a gold standard 
in numerous settings. Multiple other ICU-validated tools will be used throughout the study such as the 
RASS, CAM-ICU and CPOT. Validated tools will also be used after transfer to the ward. 
 

 
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Training will be provided to investigators in order to standardize assessment and reduce observer 
bias. Observer bias will also be minimized by the blinding of investigators to DSM-5 results. 
Additionally, DSM-5 inter-rater agreement will be assessed on one occasion for each patient. A 
notable advantage is the supplemental follow-up after transfer to ward, which increases internal 
validity by limiting loss of patients who might develop OIWS later once transferred out of the ICU. 
 
To our knowledge, no previous study has explored potential biomarkers that correlate with symptoms 
of OIWS. The exploratory use of serum cortisol in this study is thus a novel research avenue and will 
enable further characterization of OIWS. 
 
6.2 Limitations 
The study is susceptible to several limitations, most of them due to study design Due to lack of 
randomization, the study is subject to confounding. A notable covariate is the concomitant 
administration of benzodiazepines, which is difficult to control for since ICU patients frequently 
receive both opioids and benzodiazepines, and there is significant overlap in their respective 
withdrawal symptoms. However, administration of benzodiazepines will be noted during daily 
evaluations. The study is also susceptible to the “clinical trial effect” bias, since the attending 
physicians are not blinded to patient enrollment in the study and may modify their management 
consequently. To control for observer bias, pre-tested standardized data collection forms will be 
used, but it does not eliminate it completely, as evaluations will be performed by different 
investigators. 
 
Since the sample size was determined on the basis of feasibility rather than statistical power, no 
statistically significant associations can be made. Statistical analyses will thus be predominantly 
descriptive in nature. 
 
The exclusion of patients with severe or moderate traumatic brain injury requiring ICP monitoring and 
osmotherapy reduces external validity. These patients are important consumers of opioids and are 
therefore at risk of developing OIWS. However, their clinical condition would make the adequate 
assessment of OIWS impossible. 
 
7. Relevance of study 
To our knowledge, this is the first prospective study that aims to describe the clinical presentation of 
OIWS in the adult ICU setting with a standardized approach, fulfilling an identified research gap (71). 
As mentioned, OIWS is a clinical entity associated with negative outcomes that is poorly understood 
in critically ill adults because of diagnostic challenges. With a more accurate description of the 
clinical presentation, it would be possible to develop reliable screening tools to identify patients most 
at risk of OIWS and to sensitize the clinician to adopt appropriate measures in their management. An 
accurate description of the clinical presentation of OIWS is the first step in a series of research 
advances aimed at correctly recognizing and managing OIWS in adult ICU patients. 
 
8. Ethical considerations and patient consent 
The study protocol will be approved by the MUHC Research Ethics Board prior to enrollment. The 
study procedure does not require direct medical intervention as it is observational in design. The 
evaluation of signs and symptoms will mostly be done using ICU standard of care assessment tools 
(e.g. CAM-ICU, CPOT, RASS). Assessments that are not part of routine ICU care include collection of 
two blood samples per patient for serum cortisol measurement and DSM-5. Investigators will not 
interfere with usual care, which prevents patient exposure to additional risk 
 
Written and informed consent will be obtained prior to enrollment and a copy will be given to the 
patient. Consent forms will be available in English and French with detailed descriptions of the study 
procedure and interventions. If the patient is inapt, consent will be obtained from a legal 
representative (e.g. family member). Once the patient is apt, direct consent will be sought. If the 

 
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patient refuses consent, previously collected data will be destroyed. Patients or their legal 
representative may decide to withdraw from the study at any moment. 
 
Patient confidentiality will be maintained throughout the study by various means. All data will be de-
identified and coded. The code will be maintained  by the principle investigator. Computers and 
files will be password protected. Paper data will be kept in opaque envelopes in a locked cabinet 
to which only the investigators will have access. Study data will be kept for 7 years and the study 
itself will be registered on clinicaltrials.gov. 
 
 
 

 
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Warren A, Soulsby CR, Puxty A, Campbell J, Shaw M, Quasim T, et al. Long-term outcome of 
patients with liver cirrhosis admitted to a general intensive care unit. Ann Intensive Care. 
2017;7(1):37. 
63. 
Wei LA, Fearing MA, Sternberg EJ, Inouye SK. The Confusion Assessment Method: a systematic 
review of current usage. J Am Geriatr Soc. 2008;56(5):823-30. 
64. 
Gusmao-Flores D, Salluh JI, Chalhub RA, Quarantini LC. The confusion assessment method for 
the intensive care unit (CAM-ICU) and intensive care delirium screening checklist (ICDSC) for the 
diagnosis of delirium: a systematic review and meta-analysis of clinical studies. Crit Care. 
2012;16(4):R115. 
65. 
Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, et al. Monitoring sedation 
status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale 
(RASS). JAMA. 2003;289(22):2983-91. 
66. 
Corrigan JD. Development of a scale for assessment of agitation following traumatic brain 
injury. J Clin Exp Neuropsychol. 1989;11(2):261-77. 
67. 
Bogner JA, Corrigan JD, Stange M, Rabold D. Reliability of the Agitated Behavior Scale. J 
Head Trauma Rehabil. 1999;14(1):91-6. 
68. 
Buttes P, Keal G, Cronin SN, Stocks L, Stout C. Validation of the critical-care pain observation 
tool in adult critically ill patients. Dimens Crit Care Nurs. 2014;33(2):78-81. 
69. 
Hjermstad MJ, Fayers PM, Haugen DF, Caraceni A, Hanks GW, Loge JH, et al. Studies 
comparing Numerical Rating Scales, Verbal Rating Scales, and Visual Analogue Scales for 
assessment of pain intensity in adults: a systematic literature review. J Pain Symptom Manage. 
2011;41(6):1073-93. 
70. 
McHugh ML. Interrater reliability: the kappa statistic. Biochem Med (Zagreb). 2012;22(3):276-
82. 
71. 
Puntillo K, Gelinas C, Chanques G. Next steps in ICU pain research. Intensive Care Med. 
2017;43(9):1386-8. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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10. Time frame and budget 
 
Table 1. Time frame 
 
Month 
Activities 
October 2017 
- 
First draft of protocol 
November 3, 2017 
- 
Protocol presentation to the Faculty 
November 2017 
- 
Creation of data collection sheets 
- 
Final version of research protocol 
December 1, 2017 
- 
Research protocol submission to the Faculty 
January 2018 
- 
Research protocol submission to the MUHC Research Ethics 
Board 
- 
Pre-evaluation of the data collection sheets 
- 
SPSS database creation 
January 23, 2018 
- 
MUHC Research Ethics Board approval 
February to October 
2018 
- 
Data collection 
- 
Data entry 
- 
Statistical analysis 
- 
First draft of manuscript 
October 2018 
- 
Manuscript review 
November 2018 
- 
Manuscript submission 
December 7, 2018 
- 
Poster presentation at the Faculty (Rendez-vous de la 
recherche pharmaceutique) 
 
Table 2. Budget 
 
Description 
Type 
Total cost 
Biomarker measure 
Material 
$900.00 
Statistician ($75.00/h) 
Human resources 
$0.00 to $200.00 
SPSS software 
Equipment 
$0.00 
Paper/Poster 
Material 
$200.00 
Total 
  
$1,300.00 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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11. Appendices 
 
Appendix I. Research strategy in Medline 
 
Search 
Terms 
A1: Opioids 
exp Narcotics/ or Narcotics, Pharmacological Action/ or exp Opiate Alkaloids/ or 
exp Fentanyl/ or exp Meperidine/ or exp Morphine Derivatives/ or exp Methadone/ 
or narcoti*.mp. or opioid.mp. or opium.mp. or opiate.mp. or remifentanil.mp. or 
fentanyl.mp. or sufentanil.mp. or alfentanil.mp. or codeine.mp. or morphine.mp. or 
oxycodone.mp. or hydrocodone.mp. or hydromorphone.mp. or methadone.mp. or 
meperidine.mp. 
A2: Sedatives 
or analgesics 
"Hypnotics and Sedatives"/ OR "Hypnotics and Sedatives, Pharmacological Action"/ 
OR Narcotics, Pharmacological Action/ OR Conscious Sedation/ OR Deep 
Sedation/ OR exp Narcotics/ OR exp Opiate Alkaloids/ OR exp Fentanyl/ OR exp 
Meperidine/ OR exp Benzodiazepines/ OR exp Morphine Derivatives/ OR exp 
Methadone/ OR Clonazepam/ OR Bromazepam/ OR hypnotic.mp. OR 
sedative.mp. OR sedation.mp. OR narcoti*.mp. OR opioid.mp. OR opium.mp. OR 
opiate.mp. OR remifentanil.mp. OR fentanyl.mp. OR sufentanil.mp. OR 
alfentanil.mp. OR codeine.mp. OR morphine.mp. OR oxycodone.mp. OR 
hydrocodone.mp. OR hydromorphone.mp. OR methadone.mp. OR 
meperidine.mp. OR benzodiazepine.mp. OR diazepam.mp. OR lorazepam.mp. OR 
midazolam.mp. OR clonazepam.mp. OR alprazolam.mp. OR oxazepam.mp. OR 
temazepam.mp. OR bromazepam.mp. OR flurazepam.mp. OR 
chlordiazepoxide.mp. OR clobazam.mp. OR clorazepate.mp. OR nitrazepam.mp. 
OR triazolam.mp. 
B: Iatrogenic 
withdrawal 
Substance Withdrawal Syndrome/ OR Iatrogenic Disease/ OR Withholding 
treatment/ OR substance withdrawal.mp. OR drug withdrawal.mp. OR taper.mp. 
OR tapered.mp. OR tapering.mp. OR wean.mp. OR weaned.mp. OR weaning.mp. 
OR abstinence.mp. OR iatrogenic disease.mp. OR "withholding treatment".mp. OR 
"withholding treatment".mp. 
C: ICU 
exp Critical Care/ OR Subacute Care/ OR Postoperative Care/ OR exp Intensive 
Care Units/ OR Critical Illness/ OR intensive care.mp. OR critical care.mp. OR 
ICU.mp. OR PICU.mp. OR subacute.mp. OR postoperative.mp. OR post-
operative.mp. OR burn unit.mp. OR burn centre.mp. OR burn center.mp. OR 
coronary care.mp. OR respiratory care.mp. OR critical illness.mp. OR critically ill.mp. 
D: Tools 
Decision Trees/ OR algorithms/ OR Checklist/ OR Questionnaires/ OR scale.mp. OR 
scaling.mp. OR score.mp. OR scoring.mp. OR tool.mp. OR checklist.mp. OR check-
list.mp. OR questionnaire.mp. OR instrument.mp. OR WAT.mp. OR WAT-1.mp. OR 
withdrawal assessment tool.mp. OR decision tree.mp. OR algorithm.mp. OR 
sedation withdrawal score.mp. OR "opioid and benzodiazepine withdrawal 
score".mp. OR OBWS.mp. OR Sophia Observation Withdrawal.mp. 
E1: Signs and 
symptoms 
exp "Signs and Symptoms"/ OR exp Neurological Examination/ OR Symptom 
Assessment/ OR exp Vital Signs/ OR Facial Expression/ OR (symptom* OR anamne* 
OR dysphor* OR nause* OR vomit* OR muscle ach* OR lacrim* OR rhinorrhea OR 
pupil* dilat* OR piloerection OR sweat* OR diarrhea OR yawn* OR fever OR 
temperature OR insomnia OR shiver* OR sleep disturbance OR tremor OR anxiety 
OR agitat* OR suction* OR irritab* OR grimac* OR startl* OR muscle tone OR 

 
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((uncoordinat* OR repetitive) AND movement) OR sneez* OR tachypnea OR 
mydriasis OR deliri* OR seiz* OR convuls*).mp. 
E2: 
Biomarkers 
exp Biomarkers/ OR "Biomarkers, Pharmacological"/ OR Monitoring, Physiologic/ OR 
Drug Monitoring/ OR Neuromuscular Monitoring/ OR Neurophysiological Monitoring/ 
OR (stress hormone OR cortisol OR cortisone OR catecholamines OR ((bio OR 
biological OR lab OR laboratory OR serum OR plasma OR endpoint? OR end-
point?) ADJ (marker? OR surrogate?))).mp. 
Run #1 (F) 
A1 AND B AND C AND D AND E1 
Run #2 (G) 
(A1 AND B AND C AND D AND E2) NOT F 
Run #3 (H) 
(A2 AND B AND C AND D AND E1) NOT (F OR G) 
Run #4 (I) 
(A2 AND B AND C AND D AND E2) NOT (F OR G OR H) 
Run #5 (J) 
A1 AND B AND E2 (NOT F OR G OR H OR I) 
Run #6 (K) 
A2 AND B AND E2 (NOT F OR G OR H OR I OR J) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix II. Study procedure 
 
 

 
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Appendix III. Dependent variables: signs and symptoms of OIWS (4, 15, 19, 20, 24)  
 
Category 
Signs and 
symptoms 
Definition 
Type of variable 
 
 
 
 
 
 
 
Central nervous 
system 
symptoms 
Agitation 
 
 
During ICU hospitalization: 
Highest RASS score recorded 
in the previous 24ha 
according to nurse 
assessment b, c 
Qualitative ordinal 
RASS -5 to 0, 1 (restlessness) or 
≥ 2  (agitation) 
Qualitative ordinal 
After ICU transfer to another 
ward: Agitated Behavior Scale 
(ABS) score during evaluation 
≤ 21: No agitation; ≥ 22: 
agitation 
Qualitative ordinal 
Anxiety 
 
According to patient or nurse 
assessment in the previous 24h 
Qualitative nominal 
(dichotomous) 
Dysphoria 
According to physician DSM-5 
evaluation 
Qualitative nominal 
(dichotomous) 
Fever 
Highest temperature value 
(°C) according to nurse 
assessment in the previous 24h 
Quantitative continuous 
 
Temperature ≥ 38.3 degrees in 
the previous 24h 
Qualitative nominal 
(dichotomous) 
Hallucinations 
Patient seems to see, hear or 
feel things that are not there 
in the previous 24h, according 
to patient or nurse assessment 
Qualitative nominal 
(dichotomous) 
Insomnia/sleep 
disturbance 
Number of hours of 
sleep/night between 10PM 
and 6AM the night before 
evaluation according to nurse 
assessment 
Quantitative discrete 
Lack of sleep defined as less 
than 4 hours of continuous 
sleep between 10PM and 
6AM 
Qualitative nominal 
(dichotomous) 
Startle to 
stimulus 
Startle occurs when patient is 
stimulated verbally or by light 
touch during evaluation 
Qualitative nominal 
(dichotomous) 
Time to regain 
calm post-
stimulus 
Time (minutes) needed to 
regain calm post-stimulus 
Quantitative continuous 
Normal: < 2 min; Increased: 2 
to 5 min; High: > 5 min  
Qualitative ordinal 
Seizure 
 
Presence not explained by 
metabolic disturbances or 
history of seizures in the 
previous 24h according to 
medical chart  
Qualitative nominal 
(dichotomous) 
Tremor 
Presence of trembling, 
involuntary sustained rhythmic 
movements of hands and/or 
Qualitative nominal 
(dichotomous) 

 
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feet during evaluation or 
according to nurse 
assessment in the previous 24h 
 
Pupil size 
Size (mm) according to nurse 
assessment in the previous 24h 
Quantitative continuous 
≤ 2 mm, > 2 mm 
Quantitative discrete  
(dichotomous) 
Yawning 
 
Number of yawns in the 
previous 24h according to 
nurse assessment 
Quantitative continuous 
If ≥ 2 yawns observed during 
evaluation or in the previous 
24h according to nurse 
assessment 
Quantitative discrete 
(dichotomous) 
Cardiac 
symptoms 
Hypertension 
Highest Systolic blood pressure 
(mmHg) according to nurse 
assessment in the previous 24h 
Quantitative continuous 
Highest MAP (mmHg) 
according to nurse 
assessment in the previous 24h 
Quantitative continuous 
Tachycardia 
Highest HR in the previous 24h 
 
Quantitative continuous 
Lowest heart rate in previous 
24h 
Quantitative continuous 
Is patient on a beta-blocker ; 
Yes or No 
Qualitative nominal 
(dichotomous) 
 
Respiratory 
symptoms 
Frequent 
suction 
Number of times patient 
required endotracheal 
suctioning in the previous 24h 
according to nurse 
assessment 
Quantitative continuous 
Lacrimation 
Presence during evaluation or 
according to nurse 
assessment in the previous 24h 
Qualitative nominal 
Rhinorrhea 
Presence during evaluation or 
according to nurse 
assessment in the previous 24h 
Qualitative nominal 
(dichotomous) 
Sneezing 
Number of sneeze observed 
during evaluation or 
according to nurse 
assessment in the previous 24h 
Quantitative continuous 
If more than 1 sneeze 
observed during evaluation or 
according to nurse 
assessment in the previous 24h 
Qualitative nominal 
(dichotomous) 
Significant 
dyspnea 
Highest respiratory rate (RR) 
recorded in the previous 24h 
according to nurse 
assessment 
Quantitative continuous 
Lowest respiratory rate (RR) 
recorded in the previous 24h 
Quantitative continuous 
 

 
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according to nurse 
assessment 
Gastrointestinal 
symptoms 
Diarrhea 
Presence of ≥ 3 BMs 
(loose/watery stools), in past 
24 hours  according to nurse 
assessment 
Qualitative nominal 
(dichotomous) 
Number of BM in the previous 
24h  according to nurse 
assessment 
Quantitative continuous 
Rectal tube required (yes or 
no) 
Qualitative nominal 
(dichotomous) 
Feeding 
intolerance 
(gastric 
residuals) 
Present if nurse discontinued 
or decreased enteral feeding 
during previous 24h due to 
gastric residuals of more than 
500 mL according to nurse 
assessment 
Qualitative nominal 
(dichotomous) 
Nausea 
 
 
Presence during previous 24h 
according to patient, nurse 
assessment or use of 
antiemetic medications such 
as dimenhydrinate and 
ondansetron (indication to 
validate with nurse when 
necessary) 
Qualitative nominal 
(dichotomous) 
Vomiting 
 
Presence or absence of 
vomiting episode(s) or 
retching or gagging in the 
previous 24h according to 
nurse assessment 
Qualitative nominal 
(dichotomous) 
Dermatologic 
symptoms 
Mottling 
 
Presence of violaceous 
marbled discoloration of the 
skin during evaluation or 
according to nurse 
assessment in the previous 24h 
Qualitative nominal 
(dichotomous) 
Piloerection 
Presence during evaluation or 
according to nurse 
assessment in the previous 24h 
Qualitative nominal 
(dichotomous) 
Sweating 
Presence without apparent 
reason (not caused by room 
temperature) during 
evaluation or according to 
nurse assessment in the 
previous 24h 
Qualitative nominal 
(dichotomous) 
Musculoskeletal 
symptoms 
Bone, joint or 
muscle aches 
Presence during evaluation or 
according to nurse 
assessment in the previous 24h 
Qualitative nominal 
(dichotomous) 
Muscle cramps 
Presence during evaluation or 
according to nurse 
assessment in the previous 24h 
Qualitative nominal 
(dichotomous) 
Muscle tone 
 
Presence during evaluation or 
according to nurse 
assessment in the previous 24h 
Qualitative nominal 
(dichotomous) 

 
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a Previous 24h designate the interval between midnight of the previous day and midnight of the day 
on which evaluation of the signs and symptoms occurs. A fixed time frame was chosen to 
standardize collection of signs and symptoms.  
 
b Nurse assessment comprises written (i.e. notes in medical chart or patient flow sheet) and/or verbal 
communication. 
 
 c On the day of transfer, patients will be evaluated from midnight of the previous day until time of 
evaluation. Following transfer to ward, patients will be evaluated from midnight of the current day to 
time of evaluation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(e.g. clenching wrists and 
toes, hunched shoulders, 
abnormal tense position of 
head, arm or legs) 
Uncoordinated/ 
repetitive 
movement 
Presence of involuntary 
movements of arm and/or 
legs, muscle twitches, during 
evaluation or according to 
nurse assessment in the 
previous 24h 
Qualitative nominal 
(dichotomous) 

 
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Appendix IV. Diagnostic and Statistical Manual of Mental Diagnosis-V (DSM-5): “Opioid Withdrawal” 
criteria.  
 
Diagnostic criteria: 
A. Presence of either of the following;  
1. Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e., several 
weeks or longer).  
2. Administration of an opioid antagonist after a period of opioid use. 
 
B. Three (or more) of the following developing within minutes to several days after  
1. Dysphoric mood.  
2. Nausea or vomiting.  
3. Muscle aches.  
4. Lacrimation or rhinorrhea.  
5. Pupillary dilation, piloerection, or sweating.  
6. Yawning.  
7. Fever. 
8. Insomnia.  
 
C. The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, 
occupational, or other important areas of functioning.  
D. The signs or symptoms are not attributable to another medical condition and are not better 
explained by another mental disorder, including intoxication or withdrawal from another substance. 
 
Reference: Association AP. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. 
Washington, DC: American Psychiatric Publishing; 2013. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix V. Acute Physiology and Chronic Health Evaluation II (APACHE II) developed by Knaus et 
al. 
 
 
 
Reference: Knaus W, Draper E, Wagner D, Zimmerman J. APACHE II: a severity of disease 
classification system. Crit Care Med. 1985;13(10):818-29. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix VI. Glasgow Coma Scale (GCS) developed by Jennett et al. 
 
 
 
Reference: Jennett B. The Glasgow Coma Scale: History and current practice. Trauma. 2002;4(2):91-
103 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix VII. Child-Turcotte-Pugh score developed by Pugh et al. 
 
 
 
Reference: Pugh R, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. British Journal of Surgery. 1973 Aug 1;60(8):646-9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix VIII. Confusion Assessment Method in the Intensive Care Unit (CAM-ICU) developed by Ely 
et al. 
 
 
 
Reference: Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al. Delirium in mechanically 
ventilated patients: validity and reliability of the confusion assessment method for the intensive care 
unit (CAM-ICU). Jama. 2001;286(21):2703-10. 
 
 
 
 

 
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Appendix IX. Confusion Assessment Method (CAM) developed by Inouye et al. 
 
 
 
 
Reference: Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: The 
confusion assessment methoda new method for detection of delirium. Annals of internal medicine. 
1990 Dec 15;113(12):941-8 
 
 
 

 
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Appendix X. Richmond Agitation-Sedation Scale (RASS) developed by Sessler et al. 
 
 
 
Reference: Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, et al. The Richmond 
Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit 
Care Med. 2002;166(10):1338-44. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix XI. Agitated Behavior Scale (ABS) developed by Carrigan et al. 
 
 
 
Reference: Corrigan JD. Development of a scale for assessment of agitation following traumatic 
brain injury. Journal of Clinical and Experimental Neuropsychology. 1989 Mar 1;11(2):261-77. 
 
 
 
 

 
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Appendix XII. Critical-Care Pain Observation Tool (CPOT) developed by Gelinas et al. 
 
 
 
Indicator 
Score 
Checklist 
Facial expression  
Relaxed, neutral 
 
              0 
No muscle tension observable □   Eyes closed □ 
Tense  
 
 
              1 
Frowning/Brow lowering □ 
Orbit tightening/Wincing □ 
Levator contraction □  Mouth opening □ 
Eye opening □  Eye weeping/tears □ 
Eyebrow raising □  Blinking □ 
Grimacing 
 
              2 
Frowning/Brow lowering □  Eyes tightly closed □ 
Levator contraction □  Mouth opening □   
Biting endotracheal tube/Clenched teeth □  Flushing □ 
Body movements 
Absence of movements 
              0 
or normal position 
Does not move at all □ 
Normal position □ 
Protection 
 
 
1 Slow, cautious movements □  Limb flexion □  
Trying to reach pain site/tubes □ 
Touching pain site/Guarding □  Seeking attention □ 
Rubbing/Massaging pain site □ 
Shaking □  Withdrawing □ 
Decortication □  Decerebration □ 
Restlessness/Agitation 
              2 
Touching/Pulling tubes □ 
Fidgeting/Restlessness □  
Arching □  Pushing □ 
Striking at staff/Defensive grabbing □ 
Attempting to sit up □  Trying to climb out of bed □ 
Compliance with the 
ventilator (intubated 
patients) 
OR 
Tolerating ventilator or movement       0 
Alarms not activated, easy ventilation □ 
Coughing but tolerating 
             1 
Alarms activated, stop spontaneously □ 
Coughing □  Gag reflex □ 
Fighting ventilator  
            2 
Asynchrony □ Blocking ventilation □ 
Vocalization 
(extubated patients) 
Talking in normal tone  
or no sound 
 
             0 
No sound □  Normal tone □ 
Sighing, moaning                             1 
Sighing □  Moaning □  Verbal complaints of pain □ 
Crying out, sobbing 
             2 
Crying out □  Sobbing □ 
Muscle tension 
Relaxed  
 
             0 
No resistance to passive movements □ 
Evaluation by passive flexion and 
extension of upper limbs when 
patient is at rest or evaluation 
when patient is being turned 
Tense, rigid 
 
             1 
Resistance to passive movements □ 
Very tense or rigid  
             2 
Strong resistance to passive movements □   
Clenching fists □ 
TOTAL  
 
 
     ___ / 8 
 
Reference: Gelinas C, Fillion L, Puntillo K, Viens C, Fortier M. Validation of the critical-care pain 
observation tool in adult patients. Am J Crit Care. 2006;15(4):420-7. 

 
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Appendix XIII. Numeric Rating Scale (NRS) 
 
 
 
Reference: Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. 
Journal of clinical nursing. 2005 Aug 1;14(7):798-804.