Remifentanil use in intensive care units: Current evidence and future perspectives

Abstract

Pain management in intensive care units (ICUs) is crucial for improving patient outcomes. Remifentanil, an ultra‐short‐acting opioid, is metabolized independently of renal and hepatic function, making it an attractive analgesic. This article discusses the pharmacological effects of remifentanil, its usage, and potential side effects in the ICU, current evidence, and clinical situations where its use is preferred. Currently, patients for whom remifentanil use might be considered include (1) post‐cardiac surgery patients, (2) patients requiring frequent neurological assessments, (3) patients with hepatic or renal failure, and (4) patients with acute respiratory distress syndrome who are at high risk of self‐inflicted lung injury. In these patient groups, remifentanil's unique properties may contribute to effective pain management. However, data on its long‐term use in ICUs remains limited. To establish appropriate usage, further research is needed, particularly on withdrawal symptoms, opioid‐induced hyperalgesia, and optimal transition strategies following prolonged administration. Furthermore, cost‐effectiveness analyses are essential to assess its economic feasibility in ICU settings.

INTRODUCTION

Over 70% of patients admitted to the intensive care unit (ICU) report pain. ¹ Severe pain is associated with complications, prolonged ICU stay, and long‐term reduction in quality of life. ² Uncontrolled pain can lead to adverse physiological and psychological effects, such as increased heart rate, blood pressure, and oxygen consumption, as well as anxiety, depression, and sleep disturbances. ³ Moreover, inadequate pain control can result in chronic pain syndromes, post‐traumatic stress disorder, and post‐intensive care syndrome, which includes persistent physical, cognitive, and psychological impairments even after ICU discharge. ⁴ , ⁵

Standardized analgesia protocols based on pain assessment have been shown to improve outcomes in critically ill patients. The 2018 PADIS guidelines emphasized the importance of pain management and recommend an assessment‐driven, protocol‐based approach, highlighting the growing role of analgesia‐first sedation. ³

Fentanyl and morphine remain the primary opioids used in Japanese ICUs. ⁶ , ⁷ However, these opioids have limitations, such as accumulation in patients with organ dysfunction and accumulation effects that may hinder weaning from mechanical ventilation. ⁶ Contrastingly, remifentanil, an ultra‐short‐acting opioid, is metabolized independently of renal and hepatic function, making it an attractive option for critically ill patients. Remifentanil was initially approved in Japan in 2016 for analgesia during general anesthesia. ⁸ In 2022, it gained an approval for analgesia during mechanical ventilation in ICUs after a phase 3 trial demonstrated its non‐inferiority to fentanyl. ⁸

However, uncertainties remain regarding the long‐term use of remifentanil in the ICU. Prolonged administration may alter pharmacodynamics, leading to potential drug accumulation effects. Concerning acute tolerance, opioid‐induced hyperalgesia, and the ideal infusion rate also remain unresolved. Additionally, its higher cost compared to conventional opioids may limit widespread adoption. ⁹ , ¹⁰ Despite its widespread use in critically ill patients, the optimal strategy for its administration remains unclear.

This article discusses the pharmacological effects of remifentanil, its use and potential side effects in the ICU, current evidence, and clinical situations where its use might be considered, with the aim of providing insights into the potential benefits and challenges of using remifentanil in critically ill patients.

PHARMACOLOGICAL EFFECTS

Remifentanil is a potent, selective μ‐opioid receptor agonist with a unique ester structure that allows for rapid hydrolysis by nonspecific plasma and tissue esterases. ¹¹ This metabolic pathway is distinct from other opioids that primarily undergo hepatic metabolism and renal excretion. Consequently, remifentanil's pharmacokinetics are minimally affected by renal or hepatic dysfunction, making it particularly suitable for use in critically ill patients who often have organ impairment. ¹²

The primary metabolite of remifentanil is remifentanil acid (GI90291), which has negligible pharmacological activity (1/300 to 1/4600 the potency of remifentanil). ¹³ Remifentanil acid is mainly excreted by the kidneys, with >90% of the administered dose recovered in the urine within 24 h. ¹¹ The rapid metabolism and lack of active metabolites contribute to remifentanil's predictable and easily titratable effects. Compared to other opioids, remifentanil acts rapidly, with peak analgesic effects achieved within 1–3 min of intravenous administration ⁸ , ¹⁴ , ¹⁵ (Table 1). This is due to its short blood–brain equilibration half‐time (1.2–1.4 min), which allows for quick penetration into the central nervous system. ¹⁶ , ¹⁷ One of the most distinguishing features of remifentanil is its short context‐sensitive half‐time (3–4 min), which remains constant regardless of the duration of infusion. ¹⁸ Conversely, the context‐sensitive half‐times of other opioids increase with prolonged infusion, leading to accumulation and extended effects. The short duration of action allows for rapid titration and adjustment of analgesic levels, which is especially beneficial in the dynamic ICU environment where patients' pain control needs may change rapidly. Thus, the unique pharmacological properties of remifentanil, including its rapid metabolism independent of organ function, fast onset, short context‐sensitive half‐time, and wide therapeutic index, make it a versatile and attractive option for providing analgesia in the complex and dynamic ICU environment.

TABLE 1.

Pharmacologic actions of opioid analgesics.

Opioids (route)	Equianalgesic dose	Onset	Elimination half‐life	Intermittent dosing	IV infusion rate	Side effect
Remifentanil (IV)	80–100 μg	1–3 min	3–10 min	None	Bolus injection is prohibited in Japanese ICU Maintenance dose: 0.008–0.25 μg/kg/min	Available regardless of liver and kidney dysfunction
Fentanyl (IV)	100 μg	1–2 min	2–4 h	0.35–0.5 μg every 0.5–1 h	0.7–10 μg/kg/h	Accumulation in patients with kidney and liver dysfunction, release of histamine
Morphine (IV)	10 mg	5–10 min	3–4 h	2–4 mg every 1–2 h	2–30 mg/h	Accumulation in patients with liver dysfunction

USE AND POTENTIAL SIDE EFFECTS

In Japanese ICUs, remifentanil is indicated for analgesia during invasive mechanical ventilation in adults, with the option to continue administration from intraoperative use. Similarly, in Europe, remifentanil is approved for analgesia in mechanically ventilated ICU patients. In the United States, it is indicated for pain management in the postoperative care unit or ICU, where it can also be continued from intraoperative use. The approved administration method for adult ICU patients in Japan is to start a continuous intravenous infusion at 0.025 μg/kg/min, adjusting the rate as needed to achieve adequate analgesia while monitoring the patient's overall condition. In clinical trials, the maximum infusion rate was set at 0.5 μg/kg/min. ⁸ However, significant interindividual variability has been noted. In ICU practice, the infusion rates are considerably lower, with Doi et al. ⁸ reporting a dosage of 0.046 ± 0.036 μg/kg/min, and Aoki et al. ⁶ reporting an infusion rate of 0.038 ± 0.022 μg/kg/min.

Potential side effects ¹⁹ include (1) apnea, muscle rigidity, and laryngospasm; (2) circulatory deterioration (bradycardia and hypotension); and (3) withdrawal symptoms (opioid‐induced hyperalgesia [OIH]).

OIH is a concern with prolonged remifentanil use, as reported in both clinical and experimental studies. Long‐term administration may lead to paradoxical pain sensitization, requiring increased opioid doses to achieve the same analgesic effect. ²⁰ However, experience with long‐term remifentanil use in the ICU is limited, and sufficient knowledge regarding OIH in ICU settings remains lacking. In Europe, caution is advised for use exceeding 3 days, ²¹ but similar concerns exist globally regarding the potential for OIH with prolonged opioid use. Strategies like multimodal analgesia, gradual weaning, and opioid rotation have been suggested to mitigate these effects. ²⁰ , ²²

Clinicians should also be aware of delayed ventilatory depression that may occur if residual remifentanil in intravenous tubing is inadvertently flushed into the patient following discontinuation of the infusion.

EVIDENCE AND SIGNIFICANCE OF REMIFENTANIL USE

Several systematic reviews have evaluated the efficacy of remifentanil in mechanically ventilated patients, but findings remain inconsistent owing to significant heterogeneity. ⁹ , ²³ , ²⁴ Zhu et al. ⁹ suggested a potential reduction in mechanical ventilation duration but could not draw definitive conclusions due to high heterogeneity (I ² = 89%). Yang et al. ²³ focused on critically ill adults and reported a significant reduction (standardized mean difference: −0.23 h; 95% confidence interval [CI]: −0.41 to −0.06; p = 0.01; I ² = 50%); however, no studies have directly compared remifentanil with fentanyl. Lu et al. ²⁴ addressed this gap through a network meta‐analysis (3442 patients), concluding that remifentanil does not reduce mechanical ventilation duration compared to fentanyl (mean difference: −0.16 h; 95% credible interval −4.75 to 5.63). The studies included in previous systematic reviews were predominantly conducted in postoperative patients. In postoperative patients, including those undergoing cardiac surgery, remifentanil has been shown to improve outcomes such as intubation time, ²⁵ , ²⁶ , ²⁷ appropriate analgesia/sedation time, ²⁸ , ²⁹ and delirium. ³⁰

Overall, systematic reviews ⁹ , ²³ have suggested that remifentanil may reduce the duration of mechanical ventilation compared to other opioids. These findings should be interpreted with caution due to significant heterogeneity across included studies. This heterogeneity likely arises from multiple factors, including variations in dosing protocols, comparator opioids, outcome definitions, patient characteristics, and institutional practices. Moreover, most randomized controlled trials ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ have focused on postoperative patients, which limits the generalizability of the findings to the broader population. To clarify the clinical role of remifentanil, further high‐quality trials are needed. These studies should include more diverse ICU populations and employ standardized intervention protocols with adequate statistical power.

REMIFENTANIL COST

When assessing the cost of remifentanil in the ICU, both direct drug costs and potential cost savings from improved clinical outcomes must be considered. Remifentanil is generally more expensive than traditional sedatives and analgesics, such as fentanyl, raising concerns about its higher acquisition cost. For example, remifentanil for intravenous injection (Daiichi Sankyo) costs $13.95 per 5000 μg whereas fentanyl (Terumo) is $5.84 per 500 mcg. However, while remifentanil has a higher upfront cost, it may offset expenses through improved clinical outcomes and reduced resource utilization. Maiwenn et al. ³¹ suggested that remifentanil‐based analgo‐sedation (RS) may reduce mechanical ventilation duration, ICU length of stay, and overall hospital length of stay, potentially lowering healthcare costs. Their cost analysis in mechanically ventilated ICU patients found that RS ($16,234) was $1531 less expensive than conventional sedation (CS) ($17,766; 95% CI −2163 to 5110). The length of ICU stay was 7.6 days (RS) vs. 8.5 days (CS), and mechanical ventilation duration was 5.0 days (RS) vs. 6.0 days (CS), indicating a trend toward reduced ICU resource utilization.

Despite these potential benefits, research on the economic impact of remifentanil in the ICU remains limited, particularly in Japan, where cost‐effectiveness data are scarce. Given its higher drug acquisition cost, further real‐world studies, including claims database analyses and cost‐effectiveness evaluations, are needed to determine whether remifentanil's potential clinical advantages translate into meaningful cost savings in diverse ICU populations.

PATIENTS FOR WHOM REMIFENTANIL USE MIGHT BE CONSIDERED

The Spanish guidelines for sedation, analgesia, and delirium management in the ICU recommend remifentanil administration for reducing the duration of mechanical ventilation after cardiac surgery (strong recommendation, moderate level of evidence). ³² A survey in the United Kingdom found that remifentanil is considered a higher priority than fentanyl or morphine for patients requiring frequent neurological assessments and those with hepatic/renal failure. ³³

Remifentanil may represent a viable analgesic option in the management of acute respiratory distress syndrome (ARDS), particularly due to its potential to modulate respiratory effort through its respiratory depressant properties.  ³⁴ Nonetheless, the role of remifentanil in regulating respiratory drive remains a subject of ongoing debate, and its application in this context warrants careful consideration.

Accordingly, the use of remifentanil for the purpose of modulating respiratory drive should be approached with caution and limited to appropriately selected cases.

In patients with ARDS, discomfort may contribute to heightened respiratory effort, which in turn increases the risk of patient self‐induced lung injury (P‐SILI). ³⁵ In such scenarios, the respiratory depressant effects of remifentanil may mitigate the development of P‐SILI. Moreover, suppression of respiratory drive may enhance patient–ventilator synchrony, potentially reducing the need for deep sedation and neuromuscular blockade. ³⁶

Based on these potential benefits, remifentanil may have a role in selected ARDS patients; however, careful patient selection and continuous monitoring are essential to ensure safety and efficacy. Expert consensus highlights that opioid‐induced suppression of respiratory drive should be reserved for cases in which excessive drive is clearly attributable to pain or dyspnea. ³⁷ , ³⁸ This is because inappropriate suppression of respiratory effort in the absence of discomfort may lead to hypoventilation and delayed recognition of respiratory compromise. ³⁹ Moreover, remifentanil itself does not inherently suppress respiratory drive. ³⁷

Currently, patient groups for whom remifentanil use might be considered include: (1) post‐cardiac surgery patients, (2) patients requiring frequent neurological assessments, (3) patients with hepatic or renal failure, and (4) patients with ARDS with high respiratory drive due to pain and/or dyspnea.

CONCLUSION

Remifentanil is a newly available opioid in Japanese ICUs. Its properties suggest that it may improve outcomes in mechanically ventilated ICU patients, but careful attention to side effects is necessary.

FUNDING INFORMATION

The authors received no financial support for the research, authorship, and/or publication of this article.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interests.

ETHICS STATEMENT

Approval of the research protocol: N/A.

Informed consent: N/A.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.

Okano H, Okamoto H, Sakuraya M, Aoki Y. Remifentanil use in intensive care units: Current evidence and future perspectives. Acute Med Surg. 2025;12:e70087. 10.1002/ams2.70087

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.