Intractable abdominal pain commonly develops in patients with pancreatic cancer. Oral pharmacologic therapy is ineffective for many patients and side effects commonly occur. Celiac neurolysis (CN) is sometimes performed to enhance pain relief. Percutaneous approaches were initially described, with endoscopic ultrasound (EUS)-guided CN more recently introduced. There is uncertainty regarding the efficacy and role of CN in managing pancreatic cancer pain, but CN should still be considered in this difficult-to-treat cohort of patients. EUS-guided approaches may be favored when EUS is otherwise indicated for diagnostic or staging purposes. When EUS is not otherwise indicated, percutaneous approaches are likely favored.
Introduction
Patients who have pancreatic cancer frequently experience abdominal pain that is often difficult to control. Although initial therapy with nonsteroidal antiinflammatory agents is advocated, the limited efficacy routinely necessitates opioid administration. Although opioids may alleviate pain, their use is commonly associated with dry mouth, constipation, nausea, vomiting, drowsiness, delirium, and impaired immune function. Celiac neurolysis (CN) may be performed with the goal of improving pain control and quality of life (QOL) and to reduce the risk of drug-induced side effects.
This article reviews the various techniques for performing endoscopic ultrasound (EUS)-guided CN (EUS CN) and considers its role in patients with pancreatic cancer. Given the limited number of EUS CN studies, relevant literature is also discussed pertaining to percutaneous (PQ) and surgical methods for performing CN, which provide some perspective when considering the EUS data.
Relevant anatomy
A discussion of the relevant anatomy is key to understanding the different approaches to CN. The terms celiac plexus and splanchnic nerves are often used interchangeably. However, they represent anatomically distinct structures. The splanchnic nerves are located cephalic to the diaphragm (in a retrocrural position), and anterior to the 12th thoracic vertebra. The celiac plexus is located caudal to the diaphragm (in an antecrural position), surrounds the origin of the celiac trunk, and comprises a dense network of ganglia and interconnecting fibers. Celiac ganglia vary in number (1–5), size (diameter 0.5–4.5 cm), and location (T12–L2). The celiac plexus transmits pain sensation for the pancreas and most of the abdominal viscera except the left colon, rectum, and pelvic organs. The neurons that innervate the pancreas can receive nociceptive stimulation and then transmit this pain information to the celiac plexus. Stimuli reach the thalamus and cortex of the brain, inducing the sensation of pain. Descending inhibitory mechanisms may also modulate the ascending pain information.
Relevant anatomy
A discussion of the relevant anatomy is key to understanding the different approaches to CN. The terms celiac plexus and splanchnic nerves are often used interchangeably. However, they represent anatomically distinct structures. The splanchnic nerves are located cephalic to the diaphragm (in a retrocrural position), and anterior to the 12th thoracic vertebra. The celiac plexus is located caudal to the diaphragm (in an antecrural position), surrounds the origin of the celiac trunk, and comprises a dense network of ganglia and interconnecting fibers. Celiac ganglia vary in number (1–5), size (diameter 0.5–4.5 cm), and location (T12–L2). The celiac plexus transmits pain sensation for the pancreas and most of the abdominal viscera except the left colon, rectum, and pelvic organs. The neurons that innervate the pancreas can receive nociceptive stimulation and then transmit this pain information to the celiac plexus. Stimuli reach the thalamus and cortex of the brain, inducing the sensation of pain. Descending inhibitory mechanisms may also modulate the ascending pain information.
PQ and surgical approaches and outcomes
CN was first performed by Kappis in 1914 via a PQ route. Technical modifications have been introduced, with the goal of improving the precision of needle placement and pain relief and to reduce procedure-related complications. These techniques differ with respect to the route of needle insertion, as well as the use and type of radiologic guidance.
Three meta-analyses have reached conflicting conclusions regarding PQ-guided celiac plexus neurolysis (CPN) (PQ CPN). The investigators note the difficulty in analysis given the mostly retrospective and uncontrolled nature of the studies. The evaluation of varied patient populations, including patients with cancer involving the breast, lungs, esophagus, stomach, colon, rectum, liver, gallbladder, bile ducts, adrenal glands, kidneys, and pancreas, also hinders the analysis. Lebovits and Lefkowitz concluded that CPN leads to successful relief of pancreatic cancer pain. In contrast, Sharfman and Walsh found the data insufficient to judge the efficacy, long-term morbidity, or cost-effectiveness. Eisenberg and colleagues reviewed 24 studies, of which 2 were randomized controlled trials (RCTs), 1 was prospective, and 21 were retrospective uncontrolled trials. The cancer type was specified in 1117 patients (63% pancreatic, 37% nonpancreatic). Good to excellent pain relief was reported in 89% of patients during the first 2 weeks after CPN. Partial to complete pain relief was reported in about 90% of patients at 3 months and 70% to 90% at the time of death. The investigators concluded that: (1) CPN has long-lasting benefit for 70% to 90% of patients with pancreatic and other intra-abdominal cancers, regardless of the technique used; and (2) adverse effects are common but generally transient and mild.
In a subsequent prospective, randomized, double-blind study of 21 patients with pancreatic cancer the PQ CPN group had a significant reduction in analgesic use and drug-induced side effects compared with patients receiving drug therapy alone. Kawamata and colleagues showed that PQ CPN results in less deterioration in QOL added to morphine therapy versus either morphine or nonsteroidal antiinflammatory drug therapy alone. Improved outcomes were attributed to increased duration of the analgesic effect and reduced opioid side effects.
More recently, Wong and colleagues evaluated 100 patients with unresectable pancreatic cancer to determine the effect of PQ CPN on pain relief, QOL, and survival in a double-blind RCT. Patients underwent either PQ CPN via a posterior approach or received systemic analgesic therapy alone with sham injection. At 1 week after therapy, patients in both groups experienced improved pain control ( P ≤.01) and QOL ( P <.001), with an advantage for those randomized to PQ CPN ( P = .005). The analgesic benefit of PQ CPN over analgesic therapy alone was sustained over the 12-month follow-up or until death. However, opioid consumption, the frequency of opioid-induced adverse effects, QOL, and survival duration were similar between groups.
Yan and Myers subsequently evaluated the non-EUS literature from 1966 to 2005 selecting only RCTs, of which 5 studies were identified. CPN was associated with lower visual analogue scores (VAS) for pain and patient opioid use at 2, 4, and 8 weeks when compared with controls. Although statistically significant, the overall benefit was only a 6% reduction in mean VAS. However, improved pain control resulted in a significant decrease in opioid use (mean reduction 40–80 mg/d) and constipation. Nevertheless, the reduction in opioid use was not associated with a decrease in opioid-associated adverse effects, including nausea, vomiting, and sedation, or an effect on QOL or survival. CPN did not eliminate the requirement for opioids.
CPN may also be performed surgically. Lillemoe and colleagues published a prospective randomized trial in 137 patients with unresectable pancreatic cancer. Neurolysis improved pain control versus placebo at 2, 4, and 6 months’ follow-up. When the study stratified treatment groups, patients with preoperative pain had a significant survival advantage after neurolysis versus those patients in the control arm. The reason is unclear, but may relate to reduced opioid-induced side effects, improved nutritional status, and emotional well-being. No study has reproduced these investigators’ findings. Potential disadvantages of surgical neurolysis include reduced pain relief reported by some, uncertainty regarding response to therapy because of difficulty differentiating postoperative pain from cancer pain, and limited surgical access that prolongs procedure time. In addition, the frequency of surgery for unresectable pancreatic cancer would be expected to decline with more sensitivity of cross-sectional imaging, thereby limiting the population of patients who may benefit from this approach.
EUS techniques
EUS CN is usually performed in the outpatient setting, often during the index examination conducted for the purpose of pancreatic cancer diagnosis and staging. The patient is questioned regarding relevant allergies and anticoagulant use. Informed consent is obtained, with a focus on the unique complications associated with neurolysis. In our practice, contraindications to CN include: (1) uncorrectable coagulopathy (international normalized ratio (INR) >1.5), (2) thrombocytopenia (platelets <50,000/L), (3) inadequate sedation, or (4) altered anatomy (eg, gastric bypass or an extensive mass or lymphadenopathy prohibiting visualization or access). Patients are initially hydrated with 500 to 1000 mL normal saline to minimize the risk of hypotension. The procedure is performed with the patent in the left lateral decubitus position under moderate or heavy sedation. Continuous monitoring is necessary during and for 2 hours after the procedure. Before discharge, the blood pressure is rechecked in a supine and erect position to assess for orthostasis.
Described EUS-guided techniques for performing CN include: (1) CPN, (2) celiac ganglia neurolysis (CGN), and (3) broad plexus neurolysis (BPN).
EUS-Guided CPN
The initially described and most widely performed approach to EUS CN involves diffuse injection into the celiac plexus. Linear array imaging from the posterior lesser curve of the gastric fundus allows identification of the aorta, which appears in a longitudinal plane ( Fig. 1 ). The aorta is traced distally to the celiac trunk, which is the first major branch below the diaphragm. Targeting is based on the expected location of the celiac plexus relative to the celiac trunk. Doppler may be used to distinguish vascular structures. A 22-gauge needle is primed with the injectate, advanced through the biopsy channel, and affixed to the hub. The needle is inserted under EUS guidance, and the needle tip is placed approximately 5 to 10 mm away from the origin of the celiac trunk ( Fig. 2 ). In our practice, we usually inject the entire volume in a single site (unilateral or midline) if possible. Some prefer to inject half the volume on 1 side and the remainder on the opposite side of the aorta (bilateral). Occasionally, altered anatomy resulting from significant lymphadenopathy or bulky tumors may necessitate injection of the entire solution into a single site.
There are limited data regarding the efficacy of single versus bilateral injection. Sahai and colleagues compared unilateral with bilateral injection in a mixed population of patients with pancreatic cancer or chronic pancreatitis. These investigators determined that bilateral CN was significantly more effective than single injection, with a mean pain reduction of 70.4% versus 45.9% ( P = .0016). Their study offers preliminary data to suggest that bilateral injection may offer enhanced pain relief. These findings were supported by the results of a meta-analysis from Puli and colleagues that revealed that the proportion of patients with pain relief was 84.54% and 45.99% after bilateral versus unilateral EUS-guided CPN (EUS CPN), respectively.
EUS-Guided CGN
Although CPN is considered safe, the degree and duration of pain relief are suboptimal. The limited efficacy may partially be explained by the diffuse injection into the region of the plexus without targeting of the ganglia. Until recently it was believed that the celiac ganglia could not be imaged and could be identified only at surgery. The recent recognition that celiac ganglia can be visualized and accessed by EUS allows for direct injection into individual celiac ganglia to perform CGN. This more precise delivery of therapy offers the potential for enhanced efficacy and safety.
A ganglion is defined as a collection of nerve cell bodies and glial cells that are interconnected via a dense network of neural rami and septae of connective tissue. We recently reported the ability to detect the celiac ganglia using EUS. Visualized ganglia are typically located adjacent to the celiac artery, anterior to the aorta, and are predominantly oval or almond-shaped, with irregular margins, ranging in size from 2 to 20 mm ( Fig. 3 ). Compared with the surrounding retroperitoneal fat, ganglia are echo poor and show similar echogenicity to the adrenal gland. Central echo-rich strands or foci are commonly present with echo-poor threads (presumed neural fibers) extending from ganglia. These threads connect ganglia or course along the anterior surface of the celiac trunk. Color Doppler confirms little or absent flow within these structures.
It was initially unclear how often ganglia could be visualized by EUS. We prospectively evaluated 200 consecutive nonselected patients and documented ganglia detection in 81% of patients. The rate of ganglia detection varied based on the instrument used (radial EUS 79.2% vs linear EUS 85.6%) and among endosonographers (65%–97%). Ganglia detection and appearance did not vary with patient age, alcohol consumption, cigarette use, body mass index (calculated as weight in kilograms divided by the square of height in meters), chronic abdominal pain, or presence of malignancy. The high rate of ganglion visualization and the lack of correlation with other pathologic processes suggested that factors such as edema, fibrosis, inflammation, and malignancy were unnecessary for the visualization of ganglia. Subsequently, a Korean group evaluated 57 consecutive patients using radial EUS, allowing detection in 89% of patients.
The technique for celiac ganglia injection has not been standardized. Our report is the only one thus far to provide any details regarding the specifics of injection. Our general approach for ganglia smaller than 1.0 cm is to position the needle tip within the central point of ganglia and for ganglia 1.0 cm or larger in the needle plane axis, the needle tip is advanced into the deepest point within the ganglia ( Fig. 4 ). The injection is then performed as the needle is slowly withdrawn, with care taken to inject the agent evenly throughout each ganglion. As many ganglia as can be identified are injected. Other aspects, such as the total volume injected and volume per ganglion, have not been standardized, as discussed later.
EUS-Guided BPN
Sakamoto and colleagues described the technique of EUS-guided BPN (EUS BPN). The technique involves passing the needle under direct EUS visualization adjacent and anterior to the lateral aspect of the aorta over the level of the superior mesenteric artery (SMA) trunk. There are no other unique aspects to this approach.
EUS Studies
Wiersema and Wiersema published the initial study evaluating EUS CPN and subsequently updated their experience ( Tables 1–4 ). The later prospective study, which included the patients from their initial report, involved 58 patients with pain secondary to inoperable pancreatic cancer. Three to 6 mL (0.25%) of bupivacaine and 10 mL (98%) of alcohol were injected into both sides of the celiac trunk. Pain scores were assessed using a standardized 11-point visual analogue scale. Forty-five patients (78%) experienced a decrease (≥1 point) in pain score after EUS CPN. The pain scores were significantly lower ( P <.0001) 2 weeks after the procedure. On multivariate analysis, sustained pain relief was found for 24 weeks independent of narcotic use or adjuvant therapy. Although opioid use escalated over time, the increase was not statistically significant. There were no major complications. Minor complications were mild and transient and included hypotension (20%), diarrhea (17%), and pain exacerbation (9%). Although this study offered preliminary data suggesting the efficacy and safety of EUS CPN, the small sample size, absence of a placebo control group, and absence of physician or patient blinding limits the strength of the conclusions. In addition, despite 45 patients (78%) experiencing a decrease in pain score, only 31 (54%) experienced a decline of 3 points pr more (or a 50% decrease), which are measures of improvement that some consider necessary to signify efficacy. Furthermore, the efficacy of EUS CPN was relatively short-lived, with escalating pain scores reported at 8 to 12 weeks.
| Study | Inclusion Criteria | Exclusion Criteria |
|---|---|---|
| Gunaratnam et al, 2001 |
|
|
| Levy et al, 2008 |
|
|
| Sakamoto et al, 2010 |
| Not stated |
| Ascunce et al, 2011 |
| Not stated |
| Iwata et al, 2011 |
|
|
| Study | Design | No. of Patients | Site of Injection | Injectate (Total Volumes) |
|---|---|---|---|---|
| Gunaratnam et al, 2001 | Prospective | 58 | Celiac plexus-bilateral around celiac artery (n = 58) | Bupivacaine (0.25%, 6–12 mL) Alcohol (98%, 20 mL) |
| Levy et al, 2008 | Retrospective | 17 a | Celiac ganglia (n = 17) | Bupivacaine (0.25%, 8.3 mL) Alcohol (99%, 12.7 mL) |
| Sakamoto et al, 2010 | Retrospective | 67 | Celiac plexus-bilateral around celiac artery (n = 34) Broad plexus-bilateral around superior mesenteric artery (n = 33) | Lidocaine (1%, 3 mL) Alcohol (9 mL) Contrast (1 mL) |
| Ascunce et al, 2011 | Retrospective | 64 | Celiac plexus-bilateral around celiac artery (n = 24) Celiac ganglia (n = 40) | Lidocaine (1%, 10 mL) Alcohol (98%, 20 mL) |
| Iwata et al, 2011 | Retrospective | 47 | Celiac plexus-multiple injections | Bupivacaine (2–3 mL) Alcohol (≤20 mL) |
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