Morphine prophylaxis alleviates pain in transjugular intrahepatic portosystemic shunt procedure: A randomized clinical trial

1. Introduction

Transjugular intrahepatic portosystemic shunt (TIPS) is an accepted minimal invasive procedure for the management of complications of portal hypertension, specifically for patients with bleeding secondary to variceal or uncontrolled ascites. This was first described by Rosch et al. [1] in 1979, and subsequently the first procedure was performed by Richter in Freiburg, Germany in 1990 [2, 3, 4]. Globally, TIPS has been presently applied to severely cirrhotic patients [5], who are otherwise untreatable or have end-stage liver disease due to liver synthesis and metabolic dysfunction, such as bleeding, ascites, multiple organ dysfunctions. One of the challenges of the intra-operational procedure during TIPS is severe pain, which mainly occurs when the needle was transhepatically punctured through the portal vein, and during the intrahepatic balloon dilatation of the shunt tract.

Although the majority of TIPS centers apply general anesthesia, in China, TIPS is performed under local anesthesia due to the fact that the general condition of most patient’s is ASA III to IV, and that these patients often have difficulty tolerating general anesthesia. Furthermore, for these patients, an option for general anesthesia is almost impossible. Since these patients are treated under local anesthesia, during TIPS, most patients experience mild-to-moderate intraoperative subjective pain, and more than half of the patients have reported severe intraoperative pain. Acute pain is mainly manifested as moans, restless sleep, shortness of breath. Due to this, patients cannot cooperate with the doctor, and some patients also suffer from vagus nerve reflex, which seriously affects their safety [6]. Most pain control studies correlated to TIPS in literature have focused on postoperative, rather than preemptive, medication regimens for pain management, and there is presently no standard of care for recommending an effective regimen [7, 8]. Some studies [8, 9] have revealed that palmitoylethanolamide (PEA), through predictive analgesic measures, provides analgesic treatment before the onset of pain, which can effectively reduce or eliminate the pain effect on a patient’s physical and psychological status, and ensure the uneventful implementation of the procedure. In 1993, Richmond et al. reported that the preoperative administration of IM and IV morphine reduced postoperative pain, analgesic use and secondary hyperalgesia, and that this may exert a preemptive effect of surgical pain [9].

The general condition of most cirrhotic patients is weak, and these patients often have difficulty tolerating general anesthesia during TIPS. Thus, they may benefit from the preemptive administration of morphine to relieve pain, and improve patient comfort and compliance during the procedure. The present study presents a solution for managing intra-operational pain secondary to TIPS by evaluating the value of the preemptive administration of morphine, when compared to on-demand morphine, in pain management during the TIPS procedure. To our knowledge, PEA related to intraprocedural pain during TIPS has not been established according to the level of self-reported pain using the visual analogue scale (VAS).

2. Material and methods

3. Results

The goal accrual of 80 patients was enrolled between September 2016 to May 2018, with 49 patients completing the study and available for analysis. Thirty-one patients were excluded from the present study. The exclusion reason was that the patients had a history of long-term use of opioids or alcohol hepatic failure or renal failure. The demographic and clinical characteristics of these patients were well-balanced between the two study groups (Table 1).

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There was no statistically significant difference between the two groups at the T0 ( $P>$ 0.05, Table 2). Severe pain during the TIPS procedure occurred mainly when the needle was transhepatically punctured through the portal vein (T1), and during the intrahepatic balloon dilatation of the shunt tract (T2). Patients with moderate VAS scores (subjective scores within 4–6 points for pain) often had frowns and made fists, but cooperated well with their doctors. Patients with severe VAS scores (subjective scores within 7–9 points) often demonstrated involuntary body movement, delirium, deep breathing and accelerated breathing, and these affected the TIPS procedure.

In group A, the proportion of severe pain at T1 was 4.3% (1 case), two cases were combined with vagus reflex, and the proportion of severe pain at T2 was 65.2% (15 cases). However, no severe pain occurred in group B. The VAS score significantly decreased in group B at T1, T2 and T3, when compared to group A ( 0.05; Table 2, Fig. 1). HR, systolic pressure and diastolic pressure significantly decreased at T2 and T3 in group B, when compared with group A ( 0.05, Table 3). There was no significant difference between the two groups in terms of SPO 2 ( $P>$ 0.05, Table 3).

In China, liver cirrhosis remains as a major disease burden. Viral hepatitis B and C remains as the primary etiological factors for hepatic cirrhosis, and a recent increase in alcoholic cirrhosis has been noted [10, 11]. TIPS is considered the treatment of choice for severely cirrhotic patients, who are considered untreatable or have end-stage liver disease. The general condition of these patients is weak, and these patients often have difficulty tolerating general anesthesia. Therefore, the TIPS procedure is mostly performed under local anesthesia. However, it is undeniable that patients who received TIPS under local anesthesia likely experienced intense intraoperative pain. Pain perception can cause accelerated breathing and posture changes that could directly affect a patient’s surgical compliance. Thus, these patients cannot cooperate with their doctors, and some patients even become psychologically agitated or refuse to continue with the procedure. Preemptive analgesia was proposed by Crile et al. in the early 20 th century through clinical observations. This approach decreases pain by preventing the hyperalgesia related to the sensitization of pain fibers in the central and peripheral nervous systems. This strategy was reintroduced in the early 1980s in a series of animal studies conducted by Wolf [12]. Over the past several years, many novel studies on preemptive analgesia have been published and summarized in several reviews [13, 14, 15, 16]. However, the use of preemptive analgesia during the TIPS procedure remains unreported. The nature of pain during the TIPS procedure is consistent with the characteristics of visceral pain, with a persistent dull pain that progressively increases. Some patients may demonstrate severe pain, which is often accompanied by unpleasant emotional activity. The proportion of severe pain in group A was 65.2% (15 cases), while the proportion of severe pain at T1 was 4.3% (one case). Therefore, severe pain during TIPS occurred mainly during intrahepatic balloon dilatation (T2), and when the needle was transhepatically punctured through the portal vein (T1). In the present study, two cases developed vagal reflex at T1, which was presumably associated with visceral pain and autonomic reflex activity, and this manifested as decreased HR, low blood pressure, chest tightness, pale complexion, and cold and wet skin, which improved after with the administration of atropine. According to the present observations, during the TIPS procedure, most patients experienced mild-to-moderate intraoperative subjective pain, with some patients reporting severe intraoperative pain. Patients with severe VAS scores often demonstrate involuntary body movement, delirium and accelerated breathing. In our study, the results showed that there is no significant difference in the procedural time between the two groups. The reason maybe due to the limited sample size.

Through the advice of pain specialists and evidence from the literature review, morphine was selected as the primary drug for preemptive analgesia. Morphine is a pure opioid receptor agonist that has a potent analgesic effect, and is the first choice for preemptive analgesia. Morphine activates the central nervous opioid receptor by simulating the endogenous analgesic substance encephalin, which has a substantial impact on persistent visceral pain. Morphine, which is a classic opioid, has been often used in clinic to relieve moderate-to-severe pain. The preemptive administration of morphine can reduce the physiological consequences of nociceptive transmission provoked by invasive procedures, and alleviate the patient’s postoperative pain [17, 18, 19]. Compared to short-acting opioids, such as fentanyl, a single injection of morphine, which has a half-life of 1.5 hours [20], can provide a sufficient duration of analgesic effect for the TIPS procedure. Long-term morphine treatment (continuously pumped into the vein), which has an analgesic effect of one dose for 4–6 hours, can cover the TIPS procedure time or time of pain, ensuring satisfactory results.

After PEA administration, the present patients had no severe pain, and the TIPS procedure was successful performed with no interruptions due to pain. At the T1, T2 and T3 time points, the VAS scores were significantly lower in group B than in group A. Furthermore, the HR, systolic blood pressure and diastolic blood pressure at T2 and T3 were significantly lower in group B than in group A. Unlike in theater, whereby the anesthesiologist is the one responsible for managing a patient’s pain, and ensures a smooth operation and the patients’ cooperation in most of the catheterization in the laboratory, nurses (catheterization laboratory nurses) are the ones tasked with the above responsibilities. Hence, these present findings may help these nurses and other health care providers when dealing with such type of or related conditions once tasked. It was revealed that this simple intervention improved patient comfort and compliance during the procedure, ensured the smooth performance of the routine procedure by both doctors and nurses, and ensured the radiation exposure reduction for both the patient and operating staff by reducing total time of operation in the catheterization laboratory. Overall, this is a safe, effective and successful pain management intervention.

5. Conclusion

The preemptive administration of morphine reduced severe pain during TIPS procedures, improves patient comfort and compliance during the procedure, ensures the smooth performance of the routine procedure by both doctors and nurses, and ensures the radiation exposure reduction for both the patient and operating staff by reducing the time of operation. Overall, this approach is a safe, effective and successful pain management intervention.