Author Affiliations
Abstract
The management of pain and opioid dependence in the intensive care unit (ICU) presents unique challenges, necessitating alternative strategies beyond traditional opioids. Methadone and buprenorphine have emerged as promising options due to their distinct pharmacological profiles. This comprehensive review examines the pharmacology, efficacy, safety profile, and practical considerations of methadone and buprenorphine use in the ICU. Both agents provide analgesia and manage opioid dependence, with favorable safety profiles when used judiciously. However, careful dosing and monitoring are essential, particularly regarding methadone’s QT prolongation risk and buprenorphine’s hepatic metabolism. This review addresses the role of methadone and buprenorphine in ICU patients.
Keywords
Intensive care unit, Critical care, Pain management, Methadone, Buprenorphine, Opioid withdrawal.
Introduction
The introduction of Medications for opioid use disorder (MOUD) in the hospital requires some important considerations. These include dosing and route of initiation, monitoring symptoms, pain control, use of adjunctive supportive medications for withdrawal symptoms, and transition to outpatient therapy.[1] Often, patients in the intensive care unit (ICU) are challenging compared to outpatients for management of opioid use disorder (OUD) due to multiorgan dysfunction, hemodynamic instability, respiratory instability, drug-drug interactions, delirium, constipation, and the inability of ICU patients to communicate pain due to mechanical ventilation, ICU sedation and symptoms of withdrawal. If pain is not adequately managed post-surgery, it can lead to adverse cardiovascular and respiratory outcomes as well as the development of chronic pain syndrome.[2] OUD survey scales, like the clinical opiate withdrawal scale, are not possible in the ICU setting.[1] Medications commonly used for OUD in the ICU include Buprenorphine, Methadone, Buprenorphine/Naloxone, and naltrexone.[3] Challenges after MOUD initiation in the ICU setting include the outpatient establishment of treatment programs for the continuation of treatment and strategies to reduce the return to opioid use after discharge. Due to the increasing incidence of opioid use, clinicians encounter more OUD patients in the ICU. It is, therefore, necessary for ICU physicians to understand the score of buprenorphine and methadone in the ICU and the management of patients admitted with OUD.
In a study by Casamento et al. on opioid-naïve patients who were mechanically ventilated and received fentanyl or morphine for sedation in the ANALGESIC trial, one in seven patients received opioid medications at hospital discharge.[4] Patients with surgical reasons for admission or chronic comorbidities were at a higher risk of being prescribed opioids. Three patients for every 100 ICU discharge opioid prescriptions continued to use opioids for 6 months and 1 year following discharge. Several studies present similar rates of opioid use after ICU discharge, ranging from 15 -76%, and persistent use, ranging from 2.6 – 19%. Often, surgical ICU units and longer hospital stays were risk factors for persistent opioid use on discharge.[5-9] With the rising opioid epidemic, it is necessary to find alternative medications for pain control in the ICU. Further medications such as fentanyl, morphine, and oxycodone that are used in the ICU rapidly induce tolerance. These medications can cause hyperalgesia and chronic pain syndrome due to increased sensitivity to pain.
Hsiang Ma et al., in their systematic review and meta-analysis of randomized controlled trials, found that systemic non-steroidal anti-inflammatory drugs reduced 24-hour opioid consumption and reduced pain scores.[10] Therefore, it is imperative to find alternative medications for pain control in the ICU to decrease long-term opioid use, further in a large database analysis on cardiopulmonary resuscitation or arrest (CPRA). Patients on opioids and sedatives had a 3.47 odds ratio for CPRA. Fifty-four percent of these patients were in the intensive care unit. This further necessitates finding alternatives for opioid-sparing pain medications and sedatives in the ICU.[11] Resources for the management of opioid use disorders in the ICU are limited, and ICU teams often lack information on the sedation needs of patients with OUD, knowledge of the continuation of medications such as methadone in the ICU, and guidelines to manage opioid withdrawal.[12]
Methadone: Pharmacology and dosing
Methadone is a synthetic opioid medication that is used primarily in the treatment of opioid dependence. It also has numerous roles in being an effective analgesic agent.[13] Methadone is a long-active opioid with a single chiral center that forms an R enantiomer (lev-methadone) and S enantiomer (Dextro-methadone). R-Methadone is a mu-opioid receptor agonist that mimics the body’s natural endogenous opioids, endorphins, and enkephalins. Methadone is also a weak antagonist at the N-methyl-D-aspartate (NMDA) receptor, which potentiates opioid analgesia and decreases hyperalgesia, opioid tolerance, and chronic pain.[14] Methadone can elevate mood in a percentage of patients by inhibiting the reuptake of serotonin and norepinephrine in the brain.[15,16]
Changes in the metabolism and elimination of methadone are dependent on the induction or inhibition of CYP2B6 and CYP3A4 in the liver. Therefore, medications used in the ICU that affect the metabolism of methadone may need additional dose alteration and monitoring. Methadone is metabolized exclusively by the liver and partially in the small intestine. It has 80% bioavailability when given orally.
Methadone has a biphasic pattern of slow elimination, an α- α-elimination lasting phase 8-12 hours and β- β-elimination phase lasting 30–60 hours.[17] The α-elimination defines the duration of analgesia, and during β-elimination, the methadone levels are sub-analgesic and prevent the development of withdrawal symptoms. Therefore, for analgesic effects, the dosing is 3-4 times/day, whereas for methadone maintenance treatment, it is once a day.[18]
Dosing is dependent on multiple permutations of a patient’s history. In patients requiring methadone for opioid use disorder and patients who are naïve to opioid treatment, the dose should not exceed 7.5 mg of oral methadone daily for pain.[17] It can be started at 2.5mg orally every 8-12 hours and increased every 5-7 days. In patients on opioid doses < 40-60 mg, median cumulative intraoperative opioid consumption morphine milligram equivalent (MME)/day, methadone dose can be started similarly to opioid-naive patients. In patients on higher doses, conversion from morphine to methadone should be done based on the patients’ total MME/day.[19] Patients who have been opioid tolerant prior to admission should receive dosages no greater than 30-40mg per day to prevent withdrawal symptoms if there is no plan for giving an outpatient methadone prescription.[17]
Pain relief with methadone is rapid in onset and starts within 30 minutes and peaks in 2-4 hours after ingestion. Methadone does not require dose alterations in critically ill patients and is not removed by hemodialysis. There is a lack of published data on its safety in patients with acute liver failure; therefore, cautious use is recommended. In patients admitted to the ICU previously on methadone and who cannot take oral formulations, the common conversion is 1:1.3 from parenteral to enteral route based on a scoping review of available literature by Liu et al. or 1 1.2.[20] Clinicians can often start with a conservative dose of 1:1 and increase if required. IV dosing of methadone for surgery and analgesia is given at 0.2 mg/kg or a fixed dose of 20 mg.[21] The elimination half-life can be between 24-36 hours. The effects of methadone can be reversed with naloxone. Monitoring patients while on methadone for respiratory depression, opioid withdrawal symptoms, sedation, and lethargy is needed. NSAIDs and short-acting agents such as morphine can be used for breakthrough pain.[19]
Buprenorphine: Pharmacology and dosing
Buprenorphine is an effective treatment for OUD. It binds to the mu-opioid receptor and produces typical opioid effects. Due to its high-affinity partial agonist effects, buprenorphine can achieve a maximal effect compared to a full mu-opioid receptor agonist.[22] The high affinity for the mu-opioid receptor makes it extremely difficult to displace from its site, which explains its ability to block the subjective and physiologic effects of other opioids.[22]
Sublingual buprenorphine has a half-life of 37 hours. It is metabolized by the CYP3A4 in the liver. For acute pain, IV buprenorphine is initially started at a 0.3mg dose every 6 to 8 hours as needed. Patients who are naïve to receiving the transdermal patch are started with a 5mcg/hour dose applied once every 7 days.[23] In patients who are withdrawing from opioids in the hospital, they are given an intravenous (IV) buprenorphine starting at 0.3mg up to 0.9mg over 20 to 30 minutes every 6 to 12 hours.[24] Buprenorphine dose may require reduction in patients with impaired hepatic function. It is not affected by renal dysfunction. Buprenorphine can also be combined with naloxone, a pure opioid antagonist, to prevent adulteration. Table 1 shows the characteristics of methadone and Buprenorphine.
| Buprenorphine | Methadone |
| Partial agonist at mu receptors | Full agonist at mu receptors |
| Metabolized by the Cytochrome P450 3A4 (CYP3A4) in the liver | Metabolized in liver by Cytochrome P450 2B6 (CYP2B6) and CYP3A4 |
| The onset of action in 15 minutes and peak action in 1 hour, mean elimination half-life of 2.2 hours for an intravenous dose | The onset of action in 30 minutes and peak in 2-4 hours, with a half-life of 24-36 hours or longer |
| Intravenous dose of 0.3 mg up to 0.9 mg over 20 to 30 minutes every 6 to 12 hours as needed | A dose of 2.5 mg daily twice or thrice daily and increased every 5-7 days. Dosing for opioid use disorder based on median cumulative intraoperative opioid consumption (MME)/day |
| Effects reversed with naloxone |
Table 1: Characteristics of methadone and buprenorphine in the ICU
Clinical application of methadone in the ICU
Methadone can be used in the critically ill population for transitioning from IV fentanyl to enteral opioid medications, perioperatively to decrease post-operative opioid consumption, for treatment of true morphine allergy, for treatment of cancer pain, for patients with renal failure, and for dialysis. Azimi et al., in their retrospective study on ICU patients who were mechanically ventilated and on continuous IV fentanyl infusion or hydromorphone for ≥72 hours, found that usage of enteral methadone resulted in faster intravenous opioid weaning compared to using enteral oxycodone.[25]. Srinivasan et al. conducted a study of 42 children who were mechanically ventilated on sedation and analgesia for >5 days.[26] The authors were able to convert using a methadone-to-fentanyl ratio of approximately 2.5:1 over a period of 48 hours. This was associated with fewer withdrawal symptoms and the need for rescue opioids. In a randomized controlled trial on mechanically ventilated ICU patients on fentanyl for >5 days, the authors compared methadone to placebo administration for weaning time and duration of mechanical ventilation. The use of methadone was associated with a shorter weaning time and successful weaning by day five after study inclusion.[27]
Klaire et al. describe rapid methadone up-titration for opioid use disorder in the ICU with a mean dose of 65 mg on day seven.[28] One percent of ninety-eight patients had sedation requiring additional monitoring. Methadone was well tolerated by the patients. Najafi et al. compared fentanyl vs methadone for opioid withdrawal symptoms in ICU patients.[29] Administration of methadone was associated with the alleviation of withdrawal signs and symptoms within 30 minutes compared to 120 minutes with fentanyl. Both drugs were comparable for treating opioid withdrawal symptoms in the ICU.
Wang et al. conducted a retrospective study of a single dose of IV methadone perioperatively for the reduction of postoperative opioid requirements.[29] In his study of 117 patients, the median cumulative intraoperative opioid consumption (MME) was lower by 44% on postoperative day zero in the methadone group. However, the MME did not differ on day one due to the waning effects of methadone. The overall pain scores and respiratory support requirements did not differ between the two groups. In a Randomized controlled trial by Murphy et al. on 156 cardiac surgical patients who received IV methadone (0.3 mg/kg) vs fentanyl (12 μg/kg) intraoperatively.[30] The authors showed a reduction in pain scores for 72 hours post-surgery and morphine requirements compared to patients who received IV fentanyl. Further use of intraoperative methadone also makes weaning opioids after coronary artery bypass grafting (CABG) surgery easier.[31] The addition of methadone to high-dose opioid treatment can improve pain control. However, it was associated with a risk of sedation and delirium.[32] Bastian et al. describe a single dose of methadone administered perioperatively along with anesthesia to reduce postoperative opioid consumption.[33] The median cumulative morphine consumption was lower in the post-anesthesia care unit (PACU) and for up to 72 hours after surgery. Fentanyl consumption during the surgery did not differ between the two groups.
Clinical application of buprenorphine in the ICU
Research is currently being conducted on the various applications of buprenorphine in pain management in critically ill patients in the ICU. Buprenorphine has been shown to have equivocal efficacy compared to enteral/oral oxycodone. Due to its availability in sublingual formulation, this medication is an appropriate option for ICU patients who cannot take oral/enteral medications. Furthermore, in more critically ill patients, patients who are hypotensive or hypovolemic, adequate pain control was achieved without causing alterations in hemodynamics when using buprenorphine.[34] Buprenorphine can be used in the ICU in patients with a prior history of OUD on buprenorphine outpatient. Clinical Opiate Withdrawal Scale (COWS) can be used to monitor conscious patients with opioid withdrawal, and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria can be used for patients with impaired consciousness.
In addition, patients who have OUD benefited from having low-dose buprenorphine induction as it led to reduced usage of full agonist opioids in critically ill patients.[35,36] Patients admitted to the critical care unit with prior opioid use benefit from continuing the same opioid dose during hospital admission to prevent withdrawal. Additionally, patients in acute pain need additional pain medication requirements from their baseline of MOUD.
In a retrospective study on critically ill patients with opioid use disorder, patients on buprenorphine prior to hospital admission, continuation of the buprenorphine dose was associated with a decreased use of full opioid agonists.[37] Patanwala et al. conducted a propensity-matched study of 288 ICU patients.[38] He compared sublingual buprenorphine to oral/enteral oxycodone for pain control in patients on full opioid agonists. The authors found no difference in pain control and opioid consumption between the two medications. It is, therefore, an appropriate medication in the ICU for pain control in patients unable to take oral/enteral full opioid agonist medications. Machado et al. performed a systematic review of transdermal buprenorphine (TDB) for acute post-operative pain.[39] The review comprised 615 patients and had studies that initiated buprenorphine within 48 hours of surgery and continued use up to 28 days after the procedure. The authors found a decrease in postoperative pain scores, pain medication consumption, and patient satisfaction. The studies evaluated, however, had a high risk of bias. Some conflicting evidence exists in the literature on transdermal buprenorphine use in the ICU. Patanwala et al. state that the use of TDB in post-surgical ICU patients did not improve pain scores or pain control.[40] The mean opioid consumption did not differ between the TDB and control groups. These findings necessitate randomized controlled trials to compare the benefits of Buprenorphine in pain control in the ICU.
Hamata et al. describe a case report on buprenorphine/naloxone initiation in an intubated patient with a history of OUD and opioid withdrawal using a rapid micro-induction technique.[41] The authors report no signs of precipitated withdrawal.
In a study by Feeney et al. on patients with approximately 100,000 opioid use disorder patients in the ICU, 19% of patients received medication for opioid use disorder, of which 14.4 % received buprenorphine and 20.6% received buprenorphine/naloxone.[42] Vanini et al. described buprenorphine induction for patients admitted to the ICU with a history of OUD.[35] Sixty percent underwent standard buprenorphine induction (2 mg dose after an 8–12-hour washout period) compared to 40% who received low-dose induction (5-d titration from 150 μg to 4 mg four times daily). Buprenorphine induction in the ICU for OUD was associated with a low risk of precipitating withdrawal. Use of buprenorphine was also associated with a reduction in morphine use calculated by Median morphine milligram equivalents (MMEs) from 1057 to 262 mg cumulatively in 24 hours after initiation.
Adverse effects
According to some studies, Methadone is associated with cardiotoxic effects, especially with higher doses, according to some studies. Effects included arrhythmias, QT prolongation (>200mg/day), and torsade de pointes.[43] Therefore, regularly monitoring QT levels for patients with baseline duration >450 ms in the prior 3 months while on methadone. Close monitoring is required if patients are on additional medications that can prolong the QT interval, including antimicrobials, Antiemetics, antiarrhythmics, or hypokalemia and hypomagnesemia. It is contraindicated if the QT interval is >500 ms.[19]
Intraoperative methadone is often used to provide post-operative analgesia. Some studies report respiratory depression following intraoperative methadone administration.[44] Whereas many studies report no adverse effect of methadone on respiratory parameters, including hypoxemia, hypoventilation, and extubation time.[30,45,46] Respiratory depression requires reversal with naloxone. There was no difference in the use of naloxone to reverse respiratory depression between methadone vs. morphine (0.62% vs. 0.56%) in a study by Carle et al.[47] The use of methadone was associated with a longer post-anesthesia care unit length of stay of 334 vs. 195 minutes with morphine. Therefore, methadone and morphine have a comparable safety profile for respiratory depression. Methadone can alter serotonin reuptake at high doses and has drug-drug interactions with fentanyl, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and antiemetics used in the ICU.
Buprenorphine can be given as a monthly/ weekly prescription to outpatients, whereas methadone requires daily visits to methadone clinics. QT interval prolongation is more frequent with methadone and often at lower doses than with Buprenorphine. After a dose of >40 mcg/hr. Supratherapeutic dose QT interval prolongation was seen with buprenorphine in some studies. Buprenorphine has less respiratory depression than methadone due to its ceiling effect.
Cicozzi et al. describe the use of high-dose buprenorphine for pain in terminally ill patients with liver failure and kidney failure.[48] Buprenorphine can be used with mild to moderate opioid dependence, whereas methadone can be used with mild to severe dependence. Cross-taper from methadone to buprenorphine may be necessary due to the adverse effects of methadone. This can lead to precipitated withdrawal when partial agonist buprenorphine replaces the full agonist methadone at receptors. The withdrawal is often prolonged and requires close monitoring.[49,50]
Challenges and considerations for implementation, future directions, and research
ICU teams should have access to pain physicians and addiction teams. Outpatient resources for patients with opioid use disorder, including naloxone, should be dispensed/given a prescription on discharge. Continuing medical education activity on pain and addiction medicine can help current ICU teams manage patients with OUD, use buprenorphine and methadone in the ICU, and prevent overdose with naloxone.[12] Further studies are needed to determine the dose, frequency, and duration of therapy for the conversion of IV opioids to enteral methadone based on patient profiles, pharmacokinetics, and comorbidities.
Standardized scales for monitoring opioid withdrawal, particularly in ICU patients, need to be enforced. Diagnostic and statistical manual of mental disorders – fifth edition (DSM-V) is the only appropriate scale for mechanically ventilated patients apart from the clinical opiate withdrawal scale (COWS) for awake patients. For patients requiring mechanical ventilation or those unable to communicate symptoms, instruments such as the critical care pain observation tool and the behavioral pain scale should be considered to assess pain.
Studies to determine the beneficial effects of methadone or buprenorphine on quality and duration of recovery post-surgery, hospital length of stay, outcomes after discharge, and development of chronic postsurgical pain are needed.[21] A multidisciplinary team approach with interaction between ICU physicians, nurses, addiction, pain control specialists, and anesthesiologists can help to approach MOUD in ICU patients with greater success.
Core Tip: Management of opioid use disorder (OUD) in ICU patients is challenging due to multiorgan dysfunction, comorbidities, and complex medication interactions. Effective use of methadone and buprenorphine is essential for pain control and OUD treatment. Studies indicate the benefits of these medications for transitioning from IV to oral opioids, managing withdrawal, and reducing postoperative pain. Knowledge from this manuscript can help ICU physicians understand the scope of Methadone and Buprenorphine in the ICU.
Conclusion
Buprenorphine and Methadone have scope for use in the ICU in pain control and opioid use disorder. Utilization may improve patient outcomes and reduce the rising burden of opioid use.
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Acknowledgments
Not reported
Funding
Not reported
Author Information
Corresponding Author:
Praveen Reddy Elmati
Department of Anesthesiology
Saint Clare’s Hospital, Dover, NJ, USA, 07081
Email: praveen.elmati@gmail.com
Co-Authors:
Gowthami Sai Kogilathota Jagirdhar
Department of Gastroenterology
Saint Michaels Medical Center Newark, NJ, USA, 07104
Teja Nagaradona
Department of Medicine
St. Georges University School of Medicine, West Indies, Grenada, 11739
Suresh Srinivasan
Department of Pain Medicine
Trinity Health System, Steubenville, OH, USA
Authors Contributions
Elmati PR designed the overall concept and outline of the manuscript; Elmati PR, Kogilathota Jagirdhar GS, Nagaradona T performed the research and analyzed the data; Elmati PR, Kogilathota Jagirdhar GS, Nagaradona T, and Srinivasan S contributed to the manuscript’s writing and editing; All authors have read and approved the final manuscript.
Ethical Approval
Not applicable
Conflict of Interest Statement
The authors have nothing to disclose.
Guarantor
None
DOI
Cite this Article
Praveen RE, Gowthami SKJ, Teja N, Suresh S. Methadone and Buprenorphine Use in the Intensive Care Unit: A Mini Review. medtigo J Anesth Pain Med. 2025;1(1):e3067116. doi:10.63096/medtigo3067116 Crossref
