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

Abstract

BACKGROUND:

Transjugular intrahepatic portosystemic shunt (TIPS) is an accepted minimal invasive procedure for the management of complications of portal hypertension.

OBJECTIVE:

This study aims to investigate the value of the preemptive administration of morphine, when compared with on-demand morphine, during TIPS.

METHODS:

The present study was a randomized control trial. A total of 49 patients were selected to receive 10 mg of morphine either before the TIPS procedure (group B, $n=$ 26), or on demand when needed during the TIPS procedure (group A, $n=$ 23). The patient’s pain was scored using the visual analog scale (VAS) during the procedure. VAS, pain performance, HR, systolic pressure, diastolic pressure and SPO ${}_{2}$ were recorded at four-time points: before the operation (T0), during the trans-hepatic puncture of the portal vein (T1), during the intrahepatic channel expansion (T2), and when the operation was finished (T3). The duration of the operation was also recorded.

RESULTS:

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

CONCLUSION:

Preemptive analgesia can effectively relieve severe pain during TIPS, improve patient comfort and compliance, ensure a routine procedure, and offer excellent safety, and is simple and effective.

Keywords

Preemptive analgesia morphine TIPS pain visual analogue scale

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

2.1 Patients

The present study is a randomized clinical trial conducted from September 2016 to May 2018 among eligible patients who underwent TIPS at our institution. The present study was approved by the Ethics Committee of our hospital, and all patients provided signed informed consent. The clinical trial was registered on ClinicalTrials.gov (NCT02877953).

These patients were randomized to receive morphine either on demand when needed during the TIPS procedure (group A), or before the TIPS procedure (group B). Patients were randomly assigned to group A or group B, according to a random allocation sequence using the Matlab software. The dose of morphine was 10 mg for both groups. In group B, morphine was administered at 30 minutes before the TIPS procedure. In group A, morphine was administered at the discretion of the doctor, or when requested by the patient during the TIPS procedure. The sample size was calculated by the statistic software.

2.2 Inclusion and exclusion criteria

Inclusion criteria: (1) patients with a clinical situation in line with the need for TIPS treatment; (2) patients who were $\geqslant$ 18 years old. Exclusion criteria: (1) patients who had a history of long-term use of opioids or alcohol; (2) patients who had hepatic failure or renal failure.

2.3 TIPS procedure

At pre-procedure, all symptomatic cirrhotic patients go underwent conventional enhanced abdominal computed tomography (CT). Then, the images were used for further review and interventional procedure planning. All of the present TIPS procedures were conducted through a transjugular approach using the Rösch-Uchida Transjugular Liver Access Set (Cook). Central venous pressure was obtained before the sheath was advanced towards the right hepatic vein. After the successful puncture of the liver capsule from hepatic to the portal vein, a venography was obtained, followed by the advancement of a guidewire towards the splenic vein. Once the guidewire was placed in a stable position, the balloon catheter was advanced, and balloon dilatation was carried out using a 6-mm diameter balloon, followed by stent placement. In general, a 80 mm $\times$ 8 cm bare stent was used, followed by the deployment of a 80 mm $\times$ 5 cm covered stent in the intrahepatic portal tract. Portal venous pressure was measured both at pre- and post-stent deployment. In some cases, coil embolization, sclerosing agent embolization, or both embolic were applied to facilitate the blockage of varices, when applicable. Furthermore, all patients was subjected to followup CT imaging.

2.4 Data collection

The patient’s pain was scored using the VAS (0 $=$ no pain, 10 $=$ worst possible pain) during the procedure. For all cases, local anesthesia was supplemented, as needed, in the vascular access region. The VAS score, pain performance, heart rate (HR), systolic pressure, diastolic pressure and SPO ${}_{2}$ were recorded at four time points: before the operation (T0), during the trans-hepatic puncture of the portal vein (T1), during the intrahepatic channel expansion (T2), and when the operation was finished (T3). The duration of the operation was also recorded. The nurses studied the method of the VAS. The scores were completed by the patient by rating their pain.

2.5 Statistical analysis

The statistical analysis was conducted by a statistician. The software program SPSS 20.0 (IBM, Chicago, USA) was used to conduct the statistical analysis. Continuous variables were expressed as mean $\pm$ standard deviation (SD). Discontinuous variables were expressed in percentage (%). For two comparisons, each value was compared by $t$ -test when each datum conformed to the normal distribution, while non-normally distributed continuous data were compared using non-parametric tests. The counting data were tested by chi-square test. The pain ratings were compared across all time points via a repeated-measure, mixed-model analysis, which uses all available data from each patient at each time point. A value of $P<$ 0.05 was considered statistically significant.

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).

Table 1
Patient demographics

	Group A23	Group B26	$P$ value
Sex (M/F)	15/8	19/7	0.551 ${}^{\text{a}}$
Age (year)	52.65 $\pm$ 9.25	55.08 $\pm$ 9.80	0.379 ${}^{\text{b}}$
Weight (Kg)	63.67 $\pm$ 9.06	58.47 $\pm$ 10.10	0.065 ${}^{\text{b}}$
Operation time (min)	105.22 $\pm$ 28.54	103.46 $\pm$ 36.55	0.854 ${}^{\text{b}}$

There was no significant difference ( $P>$ 0.05) between group A and group B. ${}^{\text{a}}p$ chi-square test. ${}^{\text{b}}p$ independent sample $T$ test.

Table 2

VAS score at T ${}_{0}$ , T ${}_{1}$ , T ${}_{2}$ , T ${}_{3}$

	Group A	Group B	$P$ value
T ${}_{0}$ VAS	0.13 $\pm$ 0.63	0.08 $\pm$ 0.39	0.907
T1 VAS	3.52 $\pm$ 1.34	2.12 $\pm$ 0.65	$<$ 0.001
T2 VAS	6.98 $\pm$ 1.21	5.08 $\pm$ 0.63	$<$ 0.001
T3 VAS	3.96 $\pm$ 0.64	2.38 $\pm$ 0.90	$<$ 0.001

VAS was significantly decreased in group B at T ${}_{1}$ , T ${}_{2}$ , T ${}_{3}$ compared with group A ( $P<$ 0.05).

Figure 1.

VAS score at T0, T1, T2, T3.

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 ( $P<$ 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 ( $P<$ 0.05, Table 3). There was no significant difference between the two groups in terms of SPO ${}_{2}$ ( $P>$ 0.05, Table 3).

Table 3

Heart rate, systolic pressure, diastolic pressure, SPO2 at T0, T1, T2, T3

Time point	Parameter	Group A		Group B		$P$ value
T0	Heart rate	76.39	$+$ 10.20	77.58	$+$ 13.87	0.738
	Systolic pressure	127.61	$+$ 18.25	127.07	$+$ 18.86	0.921
	Diastolic pressure	74.65	$+$ 13.48	74.19	$+$ 10.59	0.894
	SPO2	98.13	$+$ 1.36	98.69	$+$ 1.12	0.120
T1	Heart rate	78.00	$+$ 11.56	78.80	$+$ 15.19	0.837
	Systolic pressure	130.00	$+$ 24.70	131.46	$+$ 15.50	0.803
	Diastolic pressure	76.35	$+$ 18.20	76.54	$+$ 11.56	0.965
	SPO2	97.96	$+$ 1.52	98.70	$+$ 1.23	0.067
T2	Heart rate	92.96	$+$ 10.12	84.27	$+$ 15.35	0.026
	Systolic pressure	147.26	$+$ 17.94	134.77	$+$ 17.66	0.018
	Diastolic pressure	92.00	$+$ 13.11	80.88	$+$ 12.62	0.004
	SPO2	97.65	$+$ 1.92	98.50	$+$ 1.17	0.065
T3	Heart rate	89.57	$+$ 10.38	81.81	$+$ 13.64	0.032
	Systolic pressure	142.26	$+$ 15.96	130.85	$+$ 16.93	0.019
	Diastolic pressure	86.52	$+$ 11.25	77.50	$+$ 10.19	0.005
	SPO2	98.09	$+$ 1.35	98.69	$+$ 1.23	0.106

Heart rate, systolic pressure and diastolic pressure were significantly decreased in group B at T2, T3 compared with group A ( $P<$ 0.05). There was no significant difference between the two groups in SPO2 ( $P>$ 0.05).

4. Discussion

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 ${}^{\text{th}}$ 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.

4.1 Limitations

The present study has several limitations. First, the present study was an open-label trial, and the patients and investigators were not blinded to the trial design. Second, merely morphine was administered as an analgesic. Further studies should access multi-drug combinations of analgesics or sedatives. Third, merely a single dose of morphine was used. Individual patients have varying analgesic requirements. Further studies that could correlate factors to procedural pain using both a subjective pain scale and analgesics would be valuable.

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.

Footnotes

Conflict of interest

None to report.

Ethics statement

This study was conducted in accordance with the Declaration of Helsinki. Approval was obtained from the Ethics Committee of Tongji Medical College (S330/0003571). Written informed consent was obtained from all participants.

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