Liver transplant (LTx) is the most effective treatment for patients with end-stage liver disease.¹ Recovery from such a major procedure is multifaceted; however, meeting postoperative pain control milestones contributes to a shorter hospital stay and accelerates recipient physical and psychological recovery.² Conversely, poorly managed acute pain is a strong predictor of longterm disability and poor quality of life.³,⁴ Although it is well documented⁵,⁶ that LTx recipients have a decreased analgesic requirement, postoperative pain control is still important. The surgical incision for LTx surgery, specifically the subcostal component and the use of surgical retractors for a prolonged period of time, contributes to the severity of postoperative pain.⁷ Pain is further exacerbated related to location of the incision, which gets aggravated with normal activities of recovery, tidal breathing, and even minimal movement, usually necessitating a high analgesia requirement.⁸

Multimodal analgesia is a concept involving regional and systemic analgesia, in the form of opioid and non-opioid medication.⁹ It expands the prospects of analgesia to manage pain, decrease neuro-hormonal stress response to surgery, decrease metabolic demand on the newly transplanted liver and facilitate early mobilization and early weaning from mechanical ventilation.⁵ Fast tracking anesthesia for early extubation of LTx patients is an emerging concept which mandates optimal perioperative pain management.¹⁰,¹¹ Spontaneously breathing patients have reduced pleural pressure during inspiration, improving venous return and graft perfusion.¹² Thus, to meet the goal of earlier extubation, postoperative pain must be adequately controlled while preserving respiratory drive. As such, the significant role of multimodal analgesia is emphasized in all Enhanced Recovery After Surgery (ERAS) guidelines, especially the intra-abdominal surgeries.¹³ However, there are limited data regarding ERAS or other pain management protocols in LTx recipients.¹⁴ Therefore, we aim to provide an overview of the novel nonopioid per oral regimens and regional analgesia modalities for post-LTx analgesia.

It is imperative to understand that the pharmacokinetic characteristics of any drug may be altered by the distorted concentrations of plasma proteins, hepatic blood flow, and biliary flow after LTx. Moreover, graft size, graft regeneration, and elevated levels of pro-inflammatory cytokine may be other important factors that alter the metabolic capacity of the transplanted liver.¹⁵ Postoperatively, LTx patients may also have reduced renal function due to intraoperative fluid shifts, suboptimal renal perfusion during the anhepatic phase, or nephrotoxic calcineurin inhibitor immunosuppression therapy.¹⁶

Systemic analgesic therapy involves the combination of different analgesic agents that target various pain nociceptive pathways, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, gabapentinoids, and opioids.

Opioids have long been the mainstay of intraoperative analgesia in LTx. Postoperative pain has been attributed to many factors including the large surgical incision, extended pressure on the lower ribs from the surgical retractors, intraoperative hemorrhage, higher distribution clearance due to the hyperdynamic circulation of end-stage liver disease, and the enhanced metabolism of the new functioning graft.⁷ One of the most commonly used opioids is fentanyl whose metabolism may not be impaired in the presence of poor graft recovery.¹⁷ However, significant reduction in the graft blood flow can interfere with its metabolism that may necessitate dosing adjustment to avoid prolonged sedation, especially if infused throughout the lengthy surgery.² Another important element to consider is many patients’ history of alcohol or IV drug abuse, which precipitated their presentation for transplantation.⁵ Patients with substance abuse disorders may require additional monitoring and regimented control over opioid dispensing.¹⁸

Due to the growing aversion from administering opioids, clinicians have increasingly looked to employ alternative pain medications.⁹ Although acetaminophen is metabolized by the liver, producing a hepatotoxic metabolite, its clinical use up to 3 g/day for 7 days in patients with chronic liver disease was found to be safe and showed no evidence of toxicity in recent studies.¹⁹ However, regular monitoring of liver function tests for early diagnosis of graft worsening is highly recommended due to the high variability of the toxic dose and possibility of smaller doses having an increased risk of causing toxicity as well.²⁰ Gabapentinoids, such as pregabalin and gabapentin, are becoming increasingly popular components of ERAS protocols.⁹ Three recent retrospective studies concluded that a regimen of acetaminophen and gabapentin was associated with decreased opioid consumption, providing evidence for a non-opioid-centered strategy for post-LTx analgesia.¹⁴,²¹,²² Although no official recommendations include gabapentinoids in LTx pain regimens, recent evidence is supportive.¹⁴,²¹,²²

NSAIDs provide reliable postoperative pain control in many surgical populations but may not be the safest analgesic modality in LTx patients. NSAIDs have been implicated in hepatocellular damage in addition to other unfavorable effects such as temporary antiplatelet activity and inhibition of prostaglandin synthesis in the gastric mucosa.²³ Moreover, LTx patients have increased risk of renal dysfunction as a result of hemodynamic impairment, dehydration, immunosuppression, and NSAIDs administration.²³

Fast tracking anesthesia for early extubation of LTx patients is an emerging concept, which mandates optimal perioperative pain management to carefully balance analgesia and respiratory function. This concept was first introduced to LTx in 2002 by Findlay et al. at the Mayo Clinic in a consecutive series of 80 patients where they demonstrated a 60% reduction in intraoperative analgesia with fentanyl (decreased to 23 µg/kg from 50 µg/kg, P <.001) and in total mechanical ventilation time (553 minutes vs 1081 minutes, P <.001).¹⁰ A more recent review by Aniskevich and Pai in 2015 reported that 60% of their LTx recipients were extubated in the operating room and able to bypass the ICU completely.¹¹

Regional analgesia encompasses various techniques including neuraxial analgesia, paraspinal and abdominal wall blocks, and incisional field local anesthetic infiltration. These procedures involve the administration of local anesthetics and/or lower concentration opioids, compared to systemic administration, near the site of nerves carrying afferent pain signals.

There is a growing body of literature demonstrating the safe use of regional analgesia in improving perioperative pain and decreasing the use of systemic analgesia in postsurgical patients.²⁴

The metabolic pathways of local anesthetics in the anhepatic phase and in patients with deranged liver function were not well understood until recently. One of the most commonly used local anesthetics, lidocaine, is metabolized by CYP1A2 and CYP3A4, and its hepatic extraction ratio is 65%, which is much higher than that of ropivacaine (40%), a longer-acting local anesthetic.²⁵ As a result of the low hepatic extraction ratio of ropivacaine, its total clearance is less related to changes in the hepatic blood flow and depends mostly on hepatic enzyme activity and plasma protein binding.²⁵ Although the available data on the metabolism of bupivacaine is scant, it is structurally related to ropivacaine with a hepatic extraction ratio of 38%.²⁵ The current data show that end-stage liver disease has a roughly similar impact on both bupivacaine and ropivacaine clearance.²⁵