Introduction
Malignancy of the liver is increasingly prevalent and threatening with respect to morbidity and mortality. Hepatocellular carcinoma, the most common primary liver malignancy, is responsible for the third greatest number of cancer-related deaths in the world.
Patients with malignancies of the liver often have multiple symptoms that decrease the quality of life, including chronic fatigue, loss of appetite, gastrointestinal symptoms, and pain. Frequently, the disease may be at an advanced stage such that curative therapies including surgery or transplantation are no longer options. A systematic review and meta-analysis noted that 52% of patients with cancer experienced pain, irrespective of the stage of disease. Pain management is thus one of the most important components of quality of life maintenance in advanced stages of the disease.
Etiology and Pathogenesis
Pain signals generated by the liver are transmitted by the sympathetic and parasympathetic nervous systems. Nociceptive structures in the liver include the liver capsule, blood vessels, and biliary tract. Afferents travel via the celiac plexus, phrenic nerve, and lower right intercostal nerves.
Abdominal viscera have widely distributed afferents of both sympathetic and parasympathetic innervations. Painful stimuli transmit to the medullary dorsal horn of the spinal cord via unmyelinated C-fibers and lightly myelinated A-delta fibers. The parasympathetic fibers to the viscera are contributed by the vagus and sacral splanchnic nerves that pass through the superior mesenteric plexus into the celiac plexus. The sympathetic fibers are derived from thoracic, lumbar, and sacral splanchnic nerves that pass through the celiac and mesenteric plexus. Although there is substantial variability in the nerve distribution of the liver, it is generally innervated by the hepatic plexus, which is supplied by the celiac plexus and vagal trunks.
Lesions in the liver have the potential to generate pain secondary to stretching of the hepatic capsule, which is termed “hepatic distension syndrome.” A similar phenomenon may be seen with distention of the hepatic veins as seen with portal obstruction. Hepatic enlargement also has the potential to cause diaphragmatic irritation, which can manifest as referred pain to the ipsilateral shoulder. This pain is transmitted by the phrenic nerve and is known as Kehr sign .
Mechanical irritation and inflammation of the inferior pleura and peritoneum may present as referred liver pain that is somatic and carried by the lower intercostal and subcostal nerves. Compared to visceral pain, somatic pain tends to be sharper and more localized.
Clinical Features
Liver malignancies often have a silent clinical course, in part due to the deep position of the liver within the abdominal cavity. Thus, the tumor may be substantial in size and advanced in stage before diagnosis and development of symptomatology. The clinical picture is often variable and presentation is sometimes only seen with liver failure or invasion of the tumor into adjacent structures.
Early satiety, weight loss, and palpable masses in the upper abdomen may be some of the first clinical signs. Pain related to the malignancy, particularly with advanced lesions, may manifest as right upper quadrant pain that is either parietal or visceral in etiology.
Features of the pain tend to be ill-defined, dull, and aching in nature, mild to moderate in severity, and located in the epigastrium or right upper quadrant and back. Severe pain is possible and more commonly related to perihepatitis or infiltration of the diaphragm.
Cancer pain is now increasingly viewed as a distinct entity due to a complex interplay between the immune system and central and peripheral nervous systems and neoplastic cells.
Diagnosis
The evaluation of a patient with pain suspected to originate from the liver must start with a comprehensive history and physical exam aimed at identifying the primary liver disease responsible for the pain. Any other potential pathologic processes must be ruled out. An important aspect in narrowing the differential diagnosis is to characterize the quality of the symptoms. Intermittent symptoms with acute bouts of worsening may be suggestive of disease progression (liver failure). Chronic worsening symptoms may suggest a neoplastic or intrinsic cause (chronic hepatitis).
Imaging has an important role, and the choice of modality may be individualized. Modalities such as contrast-enhanced computed tomography, magnetic resonance imaging, and ultrasound all have few false positives as noninvasive diagnostic modalities. These assist with assessing the extent of the primary disease and evaluating for any potential metastatic lesions as well.
Tumor markers, particularly alpha-fetoprotein (AFP) may be helpful adjuncts to the diagnosis of liver malignancy. Although serum AFP, the most commonly used marker, has only mediocre sensitivity and specificity, testing is helpful in increasing the positive predictive value of other diagnostics such as imaging.
Differential Diagnosis
The differential diagnosis of pain suspected to be hepatic in origin is extremely diverse and span the range of spontaneously resolving aches to surgical emergencies. A careful history and physical exam is necessary to narrow the differential diagnosis and distinguish right upper quadrant pain that is of hepatic origin from pain involving other nearby structures, including the gallbladder, pancreas, and duodenum.
Disorders of the liver may be categorized as infectious or noninfectious. Infectious causes including hepatitis, amebic infections, pyogenic abscesses, and parasitic infections; all of these may also manifest as right upper quadrant pain. Direct toxic injury to the liver from alcohol consumption or medications is an additional consideration. Autoimmune inflammatory disease is a common mimic that may be suspected in the setting of rheumatologic symptoms including myalgias or rashes. Finally, serious disease such as primary or metastatic neoplasm always needs to be considered.
As previously mentioned, the pain of hepatic origin may also be mistaken for pain from the gallbladder or pancreas. Gallstone disease, including acute cholecystitis, cholelithiasis, cholangitis, and choledocholithiasis, may present with varying patterns of abdominal pain. Pancreatic disease including acute pancreatitis, pseudocysts, and abscesses may present in a similar manner.
Physical Exam Findings
The physical exam has an important role in narrowing the differential diagnosis of pain suspected to be hepatic in etiology. Vital signs, particularly temperature, are helpful in suggesting infectious processes. Abdominal palpation may help further elucidate the exact location of the pain. Palpation may also suggest the presence or absence of peritoneal signs, masses, or organomegaly. Ascites and abdominal distension may be more suggestive of a hepatic etiology.
Treatment
Pharmacologic
Pharmacologic therapy in the management of pain related to liver malignancy is often complicated by coexisting liver disease or cirrhosis. Analgesics are often metabolized by the liver and traditional dosing and frequency may manifest with untoward effects. A comprehensive understanding of pharmacokinetics is necessary due to the potential increased susceptibility to adverse effects.
Nonopioid analgesics
Acetaminophen is safely used in liver malignancy, even with coexisting liver disease, if alcohol is avoided. Although the Food and Drug Administration suggests a maximum daily dose of 4 g, the daily dose may be reduced to 2 g for age greater than 60. Acetaminophen seems to be safe in advanced chronic liver disease or cirrhosis at recommended doses.
Nonsteroidal antiinflammatory drugs (NSAIDs) comprise a diverse group of analgesics that primarily function through reduction of prostaglandins via inhibition of the cyclooxygenase enzyme. A systematic review of NSAIDs in cancer pain from 2019 concluded a paucity of quality data with respect to efficacy but observed that consideration of potential benefits is important. NSAIDs, however, should be used cautiously in the context of coexisting cirrhosis due to the potential for precipitating renal failure, ascites, or gastrointestinal bleeding.
The role of steroids in the modulation of nociceptive pain continues to be investigated as the exact mechanisms remain unclear. It is postulated that the antiinflammatory effects of steroids mediate a reduction in downstream activation of nociceptors. The most commonly prescribed corticosteroid for pain is the long-acting dexamethasone at a starting dose of 4–8 mg. In practice, steroids are prescribed for multiple nonspecific indications in cancer including bone and neuropathic pain, nausea and vomiting, and anorexia.
Extrahepatic spread of liver malignancies, particularly, hepatocellular carcinoma has an estimated rate of 5%–15%. Approximately two-thirds of those patients may experience severe and debilitating skeletal pain. Bisphosphonates are the standard of care for not only preventing, but treating a skeletal-related complications of bone metastases. Clinical trials have established an analgesic benefit to bisphosphonates but additional direct comparisons with randomized trials are needed, including cost–benefit analyses. The analgesic mechanisms continue to be speculative but current opinions center on the reduction of peripheral sensitization.
Opioids
Opioids may be effective for moderate-to-severe pain associated with malignancy of the liver but need to be prescribed cautiously with coexisting hepatic insufficiency. Opioids including tramadol and codeine undergo biotransformation to active metabolites and may be subject to high variability in clinical efficacy.
The original World Health Organization analgesic ladder was proposed in 1986 to improve strategies for cancer pain management. The modern three-step “ladder” for cancer pain in adults notes an escalation of pharmacologic agents to achieve “freedom from cancer pain.” The first step comprises nonopioids (aspirin and paracetamol) with or without adjuvants. If pain persists or increases, mild opioids (codeine) with or without adjuvants and nonopioids are trialed. If pain again persists or increases, strong opioids (morphine) with or without adjuvants and nonopioids should be considered. The original ladder was unidirectional with escalation from nonopioids to weaker opioids to stronger opioids. A fourth step to the ladder was later added that integrated nonpharmacologic procedures encompassing interventional and minimally invasive procedures in addition to a bidirectional approach.
Notable elements of the WHO strategy include oral dosing of drugs if possible (preferred to intravenous or rectal) with an around-the-clock schedule as opposed to on-demand. An understanding of the prescribed opioid is imperative as the prescription schedule should ideally follow the pharmacokinetic characteristics of the drugs.
Answering the question of which opioid analgesic to prescribe in the context of the WHO ladder may be challenging for clinicians. Mild or “weak” opioids are often considered for opioid-naïve patients with mild to moderate cancer pain. Examples include codeine, hydrocodone, or tramadol. Available formulations are principally per os (PO) with immediate and sustained release. Escalation to “strong” opioids including oxycodone, hydromorphone, morphine, and fentanyl is considered if pain persists or increases. Oxycodone is formulated PO with immediate and sustained release options. Hydromorphone and morphine have more formulation options including intravenous and subcutaneous. Fentanyl is a rapid-onset potent analgesic with formulations ranging from transdermal to intravenous to transmucosal.
Methadone is a low-cost and highly potent agent that is emerging as an effective analgesic for the management of cancer pain both in opioid-naïve patients and in rotation from other opioids. It is particularly advantageous due to its high oral and rectal absorption and long duration of action. Typical dosing intervals are 8 or 12 h.
The route of administration is important to consider as oral and rectal opioids are directly absorbed from the gastrointestinal tract and undergo significant first-pass metabolism, thus reducing the bioavailability. Hydrophilic opioids including morphine and oxycodone absorb slowly, in contrast to lipophilic opioids including fentanyl and methadone. Other options to enhance adherence or minimize pill-taking behaviors include transdermal and transmucosal opioids.
Opioid rotation is a maneuver to improve the analgesic response by changing the medication, administration route, or both. Equianalgesia tables may be used to guide opioid rotation for reasons ranging from dose-limiting adverse effects to hyperalgesia to inadequate analgesia. A 25%–50% reduction in the calculated dose accounts for incomplete cross-tolerance among opioids. Guidelines for opioid rotation continue to be primarily empirical and close monitoring in this period is crucial.
An additional consideration is the potential to trigger or worsen hepatic encephalopathy. The European Association for the Study of the Liver observes that administering naltrexone with opioids may decrease the risk of hepatic encephalopathy.
Injections
Celiac plexus block
The celiac plexus block is used as a diagnostic and therapeutic intervention that targets afferent nociceptive fibers. It is a frequently utilized technique in the management of intractable abdominal pain from liver malignancy.
The celiac plexus consists of three pairs of ganglia including the celiac ganglia, superior mesenteric ganglia, and aorticorenal ganglia that supply autonomic innervation to abdominal organs including the liver. It is located in the retroperitoneum anterolateral to the aorta at the T12-L1 vertebrae and consists of both parasympathetic and sympathetic nerves.
Multiple approaches to the technique have been described with the most common being the anterior and posterior para-aortic approaches. Imaging guidance is typically utilized, with fluoroscopy and computed tomography (CT) imaging being the most common modalities ( Table 11.1 ). A diagnostic block with local anesthetic is typically performed before a neurolytic block to confirm efficacy. Common agents such as 3%–6% phenol or 50%–100% alcohol can be used for chemical neurolysis.
Related posts:
Full access? Get Clinical Tree
