Abstract: Hepatocellular carcinoma (HCC) remains the most common primary liver malignancy. Pain comprises one of the most pervasive and troubling symptoms of HCC and may have severely negative effects on patient’s quality of life. Furthermore, because HCC frequently arises in the setting of cirrhosis, treating pain related to this malignancy poses a clinical challenge. This article summarizes manifestations of hepatocellular cancer pain, common obstacles to treatment, and practical HCC pain management.
Keywords: hepatocellular carcinoma, health-related QOL, analgesic, opioid, loco-regional therapy, cirrhosis
Hepatocellular carcinoma (HCC) has become an increasingly threatening malignancy with regard to both morbidity and mortality. It is responsible for the third greatest number of cancerous deaths worldwide.1 Patients who are diagnosed with late-stage HCC, have co-morbid liver diseases, or receive certain loco-regional therapies (LRTs) may suffer great reduction in health-related quality of life (HRQoL).2 Interviews with HCC patients revealed fatigue, diarrhea, skin toxicities, and appetite diminishment as key factors affecting the quality of life. Most notably, nine of the 10 patients queried also reported pain, assigning it an important ranking of ≥8 on a 0–10 scale. Pain has long been a significant concern for HCC patients and their clinicians; it may manifest as abdominal pain, metastatic bone pain, or in some cases, pain related to LRT.3,4 More than 80% of patients who develop HCC have underlying liver disease or cirrhosis,5 creating special challenges for pain management. Impaired hepatic function must be taken into account when administering pain medication since most traditional analgesics are metabolized in the liver, and normal doses or dosing frequency can precipitate negative side effects such as hepatic encephalopathy and somnolence.6 Procedure-based pain control, especially for patients whose HCC has metastasized beyond the liver, has also been explored.7–9,11,22–24
In the current review, we attempt to summarize known types of pain associated with HCC, challenges associated with pain treatment, and established and experimental methods for pain treatment. Previous research has demonstrated that HCC patients presenting with pain experience worse outcomes than patients presenting without pain.10 A more thorough understanding of the pain caused by hepatocellular cancer and appropriate methods to treat it may thus not only improve patient’s HRQoL but also improve patient’s prognoses.
Right upper quadrant abdominal pain is one of the most commonly reported symptoms for patients with HCC. The pain can be parietal – due to visceral lining inflammation – or visceral.4 In either case, abdominal pain is caused principally by visceral encroachment of the primary or metastatic lesion. Recent advances in the understanding of cancer pain increasingly suggest that it may be a distinct entity among other pain states.12 It is now thought that the biology of pain precipitated by tumor invasion is defined by cross-talk processes between the immune system and central and peripheral nervous systems and neoplastic cells. However, the relative contribution of this pathophysiology to overall cancer pain is still unknown. Additionally, contemporary data demonstrate that adverse structural and functional changes in the peripheral and central nervous systems may cause patients experiencing chronic abdominal pain to suffer increased pain perception.11 Peripheral inflammation and recurrent acute pain contribute to visceral hypersensitivity. At the level of the central nervous system, recurrent acute pain contributes to hyperexcitability in pain-associated brain areas by creating synaptic connections and strengthening existing connections.
Although rarer, ~3–20% of patients experience HCC that metastasizes to the bone.7 These patients often report severe nociceptive pain. Cancer-induced bone pain (CIBP) represents an intricate pain state with nociceptive, inflammatory, and neuropathic characteristics.12 Rather than degrading bone directly, cancerous cells provoke osteoclast activation. The acidic environment between osteoclast and bone activates bone sensory neurons via acid-sensing ion channels (ASICs) and transient receptor potential vanilloid receptor 1 (TRPV1), thereby producing bone pain. Cancer cell secretion of chemical mediators (such as prostaglandins and NGF) that can stimulate or sensitize bone nociceptors and compression of sensory nerve fibers by invading tumors also contributes to CIBP.
In an unusual case, a 69-year-old man reporting left pleuritic chest pain was found to have HCC.13Though uncommon, this incidence serves as a reminder that extrahepatic spread of HCC to regions such as the lungs, lymph nodes, skeletal system, and gastrointestinal system may lead to unexpected pain manifestation.
Patients also commonly experience treatment-related pain. Many HCC patients treated with transarterial chemoembolization (TACE) experience postembolization syndrome, characterized by abdominal pain, fever, nausea, and vomiting.3 They may also experience pain during the procedure. Benzakoun et al14 found that for patients receiving selective TACE, severe postprocedural pain was associated with an age of ≤55 years, the absence of underlying chronic liver disease, and the administration of a doxorubicin dose of >50% of the total theoretical dose during the TACE procedure. For patients whose HCC is in its early stages, radiofrequency ablation (RFA) and microwave ablation are the commonly used LRTs. Postoperative and intraoperative pains are common symptoms of ablative treatments; it has been found that patients who are given general anesthesia as opposed to local anesthesia and who experience more postoperative nausea and vomiting episodes are more susceptible to experiencing intense postoperative pain following RFA.15 Furthermore, a positive association has been found between pain intensity and ablation area.
Irreversible electroporation (IRE) is an alternative nonthermal ablation therapy that has generated excitement due to its ability to surmount some challenges of thermal ablation, such as secondary thermal damage.16 Informal patient and clinician accounts have also purported that IRE causes less procedure-related pain than other LRTs. IRE has been shown to be analogous to RFA in terms of both pain experienced and amount of pain medication self-administered for HCC patients. Given its comparable procedure-related pain levels and its ability to bypass some shortcomings of thermal ablation therapy, clinicians may wish to consider IRE among other LRTs for patients who are at increased risk of procedural or postprocedure pain.
The prevalence of pain symptoms in HCC patients has necessitated the development of effective protocols for pain therapy. These therapies are often either drug based or procedure based. While conventional analgesics are used as part of pharmacotherapy, it is important for clinicians to account for impaired hepatic function when administering treatment in order to avoid adverse events related to pain control.