Nalbuphine in Critical Care and Emergency Medicine

Author: Aslanidis Theodoros

MD, PhD, Anesthesiology/ Critical Care-Prehospital emergency medicine
Anesthesiology Department, Saint Paul (“AgiosPavlos”) General Hospital, Thessaloniki, Greece

*Correspondance: Doridos str 4, PC 54633, Thessaloniki, Greece, e-mail: , Tel.: +306972477166.

ABSTRACT

Nalbuphine is a synthetic mixed agonist -antagonist opioid that has long been used for perioperative care. Yet, its use in critical and emergency medicine settings was still relatively low till recently. The current article provides an update of literature regarding nalbuphine in those two specific areas.

 

INTRODUCTION

Nalbuphine, 17-(cyclobutylmethyl)-4,5-α-epo-ximorphinan-3,6α,14-triol hydrochloride,(3. 1. 85)is a synthetic narcotic analgesic structurally like oxymorphone and naloxone. Though patented in 1963, it is not until 1978 that it appears in the medical literature¹. Currently it is a world-wide used analgesic in perioperative setting. The current narrative review focuses on nalbuphine use in critical care and emergency medicine settings.

Pharmacology

Nalbuphine belongs chemically to phenanthrenes class (the other 3 opioid groups are benzomorphans, phenylpiperidines and diphenylheptanes), which are considered prototypical opioids and include morphine, codeine, hydromorphone, levorphanol, oxycodone, hydrocodone, oxymorphone, buprenorphine, nalbuphine, and butorphanol^1-2.

Regarding its action, it is a mixed opioid agonist -antagonist group (pentazocine, buprenorphine, butorphanol); it acts as a moderate-efficacy partial agonist or antagonist of the μ-opioid receptor (MOR. K_i =0.89 nM) and as a high-efficacy partial agonist of the κ-opioid receptor (KOR, K_i=2.2 nM), whereas it has relatively low affinity for the δ-opioid receptor (DOR K_i=240 nM) and σ (sigma) receptors (Ki >100 000 nM)². When administered intravenously (bioavailability 81-83%), its onset of action starts in 2-3 min, it reaches maximum concentration in 15-30 min, the effect last for 4-6 h; with a t_1/2 of 5h^2-3. It metobilisesprimarly in liver, via CYP3A4 (hydroxylation) of cytochrome P-450, and glucuronidation via phase II enzyme uridinyldiphosphateglucuronosyltransferases (UTGs), in gut and liver^3-4.

On a mg-to-mg basis nalbuphine is considered almost equivalent to morphine (0.8-1:1) and up to a dose of 30mg; maximum single dose is 20 mg; maximum daily dose is 160 mg. When used in balanced anesthesia induction schedules with nalbuphine with range from 0.3-5 mg/kg iv over 10-15 minutes and then (maintenance) 0.25-0.5 mg/kg prn for adults and 0.1-0.2 mg/kg iv q3-4hr prn for children >1year old^4-5. When used in regional anesthesia, 0.2-0.5mg/kg is administered in single doses. Some studies attempted to determine median effective dose (ED₅₀, 5.4 mg for men and 7.4 mg for women) and other related brain accumulation and risk for respiratory depression with lipidemic status; yet both conclusions need further confirmation^6-7. A recent population pharmacokinetics study in patients undergoing general anesthesia supports fixed dosage regimen over body weight dosage regimen⁸.

Just as any other pure MOR agonist, nalbuphine can cause several side effects that may attenuate with time (“tolerance”). Headache, vertigo, nausea, vomiting, bitter taste and xerostomia, are some of the most frequent, while nervousness, depression, pupillary miosis, restlessness, crying, euphoria, flushing, dysphoria or numbness, hypotention, bradycardia, speech difficulty, urinary urgency, blurred vision, flushing and warmth are rarer.⁴

Intravenous naloxone is the specific antidote, in case of overdose or adverse reaction.

Caution is needed in patients with renal and hepatic impairments, while increased respiratory depression risk exists in those with decrease respiratory reserve. Nalbuphine may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. It is contraindicated in known or suspected gastrointestinal obstruction, including paralytic ileus.Placental transfer of nalbuphine is high, rapid, and variable with a maternal to fetal ratio ranging from 1:0.37 to 1:6. Thus, it should be used during labor and delivery only if clearly indicated and only if the potential benefit outweighs the risk to the infant^4-9. Finally, despite the lack of any published report¹⁰, high vigilance is needed in case of concominant use of nalbuphine and drugs that affect the serotonergic neurotransmitter system (selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, agents that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors).

Despite these limitations, nalbuphine has been used in numerous combinations with other analgesics. Early reports have used postoperative patient-controlled intravenous analgesia (PCIA) with nalbuphine 60mg and fentanyl 600μg in 100 ml (settings: infusion rate: 2 ml/hr, bolus dose:2 ml and lockout interval:15 min) with good results¹¹. PCIA with nalbuphine 60-100 mg alone or Nalbuphine 0.3 mg/kg and 0.1mg/kg remifentanil in was used with good results in cases post subtotal or radical gastrectomy^12-13. Nalbuphine 20 mg 10 minutes before the infusion of oxytocin combined with sufentanil 2 µg/kg could be safely used for postoperative analgesia in patients undergoing a second cesarean section and could effectively inhibit uterine contractions induced by oxytocin and reduce adverse reactions^14-15. Good analgesic results were achieved also after cesarean section using PCIA with 0.11 μg/kg/h dexmedetomidine in combination with 0.03 mg/kg/h nalbuphine¹⁶ or a combination of hydromorphone 0.05 mg/mL and nalbuphine 0.7 mg/ml¹⁷. Preemtpive analgesia with nalbuphine 20mg was used also to attenuate remifentanil-induced hyperalgesia in laparoscopic cholecystectomy¹⁸. In fracture surgeries, nalbuphine 2mg/kg PCIA not only provided a good sufentanil alternative, but it also reduced the level of circulating inflammatory cytokines¹⁹. The latter effect has been further confirmed in both clinical and experimental studies^20-21. Recently, a low dose of nalbuphine co-administration with morphine led to the delayed emergence of morphine tolerance in animals with bone cancer²².

Findings from use in critical care settings

Despite the plethora of reports regarding perioperative analgesia, data about nalbuphine application in intensive care units are limited.

In paediatric and neonatal patients, nalbuphine has been used alone or in combination with paracetamol for pain management as a good fentanyl alternative, especially in postsurgical phase^23-24.Nalbuphine administration, at a dose of 0.1 mg/kg, improved urine output in a cohort of children who met criteria for opioid-associated oliguria (defined as urine output below 1 mL/kg/hr and received at least one dose of opioid therapy within the preceding 12 hr)²⁵. A large study from 30 neonatal ICUs reported a slightly different dosing average regiment with 0.13mg/kg iv as loading dose (yet rarely chosen), 0.05 mg/kg iv as initial dose and then 0.06 mg/kg/h civ as maintenance dose when nalbuphine was prescribed as continuous infusion (mean treatment duration 2.6 days with  mean cumulative dose 2.7mg/kg), or 0.2mg/kg iv or ir q6h  when prescribed as single doses or intermittent administration²⁶. A recent meta-analysis concludes that doses of 0.1 mg/kg ivnalbuphine decreased emergence delirium and postoperative pains scores in children^27. When compared with sufentanil in adult patients, average doses of 0.03 mg/kg/hprovided a equivalent and stable level of analgesic effect, yet with less hemodynamic effects²⁸. Another stratified analysis study showed that average infusion doses of 0.165 ± 0.057 mg/kgnalbuphinepresented a better analgesic and sedative effects than sufentanil in ICU patients less than 60 years of age. Yet, sufentanil analgesic effect was better for those over 60 years of age²⁹.The latter difference is still a topic of research:findings about the receptor levels and the efficiency of signal transduction after receptor binding in the elderly are controversial, yet studies have shown that the number and binding levels of κ-opioid and μ-opioid receptors in elderly rats are greatly reduced³⁰. Nalbpuphine has also been tested against fentanyl for improving gastrointestinal function in postoperative critical patients, yet with inconsistent results³¹. Earlier studies of its use in cases of delirium in adult ICUs provide limited data that need further confirmation³².Anti-inflammatory effect of nalbuphine have been also gave promising results in sepsis expertimental animal studies, where administration in continuous infusion seem to improve animal welfare^33-34. More data are also expected regarding the 90% effective dose for mechanical ventilated ICU patients, and analgesia and safety determination of nalbuphine (dosing: 0.1mg/kg loading and, then maintenance 0.04-0.08mg/kg/h civ), in patients with acute respiratory distress syndrome after surgery in ICU, and to explore its effects on respiratory function, gastrointestinal function and cognitive function^35-36.

Findings from Emergency medicine applications

Nabluphine has been used in various emergency medicine setttings. Early studies report the use of nalbuphiune 15-20 mg prehospital in a variety of conditions with good results^37-38. The safety and efficiency of prehospitalnalbuphine as monotherapy or in combination with other analgesics was further confirmed in recent paramedicine studies^39-41. Other studies identified nalbuphine as an alternative for prehospital control pain in myocardial infarction, using a relatively high dosing regimen (50mg in 2 divided doses of 30mg and 20 mg) ^42-43. Intranasal administration (about 0.1 mg/kg) provided effective pain relief in case of prehospital traumas both in tactical and civilian setting, in adult and pediatric popullation^44-45. Especially in burns victims, nalbuphine provided very good results in children^46-47. Finally, nalbuphine has been used in emergency intubation in children both as analgesia and as prevention measure (in doses of 0.2mg/kg iv) against etomidate included myoclonus^48-49.

Interestingly, despite the theoretical difficulty of opiod action after nalbuphine, there is only one, relatively old, paper that reports excessive morphine requirements after prehospitalnalbuphine administration⁵⁰.

Another aspect of nalbuphine’s use is its role as an adjunct to regional anesthesia in emergency departments. Its value has long been acknowledged in various neuraxial and regional anesthetic techniques. Nalbuphine has been compared to other commonly used spinal adjuvants like morphine and fentanyl for obstetric, orthopedic, urologic and abdominal surgeries. Various studies of intrathecalnalbuphine have used doses ranging from 0.4 to 2.4 mg and most have shown peak analgesic effects with minimal side effects at doses from 0.8 to 1.6 mg⁵². Thus, the ceiling effect might be seen at doses of 1.6 mg or lesser, and the dose should be kept within this range.The same is true about the use of epidural nalbuphine (10mg) in obstetric and orthopedic surgeries^53-54.

Its use in peripheral nerve blocks has also been studied in several procedures⁵⁵.The increasing trend of peripheral nerve blocks in emergency departments^56-58 is also a field of possible nalbuphine application.

CONCLUSION

Despite its long history, nalbuphine gained interest again in the last decade, probably because of the opioid crisis. Even now, its use in critical and emergency care settings seems relatively low in comparison with other analgesics. However, the global available knowledge is steadily rising; thus, the future will clarify nalbuphine possible roles in intensive care and emergency medicine.

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Additional materials: No

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Acknowledgements:

Not applicable

Authors’ contributions: AT: manuscript preparation, primary case-management, literature review. The author read and approved the final manuscript.

Funding: Not applicable

Availability of supporting data:Not applicable.

Consent for publication: Not applicable.

Ethical approval and consent to participate:

No IRB approval required.

Competing interests: The authordeclares no competing interests.

Received: October 2024, October 2024, Published: December 2024.

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Citation: AslanidisTheodoros. Nalbuphine in Critical Care and Emergency Medicine.Greek e j Perioper Med. 2024;23(d):3-13.

 

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