Cancer pain associated with advanced cancer of the abdominal organs, such as unresectable pancreatic cancer, can often be difficult to control, significantly reducing the patient’s quality of life and limiting daily activities.^1,2 Thus, it is obvious that adequate pain control is an extremely important issue. Pancreatic cancer remains one of the carcinomas with the poorest prognosis, with a 5-year survival rate of less than 10%.³ Most pancreatic cancers are detected at an advanced stage and are therefore unresectable.⁴ In pancreatic cancer, it has been reported that approximately 60% to 80% of patients suffer from abdominal pain due to plexus invasion of the tumor.² Most pancreatic cancer patients require continuing chemotherapy, but their treatment is often interrupted by uncontrollable cancer-related pain. Traditionally, drug therapy centered on non-steroidal anti-inflammatory drugs (NSAIDS), such as loxoprofen, and narcotic analgesics, such as morphine, have been widely used to treat cancer pain associated with abdominal malignancies. However, especially in unresectable pancreatic cancer, severe tumor pain frequently occurs, and pain control with pharmacotherapy is often inadequate. When neoplastic abdominal pain treatment by NSAIDS or opioid analgesics fail, a celiac plexus neurolysis (CPN) can be used. CPN is guided by fluoroscopy, computed tomography (CT) or echo, and their usefulness has been reported.^5–8

The usefulness of CPN using various modalities has been reported in many cases, with effective therapeutic response in more than 80% of patients.^5,6 Pain originating in intraperitoneal organs such as the pancreas is transmitted by afferent nerve fibers through the celiac plexus and reaches the central nervous system through the dorsal root of the spinal cord at the T12-L2 level. The celiac plexus is a group of nerve fibers that converge on the celiac ganglion in the retroperitoneum, immediately adjacent to the anterior external wall of the aorta at the origin of the celiac trunk. CPNs were commonly performed percutaneously under echo-guided or CT-guided techniques. However, these treatments are invasive as they puncture multiple obstacles between the ventral or dorsal skin and the celiac plexus and carry the risk of various complications. Recently, endoscopic ultrasound-guided CPN (EUS-CPN) has been performed and reported as safe and effective.⁹ EUS-guided method allows for a safer approach from a site closer to the celiac plexus. However, evidence on the effectiveness and safety of EUS-CPN is limited, and the details of endoscopic technique often vary among institutions. This review will summarize previous reports on the therapeutic efficacy and complications of EUS-CPN, as well as specific endoscopic techniques.

The indication for a CPN is visceral pain originating in the upper abdominal organs. This includes the liver, biliary tract, and gastrointestinal tract, though it is most often performed for pain originating from pancreatic cancer.

Good indications for EUS-CPN are cases that are difficult to control with NSAIDS or opioid analgesics, or cases in which the side effects of narcotic analgesics make discontinuation of medication or reduce quality of life. While cases poorly controlled with medication are considered good indications for EUS-CPN, it has also been suggested that performing EUS-CPN early in the diagnosis may lead to better analgesia and reduced opioid consumption,¹⁰ and further studies are expected in the future.

On the other hand, the efficacy of EUS-CPN for upper abdominal pain related to chronic pancreatitis has also been reported and may be indicated not only for malignant tumors such as pancreatic cancer but also for chronic pancreatitis.¹¹

Before performing EUS-CPN, contrast-enhanced CT or other imaging modality should be performed to evaluate the site of the lesion, assess involvement of the celiac plexus, and confirm vascular anatomy. It is also necessary to rule out other causes of upper abdominal pain besides tumor pain, such as acute cholangitis, cholecystitis, gastrointestinal ulcers, and ileus. In assessing the safety of the puncture, it is important to check the patient’s medical history and to confirm the risk of bleeding tendency. Most reports indicate that EUS-CPN is contraindicated in cases of impaired coagulation (international normalized ratio ≥ 1.6), thrombocytopenia (< 50,000/L), and patients with gastric and esophageal varices.^12,13

Neurolytic agent

Generally, 98% ethanol is used as a neurolytic agent in EUS-CPN, although phenol is sometimes used.¹⁴ However, alcohol injection alone may cause postoperative pain due to perineural swelling and tissue damage. To reduce post-procedural pain and discomfort, local anesthetics such as bupivacaine are used.¹⁵ As a local anesthetic, 0.25% bupivacaine is most commonly used, although 0.75% bupivacaine, lidocaine and ropivacaine have also been used.^15–17 In a multicenter, retrospective study of 150 patients who underwent EUS-CPN, Zhao et al¹⁶ reported that 0.75% bupivacaine, as a local anesthetic, when compared with 0.375% bupivacaine and 0.5% ropivacaine, significantly reduced pain within three days after EUS-CPN. In practice, drug selection and its concentration are often determined by the endoscopist and the amount of alcohol injected as a neurolytic agent varies by reports, but 10 to 20 mL is typically used.¹⁶ Within EUS-CPN, the use of neurolytic agents is described as “EUS-CPN” in the narrow sense, while the use of only local anesthetics or steroids without neurolytic agents is sometimes described as “abdominal plexus block (EUS-celiac plexus block).”

Central and bilateral techniques

EUS-CPN is performed by a convex type EUS scope. By scanning just under the esophagogastric junction, the long axis image of the abdominal aorta and the branches of the celiac artery and superior mesenteric artery can be easily visualized (Fig. 1A). The puncture line can be clearly delineated, and the puncture can be performed while confirming intervening organs and blood vessels, making it a safer and more accurate procedure than percutaneous echo-guided or CT-guided puncture. There are two main techniques for EUS-CPN: the central technique and the bilateral technique. In the central technique, a longitudinal section of the abdominal aorta is drawn from the posterior wall of the upper gastric body to identify the branches of the celiac artery. The puncture needle is advanced to the trunk of the celiac artery branch, and the agent is injected until the high-echoic area expands (Fig. 1B). In the bilateral technique, after drawing the celiac artery branch from the longitudinal section of the aorta, the scope is rotated slightly clockwise or counterclockwise to inject the drug into both sides of the celiac artery branch trunk. Usually, the average injection volume of local anesthetic is 2 to 10 mL, followed by 10 to 20 mL of alcohol.

Figure 1. (A) Convex endoscopic ultrasonography depiction of the celiac plexus and puncture sites for the central and broad techniques. (B) Practical use of the central technique. The puncture needle is advanced to the trunk of the CA branch, and the agent is injected until the high-echoic area expands. CA, celiac artery; SMA, superior mesenteric artery; Ao, aorta.

Efficacy of EUS-CPN

Efficacy of EUS-CPN for pancreatic cancer

The efficacy of EUS-CPN in reducing pain has been reported to be 45%–85%, although it varies from report to report.^18–26 Details from previous reports on the treatment efficacy and complications of EUS-CPN are shown in Table 1. In a meta-analysis by Puli et al²⁰ the therapeutic efficacy of EUS-CPN was reported to be 80.1% in patients with pancreatic cancer and 59.4% in patients with chronic pancreatitis and another meta-analysis by Asif et al²¹ reported that the efficacy of EUS-CPN in patients with pancreatic cancer was 71%. Although EUS-CPN is most commonly performed when opioid medications are ineffective, early EUS-CPN intervention has been indicated to provide better analgesia and lesser opioid consumption. Wyse et al¹⁰ reported that in a randomized trial, the early EUS-CPN group showed significant pain reduction and a trend toward lower morphine use after 3 months of treatment. On the other hand, some reports show no difference in pain relief between EUS-CPN and opioid-based medication. Kanno et al²⁷ conducted a randomized control study of EUS-CPN versus medication alone and found no significant differences in treatment efficacy or the amount of opioid use, concluding that EUS-CPN is an effective treatment option but should not be performed routinely.

Table 1 . Characteristics of the Studies on Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis.

Reference	Year	Design	Number	Technique	Pain relief (follow-up time)	Complication
Wiersema and Wiersema9	1996	Retrospective	30	Bilateral	88 (10 week)	Diarrhea 13.3%
Gunaratnam et al26	2001	Prospective	58	Bilateral	78 (24 week)	Pain 8.6%
Wyse et al10	2011	RCT	48	Bilateral vs medication	NA	None
Sahai et al35	2009	Prospective	160	Central vs Bilateral	45% vs 70% (1 week)	Bleeding 0.7%
Iwata et al13	2011	Retrospective	47	Central/Bilateral	68% (1 week)	Hypotension 17%, diarrhea 23%, inebriation 8%
Wiechowska-Kozłowska et al23	2012	Retrospective	29	Central/Bilateral	86%	Hypotension 3.4%, severe pain 6.8%, diarrhea 10.2%
Téllez-Ávila et al12	2013	Retrospective	53	Central vs Bilateral	50% vs 60% (4 week)	Transitory pain 3%
Seicean et al22	2013	Retrospective	32	Central	75% (2 week)	None
Facciorusso et al45	2020	Retrospective	215	Central	86%	24%–44% Diarrhea, fever, abdominal pain, pancreatitis
Kanno et al27	2020	RCT	48	Central, Bilateral, Broad vs medication	NA	NA
Han et al18	2021	Retrospective	58	Central and bilateral	74% (1 week) 67% (4 week)	Hypotension 1.7%, pain 5.2%, transient loose stools 3.4%

RCT, randomized controlled trials; NA, not available..

Efficacy of EUS-CPN for chronic pancreatitis

While EUS-CPN is highly effective in treating tumor-related pain in patients with pancreatic cancer, the treatment efficacy of EUS-CPN for abdominal pain caused by chronic pancreatitis is limited.^11,28–30 A meta-analysis by Kaufman et al³¹ found the efficacy of EUS-CPN in reducing pain was 72.4% for pancreatic cancer compared to 51.4% for chronic pancreatitis. Based on many reports of the poor treatment efficacy of EUS-CPN for chronic pancreatitis, Teoh et al³² suggest that EUS-CPN is not recommended for chronic pancreatitis in the consensus guidelines.

Efficacy of central vs bilateral technique

Several articles have compared the difference in pain reduction between the two techniques in randomized prospective trials. Many studies have reported no difference in pain reduction or safety between central and bilateral techniques. Bhatnagar et al³³ reported that in a randomized trial, the bilateral and central technique were comparable in pain relief and side effects. Téllez-Ávila et al¹² compared the central and bilateral technique of EUS-CPN and reported that the median pain reduction after 4 weeks of treatment had no significant difference between them. In a prospective randomized study, LeBlanc et al³⁴ randomized EUS-CPN to central versus bilateral methods and reported that pain relief time, duration of pain relief, and complications were not significantly different between the two groups. On the other hand, some reported that bilateral technique was significantly more effective in reducing pain than central technique. Sahai et al³⁵ compared the central and bilateral technique in 184 patients undergoing EUS-CPN and found that the reduction in visual analogue scale (VAS) score at day 7 was significantly higher in the bilateral group (mean pain reduction 70.4% [61.0%–80.0%] vs 45.9% [32.7%–57.4%]; P = 0.0016), and they reported that the bilateral method was the only predictor of > 50% pain reduction. However, they also reported that adrenal artery bleeding was observed with the bilateral technique.

EUS-guided celiac ganglia neurolysis

In 2006, it became clear that the celiac ganglion could be directly delineated by EUS.^36,37

EUS-guided celiac ganglia neurolysis (EUS-CGN), in which the celiac ganglia are directly punctured and blocked under EUS guided technique, was reported in 2008.³⁸ EUS-CGN is a technique for injecting a drug through a direct puncture into the visualized celiac ganglion. The celiac ganglia are commonly found at a height between the aorta and left adrenal gland and between the celiac artery and left renal artery by rotating the scope clockwise from the trunk of the celiac artery.¹⁷ The celiac ganglion is often visualized as a hypoechoic nodular structure (Fig. 2).

Figure 2. The celiac ganglia are commonly found at a height between the Ao and left adrenal gland and between the CA and left renal artery by rotating the scope clockwise from the trunk of the CA. The celiac ganglion is visualized as a hypoechoic nodular structure. CA, celiac artery; Ao, aorta.

Efficacy of EUS-CGN

Based on these findings, EUS-CPN is a safe treatment technique that greatly reduces pain associated with pancreatic cancer. However, a certain number of cases with inadequate response to treatment must be taken into consideration. Levy et al³⁸ reported the first use of EUS-CGN in patients with pancreatic cancer and obtained pain relief in 94% (16/17) of them. In some comparative studies with EUS-CPN, CGN has been reported to provide pain relief to 45%–80% of patients and many reports indicate that CGN was significantly more effective in reducing pain than EUS-CPN.^{1,17,24,38,39} Details from previous reports on the treatment efficacy and complications of EUS-CGN are shown in Table 2.

Table 2 . Characteristics of the Studies on EUS-CGN and EUS-BPN.

Reference	Year	Design	Number	Technique	Pain relief (follow-up time)	Complication
Levy et al38	2008	Retrospective	17	CGN	94% (4 week)	Diarrhea 16%, hypotension 35%, transient pain 41%
Ascunce et al1	2011	Retrospective	64	CGN vs CPN	65% vs 25% (1 week)	Diarrhea 23%, hypotension 2%, transient pain 2%
Doi et al17	2013	RCT	68	CGN vs CPN	73% vs 45% (1 week)	Diarrhea 5.9% vs 9.1%, hypotension 2.9% vs 6%, pain 29.4% vs 21.2%
Ishiwatari et al14	2014	Retrospective	22	CGN/CPN	83% (fenol) vs 69% (ethanol) (1 week)	Diarrhea 9%, hypotension 4.5%, burning pain 4.5%, inebriation 4.5%
Si-Jie et al39	2014	Retrospective	41	CGN vs CPN	80% vs 80% (3–90 day)	Hypotension 4.9%
Levy et al24	2019	RCT	110	CGN + CPN vs CPN	46% vs 40% (12 week)	Transient pain 8.3% vs 44.9%, neurolytic effect 23.3% vs 55.1%
Sakamoto et al41	2010	Retrospective	67	BPN vs CPN	NA	None
Minaga et al42	2016	Retrospective	64	BPN	77% (1 week), 67% (4 week)	Diarrhea 3.6%, hypotension 4.5%, pain 3.6%, inebriation 8%

EUS-CGN, endoscopic ultrasound-guided celiac ganglia neurolysis; EUS-BPN, endoscopic ultrasound-guided broad plexus neurolysis; CPN, celiac plexus neurolysis; RCT, randomized controlled trials; NA, not available..

Several studies have reported on the treatment efficacy of EUS-CGN compared to EUS-CPN. EUS-CGN is reported to be superior to EUS-CPN, especially in the short term pain relief. In a review by Li et al,⁴⁰ EUS-CGN had a significantly better short-term pain response rate than EUS-CPN with no difference in adverse events. Doi et al¹⁷ evaluated EUS-CPN and EUS-CGN in a randomized prospective trial where they evaluated treatment response on day 7 after treatment and found that both positive response and complete response were significantly higher in the EUS-CGN group. On the other hand, Levy et al²⁴ performed a randomized, double-blind study of EUS-CPN versus EUS-CGN in 110 patients with unresectable pancreatic cancer and reported that the treatment efficacy of EUS-CPN and EUS-CGN was comparable, but patients who received EUS-CGN had a significantly shorter median survival. Although it was unclear from the multivariate analysis whether the shorter survival of CGN compared to CPN was due to the procedure or tumor-related characteristics, the authors concluded that the indication for EUS-CGN should be carefully reexamined. Koulouris et al¹⁹ reported in a meta-analysis no significant difference in response rates between central injection, bilateral injection, and CGN at 2 and 4 weeks postoperatively. Based on these findings, EUS-CGN shows good efficacy in short-term pain reduction. However, the possibility of a shorter prognosis should be taken into account, and treatment indications may need to be more carefully evaluated.

EUS-guided broad plexus neurolysis

EUS-guided broad plexus neurolysis (EUS-BPN) was reported by Sakamoto et al⁴¹ in 2010. Broadly, the EUS scope is first rotated clockwise from the upper gastric body to delineate the longitudinal aortic cross section and the celiac artery trunk. The scope is advanced 1 to 2 cm toward the anal side of the celiac artery trunk to visualize the branch of the superior mesenteric artery, and a 25-gauge puncture needle is inserted from the lateral side of the aorta to the level of the trunk of the superior mesenteric artery (the Broad technique; Fig. 1A).

Efficacy of EUS-BPN

Broad Technique was first reported in 2010 by Sakamoto et al.⁴¹ They reported that EUS-BPN, which punctures the root of the superior mesenteric artery, significantly improved VAS pain scores after 7 and 30 days of treatment compared to EUS-CPN. Minaga et al⁴² reported that a good pain response in 112 patients who underwent EUS-BPN for pancreatic cancer were 77.7% after 1 week of treatment and 67.9% after 4 weeks of treatment. However, reports on the usefulness of EUS-BPN are limited (Table 2), and further studies are needed.

New techniques for EUS-CPN

In 2021, Saleh et al⁴³ performed EUS-CPN for pancreatic cancer with a mixture of 0.5% bupivacaine (0.5%) and dexmedetomidine, a selective agonist of alpha 2 adrenergic receptors.

They reported that the dexmedetomidine group showed an improvement in pain scores at 24 weeks post-procedure compared to the alcohol group. Recently, Bang et al⁴⁴ reported the usefulness of EUS-guided radiofrequency ablation (EUS-RFA) for advanced pancreatic cancer by targeting the celiac plexus or visualized ganglia using a 19-gauge fine needle aspiration needle with a 1F monopolar probe. When patients treated with EUS-RFA were compared to patients treated with EUS-CPN in the randomized controlled trial, RFA showed more improvement in pain scores and caused significantly fewer post-procedural gastrointestinal problems than EUS-CPN. However, further study is needed to determine the usefulness of EUS-RFA.

Predictors of treatment effectiveness

Although relatively high treatment response rates have been reported for EUS-CPN (roughly 60%–80%), there are some patients for whom EUS-CPN provides little pain relief. Several reports have examined predictors of treatment response to EUS-CPN and noted that tumor invasion into the celiac plexus is a negative factor for the response to treatment with EUS-CPN.^13,18

In a multivariate analysis, Iwata et al¹³ evaluated the effect of pain reduction in 47 patients who underwent EUS-CPN with a pain score 7 days after treatment. They reported that direct invasion of the celiac plexus and ethanol distribution on the left side only of the celiac artery on postoperative CT were significant factors for the negative effect of EUS-CPN. Han et al¹⁸ evaluated the factors involved in treatment response to EUS-CPN for pancreatic cancer and found that distant metastasis, no visible ganglia, and invasion of the celiac plexus were significant factors for negative response. Facciorusso et al⁴⁵ noted a relationship with sarcopenia. They report that in patients with sarcopenia, the median duration of pain relief was significantly shorter, and complete response rates and VAS score reductions were also significantly lower. Some reports indicate that CT is performed after EUS-CPN treatment and that the greater the contrast spread, the better the pain relief.^41,42 The findings of these studies suggest that there are two factors that influence the treatment efficacy of EUS-CPN: procedure-related factors and tumor progression-related factors. Injections only on the left side of the celiac artery or invisible ganglia may technically not provide enough neurolytic agent. It is also suggested that extensive cancer plexus invasion and pathologies associated with tumor progression, such as distant metastases and sarcopenia, may cause somatic pain and local pain control with EUS-CPN may not be sufficient.

EUS-CPN has very clear visibility of the approach route to the celiac plexus, making it easy to avoid surrounding organs and vessels to secure the puncture route. Therefore, it is considered a safer technique than CT-guided or other percutaneous drainage techniques.

As a result, complications are often transient and minor. Diarrhea, transient hypotension, and transient pain aggravation resulting from ethanol injection are commonly reported.^19,46

On the other hand, serious complications have been reported in less than 1% of cases, including retroperitoneal abscess, hemorrhage, paraplegia, and ischemia.^47–50 These complications are often attributed to incorrect injection sites, but some fatal outcomes have been reported,^48,50 and EUS-CPN should be performed by an expert endoscopist.

EUS-CPN can be performed more safely and reliably than percutaneous treatment. It is an effective treatment for reducing tumor pain, mainly from pancreatic cancer. It is highly expected that EUS-CPN will improve patients’ quality of life and provide stable and continuous treatment in patients with pancreatic cancer. In recent years, new techniques such as EUS-CGN and EUS-BPN have also been reported, which may be an effective option for difficult-to-control tumor pain. However, EUS-CPN should not be performed routinely and its indications should be carefully evaluated, because there are some reports of insufficient pain reduction and serious complications.

None.

No potential conflict of interest relevant to this article was reported.