Introduction
Pancreatic adenocarcinoma accounts for 56,000 cancer diagnoses in the United States per year and is fourth among cancer-related deaths. Pancreatic cancer has an extremely poor prognosis and the lowest 5-year survival among any cancer. Early-stage disease rarely presents with symptomatology and almost 50% of patients are advanced stage at the time of diagnosis. Currently, surgical resection via Whipple procedure and adjuvant chemoradiotherapy are the only curable treatments. Thus, palliative treatment to reduce pain and improve quality of life is a crucial aspect of management for these patients. Pain affects approximately 80% of patients with pancreatic cancer, which is also associated with decreased quality of life, impaired functional activity, and reduced survival. ,
Etiology and Pathogenesis
The pancreas is an important organ involved in digestion and has both exocrine and endocrine functions. The afferent nerve fibers of the pancreas are transmitted with the sympathetic and parasympathetic pathways through a complex collection of ganglia and plexuses en route to the spinal cord. These afferent visceral nerve axons almost completely comprise unmyelinated C and thinly myelinated Aδ fibers that transmit both mechanoreceptive and nociceptive information to the central nervous system. The pancreas specifically receives its extrinsic sympathetic innervation from the celiac plexus (with contributions from the thoracic splanchnic nerves) and parasympathetic innervation from the vagus nerve.
There are two principal mechanisms for the generation of pain in pancreatic cancer: pancreatic duct obstruction and pancreatic neuropathy, which activate mechanical and chemical nociceptors, respectively. Pancreatic duct obstruction is provoked by the release of pancreatic enzymes, particularly after eating. Duct obstruction blocks the flow of these enzymes and causes an increase in parenchymal pressure, which subsequently decreases blood flow and generates ischemic pain. Neuropathic pain occurs due to the invasion of nerves by cancer cells. The incidence of perineural invasion is estimated to be around 70%–90%. Cancer cell invasion promotes activation of local immune cells, release of neurotrophic growth factors, and tissue damage due to inflammation. These changes result in neurogenic pain. Additionally, as the tumor progresses, there is growth of new nerve fibers that also exacerbates pain.
Clinical Features
Presenting symptoms of pancreatic cancer vary based on the location of the tumor. Weight loss (92%), jaundice (87%), and pain (72%) are the most common symptoms of pancreatic cancer. Other nonspecific findings of pancreatic cancer include anorexia, dyspepsia, nausea, and vomiting. Pain in pancreatic cancer is usually described as epigastric pain that radiates to the back.
The presence of pain at the time of diagnosis was found to be a predictor of poor survival in a case series. , In an observational study by Ceyhan et al., patients who were undergoing surgical resection were classified preoperatively in three groups based on their pain scores. The median survivals, measured as the time between surgery and cancer-specific death, for patients with no pain, mild pain, and moderate-to-severe pain were 21.5, 15.0, and 10.0 months, respectively ( P = .0015).
Diagnosis
For patients presenting with nonspecific complaints, abdominal ultrasonography is often the first imaging modality that is performed. However, abdominal computed tomography (CT) scan is the gold standard for diagnosis and staging. Pancreas protocol scans require triphasic cross-sectional imaging (arterial, late, and venous phase), which allows for an enhancement between the pancreas parenchyma and adenocarcinoma. If a pancreatic mass is seen on imaging, then follow-up endoscopic ultrasound and fine-needle aspiration are indicated. If no mass is seen on imaging but there is high suspicion for malignancy, then endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography, magnetic resonance imaging, or magnetic resonance cholangiopancreatography may be performed for further characterization of disease.
Cancer antigen 19-9 (CA 19-9) is one of the tumor markers used to assess pancreatic cancer. It has limited sensitivity (50%–75%) and specificity (80%–85%). Therefore, it is a poor screening tool in asymptomatic patients. It is mainly used to confirm the diagnosis and predict prognosis in symptomatic patients. It may also be used to monitor for recurrent disease.
Typically, when patients are referred to an interventional pain physician, the diagnosis of pancreatic cancer has already been made. A multidisciplinary team approach involving gastroenterology, oncology, and surgical oncology should be involved when treating these complex patients. Diagnosis for pain secondary to pancreatic cancer is mostly clinical with epigastric discomfort radiating to the back.
Physical Exam
Physical exam findings in pancreatic cancer can be variable depending on the stage and the location of the tumor. Patients can have normal exams in the early stages of the disease. In advanced stages, general physical exam findings can include jaundice, cachexia, and abdominal tenderness. Courvoisier sign, defined as a nontender, distended, and palpable gallbladder in a patient with jaundice, is 83%–90% specific but is only 26%–55% sensitive for a biliary obstruction from malignancy. Other nonspecific physical exam findings include Trousseau sign (recurring superficial thrombophlebitis) and Virchow node (left supraclavicular lymphadenopathy), both of which can be found in other abdominal malignancies.
Treatment
Treatment for pancreatic cancer pain commonly involves both pharmacologic and interventional options. Patients are initially offered conservative therapy based on the analgesic ladder established by the World Health Organization (WHO). As patients often suffer moderate to severe pain, opioids are used as the mainstay treatment. Interventional procedures, such as celiac plexus neurolysis, intrathecal drug delivery systems, and thoracoscopic splanchnicectomy are considered in patients with intractable pain.
Conservative Systemic Therapies
As previously mentioned, conservative treatment of pain in pancreatic cancer is based on the analgesic ladder set by the WHO. For patients with mild-to-moderate pain, the first step of treatment is prescribing nonopioid analgesics, such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAID). These agents may be used alone or in conjunction with opioids. NSAIDs, which have anti-inflammatory and antipyretic properties, are efficacious for both bone and inflammatory pains. The use of these medications may be limited due to their renal, gastrointestinal, hematological, and cardiac toxicity profiles. Oral corticosteroids are also commonly used in late-stage disease for anorexia, analgesia, and nausea. Bisphosphonates are often given in conjunction with glucocorticoids, such as dexamethasone and prednisone, for malignant bone pain. Tricyclic antidepressants and gabapentinoids are effective for neuropathic pain, though their efficacy for malignancy-specific pain syndromes is not well-established.
For patients who receive inadequate relief with nonopioid analgesics, a trial of weak opioids, such as tramadol or codeine, should be done. If these provide inadequate pain relief, then more potent opioids can be prescribed. There is no significant difference in the analgesic efficacy or tolerability of agents such as oxycodone compared to morphine for moderate to severe cancer pain. Moreover, given that individuals have varying responses to different μ-agonists, opioid rotation should be considered when one agent proves to be ineffective or have intolerable side effects. In such cases, the equianalgesic dose of the new opioid should be reduced by 20%–30% to account for incomplete cross-tolerance and prevent an overdose of the new agent. If a patient is unable to tolerate oral medications and a long-acting opioid is desired, then transdermal fentanyl should be considered. Other routes of rapid fentanyl delivery for breakthrough pain include transmucosal lozenge, sublingual tablet, and nasal spray. Methadone has also been used for pain management in pancreatic cancer patients. Also, it is not uncommon for pancreatic cancer patients to be on multiple opioids at once as the disease progresses and the pain becomes more difficult to control.
As previously mentioned, long term opioid use is often accompanied by frequent side effects, including constipation, nausea, vomiting, sweating, anorexia, dyspepsia, and pruritus. As pain control is crucial for maintaining the quality of life, these side effects can be mitigated by adjuvant medications such as stool softeners, laxatives, appetite stimulants, and antiemetics. Additionally, the regular use of high dose opioids can lead to opioid-induced hyperalgesia, which results in worsening pain despite increased doses of opioids. A study by Zech et al. evaluated the efficacy of therapy according to WHO guidelines in cancer patients. The course of treatment of 2118 patients was assessed prospectively over a period of 140,478 treatment days. Over the whole treatment period, inadequate pain relief was reported in 12% of patients.
Celiac Plexus Neurolysis
The celiac plexus is a large visceral plexus located in the retroperitoneal space around the origin of the celiac trunk at the T12–L1 vertebral levels. It has contributions from multiple ganglia (celiac, superior mesenteric, and aorticorenal ganglia) and serves as a relay center for nociceptive signals that originate from the upper abdominal viscera. The nerve fibers of the celiac plexus are predominantly preganglionic sympathetic efferent nerve fibers derived from the greater splanchnic (T5–T9), lesser splanchnic (T10–T11), and least splanchnic (T12) nerves. Contributions to the celiac plexus also come from parasympathetic efferent fibers of the vagus nerve.
Indications
Celiac plexus neurolysis (CPN) is appropriate for patients with intractable abdominal pain caused by pancreatitis and malignancies of much of the gastrointestinal GI tract, starting from the distal esophagus to the distal transverse colon. , In addition to pain control, CPN has been shown to be effective in controlling severe nausea and vomiting in patients with pancreatic cancer, which is likely secondary to the resulting unopposed parasympathetic activity and increased peristaltic activity.
Contraindications
Although there are no clear absolute contraindications to CPN, relative contradictions exist. These include the presence of coagulopathy, bleeding disorders, thrombocytopenia, intraabdominal infection or sepsis, abdominal aortic aneurysms, and mural thrombosis of the abdominal aorta. , CPN is also relatively contradicted in patients with small bowel obstruction due to the effects of the block on increasing bowel motility.
Complications
The most common complication of CPN is local pain (96%), diarrhea (44%), and orthostatic hypotension (38%). Orthostatic hypotension results from local vasodilation and pooling of the blood within splanchnic vessels following sympathetic denervation. Elderly and hypovolemic patients are more prone to these hemodynamic effects. Other rare side effects include local anesthetic toxicity, injury to the aorta or IVC, retroperitoneal hematoma, surrounding organ injury, and paraplegia due to damage to the artery of Adamkiewicz. , In one report by Davies et al., the incidence of major complications (paraplegia, bladder, and bowel dysfunction) has been reported to be 1 per 683 procedures.
Neurolytic agents
The two main agents used for celiac plexus neurolysis are alcohol and phenol ( Table 10.1 ). The preferred concentration of ethanol for neurolysis is usually 50%–100%, as irreversible damage usually occurs at concentrations greater 50%. The mechanism of neurolysis is the extraction of cholesterol and lipoproteins from the nerve axon as well as precipitation of lipoproteins and mucoproteins, which cause irreversible damage to nerve fibers. ,
| Agent | Concentration | Viscosity | Onset of Action | Nerve Destruction | Pain with Injection | Mechanism of Action |
|---|---|---|---|---|---|---|
| Phenol | 3%–20% | High | Slow | + | Minimal | Protein precipitation, necrosis of neural structures |
| Ethanol | 50%–100% | Low | Fast | ++ | Can be intense | Extraction of cholesterol and lipoproteins |
Phenol, at a concentration of 6%–10%, can also be used for neurolysis. Due to the agent’s viscosity, dilute 6% phenol is usually preferred to facilitate easier injection. Similar to ethanol, phenol causes protein precipitation and necrosis of the neural structure. There is limited data comparing the efficacies of alcohol and phenol for CPN.
Ethanol is known to cause severe transient pain on injection, while phenol does not. Thus, the injection of a local anesthetic such as lidocaine or bupivacaine is recommended. Despite this, ethanol is the most commonly used agent for CPN due to its faster onset of action and longer duration of action. ,
Imaging
CPN can be performed with fluoroscopy, ultrasound (US), CT, magnetic resonance imaging (MRI), or endoscopic US. The use of modern C-arm fluoroscopy is wide-spread due to portability and lower cost. However, traditional fluoroscopy does not allow for an accurate distinction of the abdominal viscera. Therefore, the use of CT-guidance has gained popularity due to its ability to allow precise localization of the needle tip while providing visualization of the retroperitoneal anatomy, which is particularly important in cases where normal anatomy is distorted due to tumor invasion. ,
Technique
Posterior Approach: Posterior approaches are typically performed with the patient lying prone, most commonly utilizing the antecrural or retrocrural techniques. The antecrural and retrocrural sites are the spaces anterior and posterior, respectively, to the crura of the diaphragm. The antecrural approach is effective for targeting the celiac plexus while the retrocrural approach targets the splanchnic nerves.
For the antecrural technique under fluoroscopy, a single needle is inserted using a left posterior paramedian approach at the level of the L1 transverse process and advanced toward the anterior surface of the L1 vertebral body, ultimately through the posterior wall of the aorta until blood is aspirated. The needle is advanced further until the needle traverses the anterior wall and blood can no longer be aspirated. Fluoroscopy confirms the needle position in the preaortic space and injection of contrast solution should confirm diffusion into the antecrural space ( Fig. 10.1 ). It is important to note that this transaortic approach has an increased risk of retroperitoneal hemorrhage, particularly in patients with coagulation abnormalities.
