Evaluation of Atypical Antipsychotics for the Facilitation of Weaning Sedation in Mechanically Ventilated Critically Ill Patients
Abstract
Introduction
Sedatives and analgesics are commonly utilized as continuous infusions in the ICU but have complications, including an increase in mechanical ventilation days, ICU length of stay, and delirium. Atypical antipsychotics (AAPs) affect several receptors including muscarinic, histamine, and α-1 adrenergic receptors, which may allow them to act as adjunctive agents to facilitate weaning of continuous infusions.
Objective
To determine if there is a decrease in sedatives/analgesics requirements with the use of quetiapine and olanzapine in mechanically ventilated critically ill patients.
Methods
A single-center, retrospective study conducted at Brigham and Women's Hospital from 1/1/2018 to 12/31/2019. Patients were included if they were mechanically ventilated for at least 48 hours before and following AAP initiation, were receiving at least one sedative/analgesic by continuous infusion and received AAP for at least 48 hours. The major endpoint was the percentage of patients with ≥20% reduction in the cumulative dose (CD) of midazolam, propofol, or opioids using morphine mg equivalent (MME), 48 hours from AAP initiation. Minor endpoints included median changes in CD at 24 and 48 hours, and Richmond Agitation–Sedation Scale (RASS), and Critical Care Pain Observation Tool (CPOT) changes at 48 hours.
Results
A total of 1177 encounters were screened and 107 were included. Within the 48 hours after AAP initiation, 77.6% had ≥20% reduction in the CD of a sedative/analgesic. There was a significant reduction in propofol, no change in MME, and significant increase in dexmedetomidine median CD at 48 hours from AAP start. No difference was found in pain scores, but patients had significantly lighter sedation scores in the 48 hours after AAP initiation. A multivariate analysis showed that earlier initiation of antipsychotics was associated with a higher likelihood of achieving a 20% reduction in a sedative/analgesic.
Conclusion
AAP use was associated with a significant reduction in sedatives/analgesics doses. Future studies are warranted to confirm the results.
Introduction
Sedatives and analgesics are commonly administered via continuous infusion in the intensive care units (ICU) to help reduce agitation, improve patient-ventilator synchrony, and reduce work of breathing.1 However, the use of sedatives has been associated with several complications such as prolonged duration of mechanical ventilation, delirium, coma, post-traumatic stress disorder, delusional memories, impaired cognitive function, prolonged hospitalization, increased costs, and mortality.2 The 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS) recommend various sedative dose minimization strategies to achieve light sedation, such as the use of sedative guidelines or protocols, titration to objective sedative goals, analgesia-first sedation, and the combination of daily spontaneous awakening trials and spontaneous breathing trials.3
The current PADIS guidelines suggest not using antipsychotics to prevent delirium and to not routinely administer antipsychotics to treat delirium in the ICU.3 In addition to having dopaminergic activity, atypical antipsychotics (AAPs) exhibit effects at muscarinic, histamine, and α-1 adrenergic receptors which may lead to sedative effects.4,5 Moreover, antipsychotics do not suppress the respiratory drive and may have an adjunctive role to assist with weaning of continuous infusion sedatives without causing tolerance or withdrawal.6–8 Previously published studies have observed a reduction in sedatives/analgesics dose with the use of antipsychotics. In the HOPE-ICU trial, the use of haloperidol was shown to possibly reduce the need for sedatives.9 In addition, Devlin et al showed a trend toward a reduction in sedatives days and a significant reduction in fentanyl days in patients who received quetiapine compared to placebo.6
The objective of this study was to determine if there is a decrease in sedatives/analgesics cumulative dose requirements with the use of quetiapine and/or olanzapine in mechanically ventilated, critically ill patients within 48 hours after initiation.
Materials and Methods
Design and Settings
This was a single-center, retrospective, observational study conducted at Brigham and Women's Hospital, an 826-bed tertiary academic medical center. The study was approved by the Mass General Brigham Institutional Review Board (IRB). Patient's informed consent was waived by the IRB because of the retrospective nature of the study and due to the study not including factors necessitating patient consent.
Patients were identified from the electronic medical record by identifying all adult patients who were ordered for quetiapine or olanzapine between January 2018 through December 2019 while admitted to the medical ICU, surgical ICU, burn/trauma ICU, coronary care ICU, or thoracic ICU.
Institutional Guideline
Our institutional guideline for the management of pain, agitation, and delirium in adult patients who are mechanically ventilated focuses on frequent assessment, dose minimization, and both symptom and patient-specific medication selection. Patients who are receiving intermittent or continuous analgesia or sedation are assessed for pain, using the Critical Care Pain Observation Tool (CPOT), and agitation, using the Richmond Agitation–Sedation Scale (RASS) every 2 hours, as well as delirium, using the Confusion Assessment Method for the ICU (CAM-ICU) every 8 hours. Best practices, such as analgosedation, spontaneous awakening and breathing trials, and titrating medications to patient-specific targets are emphasized. If continuous infusions are deemed necessary, fentanyl and hydromorphone are preferred for analgesia, while non-benzodiazepine medications (ie, propofol and dexmedetomidine) are preferred for sedation. Antipsychotics are recommended for consideration for the management of agitation associated with hyperactive delirium, as well as for adjunctive sedation, to minimize the dose of continuous infusions of sedatives.
Inclusion and Exclusion Criteria
Patients were included if they were mechanically ventilated for at least 48 hours prior to and post the first dose of AAP (quetiapine or olanzapine), on at least one continuous infusion sedative/analgesic (dexmedetomidine, fentanyl, hydromorphone, midazolam, morphine, or propofol), and received an AAP via a standing order for at least 48 hours while on mechanical ventilation. Quetiapine and olanzapine dosage regimens were considered to be sufficient if administered at least twice daily and once daily for a minimum of 48 hours, respectively.
Patients were excluded if they met any of the following criteria: had ≥20% total body surface area burns, intubated due to drug overdose or acute brain injury, had alcohol withdrawal as primary reason for ICU admission, required extracorporeal membrane oxygenation (ECMO) support, had tracheostomy prior to or within 48 hours of the first dose of AAP, received a dose of an AAP prior to being mechanically ventilated, prescribed antipsychotic medications in the outpatient setting, or were ordered for AAP as needed for sleep only. Acute brain injury was defined as any of the following conditions: severe traumatic brain injury, subarachnoid hemorrhage, ischemic or hemorrhagic stroke.
First dose was defined as first administered dose on a scheduled regimen. However, if this dose was preceded by a one-time order or an “as needed” order which was administered within two half-lives, then the preceding dose was considered to be the first dose. In this analysis, the half-lives of quetiapine and olanzapine were defined as 6 and 24 hours, respectively.
Data Collection
The following information was collected from patient medical records: age, sex, weight, body mass index (BMI), ICU service, ICU length of stay (LOS), hospital LOS, mechanical ventilation days, time from ICU admission and time from intubation to therapy initiation in days, ICU mortality, baseline tracheostomy (defined as tracheostomy prior to ICU admission), tracheostomy during the encounter, and use of continuous infusion neuromuscular blocking agent.
The rate of sedatives and opioids infusions, cumulative dose, RASS and CPOT scores were collected hourly 48 hours prior to and post first dose of AAPs. CAM-ICU scores were collected 48 hours prior to and post first dose of AAPs. Patients were considered to be delirious if any of the CAM-ICU scores recorded during this time were positive. Starting AAP dosage regimen and individual doses were collected for 48 hours.
Concomitant opioids and sedatives (clonidine, gabapentin, ketamine, haloperidol, lorazepam, and/or midazolam) cumulative doses were collected 48 hours prior to and post first dose of AAPs. Sequential Organ Failure Assessment (SOFA) score was calculated at time first dose of AAPs. Acute Physiology and Chronic Health Evaluation (APACHE II) score was collected at first day of ICU admission.
Measures
The major endpoint of this study is the percentage of patients with at least a 20% reduction in the cumulative dose of one or more continuous infusion sedative/analgesic (midazolam, propofol, and opioids in morphine mg equivalent [MME] of fentanyl and hydromorphone) within 48 hours from AAP initiation. For example, if the cumulative dose of MME was 150 mg prior to therapy initiation and 120 mg after, the cumulative dose percentage difference was calculated and considered to meet the major endpoint if there was 20% or more reduction after AAP initiation. The 20% threshold for reduction was used as it was deemed to be clinically significant by the investigators. Dexmedetomidine was considered an adjunct sedative and was not included in the major endpoint. Minor endpoints include median changes in rate, and cumulative dose at 24 and 48 hours. Various endpoints at the 48-hour mark, such as changes in the number of continuous infusion sedatives/analgesics, RASS, CPOT, concomitant opioids, concomitant sedatives, and incidence of delirium, were collected, in addition to outcomes such as the incidence of tracheostomy and ICU mortality.
Statistics
Continuous paired data were analyzed using paired t-tests (if parametric) or Wilcoxon signed-rank test (if non-parametric). Categorical paired data were analyzed using McNamar's Chi-squared test. A subgroup analysis of median changes in cumulative dose with and without dexmedetomidine exposure was used. To evaluate individual risk factors to the dependent variable of 20% reduction, a hybrid multivariate logistic regression analysis was used.
Univariable analysis was used and it include the following variable: age, male sex, BMI, mechanical ventilation days, time from intubation to therapy initiation in days, ICU mortality, tracheostomy during the encounter, APACHE II score, SOFA score, median cumulative quetiapine dose per day in mg, dexmedetomidine exposure (defined as new dexmedetomidine start within 48 hours post-therapy initiation), medical ICU, triglyceride level on day 1 of therapy, use of continuous neuromuscular blocking agent, and CAM-ICU positive within 48 hours of AAPs initiation. Multivariable logistic regression analysis was used and it included univariable with a P-value of <0.2 only.
Results
A total of 1177 encounters screened, of which 107 were included in our analysis (Figure 1). Baseline characteristics are shown in Table 1. ICU mortality occurred in 35 (32.7%) patients. A total of 103 (96.26%) patients were on quetiapine only, one (0.93%) patient was on olanzapine only and three (2.80%) were on both olanzapine and quetiapine. The median quetiapine starting dose was 25 mg and the most common frequency was every 8 hours. The median 24-hour cumulative dose of quetiapine was 100 mg, and the median 48-hour cumulative dose was 200 mg. Haloperidol was administered to 11 (10.28%) patients in the 48-hour prior to AAPs initiation and concomitantly in 10 (9.34%) patients with a median cumulative dose of 6 and 5 mg, respectively.
| Variable | N = 107 Median (IQR) |
|---|---|
| Age (years) | 63 (53-70) |
| Malea | 58 (54.20%) |
| Weight (kg) | 84.5 (67-105.40) |
| BMI (kg/m2) | 30.12 (24.74-35.34) |
| Medical ICUa | 68 (63.55%) |
| Surgical ICUa | 14 (13.08%) |
| Thoracic ICUa | 9 (8.41%) |
| Burn/trauma ICUa | 5 (4.67%) |
| Coronary care ICUa | 11 (10.28%) |
| Tracheostomy during admissiona | 37 (34.58%) |
| ICU daysb | 16 (12-24) |
| Hospital daysc | 26 (18-40) |
| Mechanical ventilation daysd | 12 (8-19) |
| Time from ICU admission to therapy initiation (days) | 5 (4-8) |
| Time from intubation to therapy initiation (days) | 5 (4-7) |
| SOFA score at therapy initiation | 9 (6-12) |
| APACHE II score | 30 (25-36) |
a
Number (%).
b
ICU days: calculated based on days in the ICU when an AAP was initiated.
c
Hospital days: calculated based on days admitted to the hospital in the encounter where an AAP was initiated.
d
Mechanical ventilation days: calculated based on days on an invasive mechanical ventilation when an AAP was initiated.
During the 48-hour treatment period, 83 patients (77.57%) had at least a 20% reduction in the continuous infusion cumulative dose of midazolam, propofol, and/or opioids. Sedatives/analgesics reduction by at least 20% was seen in 71.25% of patients receiving propofol, 45.26% receiving opiates and 64.71% receiving midazolam. At both 24 and 48 hours, there was a significant reduction in the cumulative dose of propofol. While there was no difference in the dose of dexmedetomidine 24 hours after the initiation of AAPs, there was a significant increase at 48 hours (Table 2). Hourly changes of dexmedetomidine, propofol, and opioid infusion rates are shown in Figure 2. Additionally, there was no significant reduction in the median number of sedatives/analgesics 48-hour after therapy initiation (P = 0.91). Multivariable analysis showed female sex and shorter time from intubation to AAP initiation to be significantly associated with at least a 20% reduction in the continuous infusion cumulative dose of midazolam, propofol, and/or opioids (Table 3).
| 24-Hour prior | 24-Hour post | Absolute Difference | P-Value | |
|---|---|---|---|---|
| Dexmedetomidine, mcg (n = 65) | 955.60 (266.40-1354.80) | 916.80 (431.20-1526.40) | 19.20 (−158.80 to 548.80) | 0.16 |
| Propofol, mg (n = 80) | 2845 (1448-5837.25) | 2006.50 (18.75-4406.50) | −824 (−2341.50 to 0) | < 0.01 |
| Fentanyl, mcg (n = 72) | 1465.50 (981-2640.25) | 1061.50 (325-2099.25) | −117 (−705.75 to 85.50) | < 0.01 |
| Hydromorphone, mg (n = 31) | 34.05 (21.08-65.58) | 32.25 (17-79.15) | 0.60 (−7.68 to 8.30) | 0.41 |
| MME, mg (n = 95) | 181.30 (116.70-326.60) | 156.50 (80.90-314.50) | −8.10 (−66.30 to 32.60) | 0.19 |
| Midazolam, mg (n = 17) | 20.60 (7-40.50) | 9.60 (0-53.50) | −1.20 (−9.50 to 5.10) | 0.68 |
| 48-Hour prior | 48-Hour post | |||
| Dexmedetomidine, mcg (n = 65) | 1316.40 (516-2078.40) | 1796.80 (659.20-2866.40) | 346.40 (−350.80 to 1138) | 0.02 |
| Propofol, mg (n = 80) | 6909.50 (3866.50-11737.30) | 3552 (817.25-7466.50) | −3008 (−6941.25 to −577.25) | < 0.01 |
| Fentanyl, mcg (n = 72) | 2777.5 (1713.75-4896.25) | 1859.50 (869.50-3409) | −635 (−1932.75 to 165.25) | < 0.01 |
| Hydromorphone, mg (n = 31) | 79.85 (34.23-115) | 69.15 (25.25-151.95) | −1.85 (−36.85 to 34.625) | 0.93 |
| MME, mg (n = 95) | 395 (233.10-628.40) | 281.30 (158.30-619.80) | −39.50 (−160.60 to 59.80) | 0.06 |
| Midazolam, mg (n = 17) | 38.60 (27.70-81.20) | 9.6 (0-124.10) | −12 (−38.60 to 10.30) | 0.49 |
Values are in median (IQR).
| Variable | With 20% Reduction (n = 83) | Without 20% Reduction (n = 24) | Odds Ratio (95% CI) | P-Value |
|---|---|---|---|---|
| Age (years) | 61 (52.5-70) | 67 (56-69.5) | 0.987 (0.95-1.02) | 0.45 |
| Male sexa | 41 (49.40%) | 17 (70.83%) | 0.402 (0.15-1.07) | 0.07 |
| BMI (kg/m2) | 30.9 (25.8-35.4) | 25.3 (21.7-32.2) | 1.066 (1.07-1.14) | 0.06 |
| Mechanical ventilation days | 11 (8-16.5) | 14 (11-22.5) | 0.973 (0.93-1.01) | 0.20 |
| Time from intubation to therapy initiation (days) | 5 (4-6) | 6.5 (4-8.3) | 0.858 (0.75-0.98) | 0.03 |
| ICU mortalitya | 25 (30.12%) | 11 (45.83%) | 0.509 (0.20-1.29) | 0.16 |
| Tracheostomy during the encountera | 27 (32.53%) | 10 (41.67%) | 0.675 (0.27-1.72) | 0.41 |
| APACHE II score | 31 (25.5-35) | 27 (24.8-36.5) | 0.999 (0.94-1.06) | 0.97 |
| SOFA score | 9 (7-12) | 8.5 (6-12) | 1.036 (0.92-1.17) | 0.58 |
| Cumulative quetiapine dose (mg)/day | 106.3 (75-175) | 100 (76.6-140.6) | 1.003 (1.00-1.01) | 0.40 |
| Dexmedetomidine exposurea | 22 (26.51%) | 2 (8.33%) | 3.967 (0.86-18.27) | 0.08 |
| Medical ICUa | 70 (84.33%) | 18 (75.00%) | 1.795 (0.60-5.38) | 0.30 |
| Triglyceride on day 1 of therapy | 250 (184-327.5) | 159.5 (102.3-327.3) | 1.000 (1.00-1.00) | 0.86 |
| Use of continuous neuromuscular blocking agenta | 19 (22.89%) | 3 (12.50%) | 2.078 (0.60-7.73) | 0.28 |
| CAM-ICU positivea | 69 (83.13%) | 18 (75.00%) | 1.643 (0.55-4.88) | 0.37 |
| Multivariable analysis | ||||
| Variable | Odds Ratio (95% CI) | P-Value | ||
| Mechanical ventilation days | 1.01 (0.96-1.07) | 0.70 | ||
| Dexmedetomidine exposure | 4.53 (0.88-23.25) | 0.07 | ||
| BMI | 1.06 (0.99-1.14) | 0.10 | ||
| Male sex | 0.32 (0.11-0.95) | 0.04 | ||
| Time from intubation to therapy initiation in days | 0.83 (0.70-0.99) | 0.04 | ||
| ICU mortality | 0.47 (0.17-1.32) | 0.15 | ||
a
Number (%), otherwise median (IQR).
During the 48-hour treatment period, 31 (28.97%) and 38 (35.51%) received concomitant opioids (not continuous infusion) as scheduled or as needed intravenously or orally before and after AAP initiation. The median concomitant opioids MME cumulative dose prior to therapy initiation was 10 mg (0-23.45) and 20.1 mg (2.5-55) after therapy initiation (P = 0.029). A total of 16 (14.95%) and 18 (16.82%) patients received concomitant benzodiazepines before and after AAP initiation. The median lorazepam equivalent cumulative dose was 2 mg (1-4.75) versus 1.25 mg (1-3.25), respectively. The number of patients on concomitant ketamine, clonidine, gabapentin before and after AAP initiation was 5 (4.67%) versus 3 (2.80%), 1 (0.93%) versus 1 (0.93%), and 10 (9.35%) versus 10 (9.35%), respectively.
Median RASS scores were significantly higher during the 48-hour pre-AAP initiation compared to post-AAP (−3 [−4 to −2] vs −2 [−3 to −1], P < 0.01). There was no statistically significant change in CPOT scores (0 [0-0] vs 0 [0-1], P = 0.14). Of note, due to documentations limits, RASS and CPOT scores were not always recorded, and the median RASS and CPOT scores were calculated based on the available scores. The number of patients who were CAM-ICU positive, negative, and unable to assess were 71 (66.35%), 5 (4.67%), and 30 (28.04%) versus 87 (81.31%), 1 (0.93%), and 19 (17.76%) prior to and post-AAP initiation (P < 0.01), respectively.
The impact of AAPs was compared in patients receiving dexmedetomidine to those who were not. This subgroup analysis showed a significant reduction in the median cumulative dose of propofol at 48-hour mark, both in patients who were receiving dexmedetomidine (5213 mg [2402-7426] vs 2556.5 mg [0-6198], P = 0.033) and those that were not receiving dexmedetomidine (7333 mg [4127-16605] vs 3773 mg [2336-11260], P = 0.001). No significant changes in MME or midazolam with or without dexmedetomidine exposure.
Discussion
To our knowledge, this is the first analysis to demonstrate a significant reduction in sedatives/analgesics requirements after AAP initiation. Almost all patients received quetiapine, with a median starting dose of 25 mg and a frequency of 8 hours. Few patients received olanzapine and the decision was made to not exclude them, as this is unlikely to alter the results of the study. Overall, we found over 75% of patients experienced a ≥20% reduction in the cumulative doses of continuously infused sedatives/analgesics (propofol, midazolam, and opioids). In patients who were on propofol and dexmedetomidine, there was a significant reduction in propofol at both 24 and 48 hours despite no significant change in dexmedetomidine dose at 24 hours. There was an increase in concomitant MME but no difference in pain scores, and patients had significantly lighter sedation scores at 48 hours. Interestingly, we found shorter time from intubation to AAP initiation to be significantly associated with an increased chance of sedatives/analgesics reduction. However, the optimal time to start AAPs is unknown and future studies are warranted to further investigate this relationship. Moreover, we found a significant increase in dexmedetomidine cumulative dose at 48-hour mark, which could have influenced the reduction in sedatives/analgesics cumulative doses as well.
Several studies have described the effect of AAPs on sedation requirements. Devlin et al conducted a randomized double-blind placebo-controlled trial to evaluate the efficacy and safety of quetiapine in critically ill patients with delirium.6 The study demonstrated a trend toward a reduction in sedatives days (1 [0-3] vs 4 days [1-9]; P = 0.09) and a significant reduction in fentanyl days (0 [0-3] vs 4 days [1-9]; P = 0.03) in patients who received quetiapine compared to placebo. Although the study objective was quetiapine efficacy and safety for the treatment of delirium in the ICU, it provided preliminary data on potential sedative use reduction with the use of quetiapine. Our study did not assess sedative days; however, we found a significant reduction in fentanyl cumulative dose but no change in MME cumulative dose at 24 and 48 hours.
Abraham et al did a prospective, open-label, single-center study in patients at high-risk for developing delirium. Patients were randomized to quetiapine 12.5 mg every 12 hours or no pharmacological prophylaxis.7 The study demonstrated a reduction in sedative use within the first 24-hour of ICU admission (3 [13.6%] vs 20 [40.8%], P = 0.024), reduction in propofol use (4 [18.2%] vs 17 [34.7%]) and trend toward lower mechanical ventilation days (14 [63.6%] vs 25 [51.0%], P = 0.32). Similarly, we found a significant reduction in propofol cumulative dose 24-hour after AAPs initiation, and we observed a sustained reduction at 48 hours.
Moreover, Ohman et al conducted a retrospective study to evaluate quetiapine as an adjunct sedative in mechanically ventilated medical ICU patients without delirium. The study demonstrated a significant increase in 48-hour dexmedetomidine requirements (P = 0.03), and an observed non-significant decrease in propofol and benzodiazepine requirements 48-hour after quetiapine initiation.8 In addition, there was no significant changes in RASS scores during the 24-hour after quetiapine initiation. In our analysis, we included patients regardless of their delirium status, and we also found a significant increase in dexmedetomidine cumulative dose at 48-hour. However, we found a significant reduction in propofol cumulative dose regardless of dexmedetomidine exposure and significant lighter sedation scores at 48 hours. One explanation for propofol cumulative dose being significantly reduced is the larger sample size we have in our study. Moreover, we found a higher number of patients who were delirium positive in the 48-hour post-therapy initiation, which could be explained by the lighter level of sedation.
Our study has several strengths, including a larger sample size compared to previously published studies, thorough exclusion criteria to limit confounding variables, and real-world evaluation of all continuously infused sedatives and analgesics used in our ICUs. However, our study also has several limitations. It was a single-center, retrospective, and non-comparative observational study. Due to lack of comparative group, other factors that could influence sedatives/analgesics requirements in the ICU were not evaluated (eg, progression of ICU care, time in the ICU, sedatives/analgesics accumulative overtime, and desired goal of sedation). Future randomized clinical trials would be an ideal design to control for the previously mentioned confounding factors and to determine whether AAPs have an impact on sedatives/analgesics dose requirements. Sedatives/analgesics alteration, which could have an influence on cumulative dose requirements, was not assessed. For example, the increase in dexmedetomidine use in the 48-hour after therapy initiation could have an influence on weaning off other sedatives/analgesics. However, we did a subgroup analysis with and without dexmedetomidine and the results were consistent with significant reduction in propofol dose requirements only. Selection and titration of sedatives/analgesics was not standardized but reflected clinical practice, and patients who were extubated during the 48 hours were excluded which limited assessing if adding quetiapine would facilitate extubation. The use of continuous neuromuscular blocking agents was not excluded which could have an influence in sedatives/analgesics cumulative dose reduction. Finally, although AAP safety was not evaluated in this analysis, a previous study that was done at our institution showed QTc prolongation to be relatively uncommon with quetiapine use but the use of concomitant medications known to prolong QTc may increase the risk for QTc prolongation.10
Conclusions
AAP use was associated with a significant reduction in sedatives/analgesics cumulative doses at 24 and 48 hours. Shorter time from intubation to AAP initiation appears to be associated with significant reductions in sedatives/analgesics cumulative doses. Future studies are warranted to confirm the results of this study.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD
Maha S. Assadoon https://orcid.org/0000-0003-1765-9306
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Article first published online: July 10, 2023
Issue published: January 2024
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PubMed: 37431208
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All authors contributed equally to this work.
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