PAIN MANAGEMENT AND ASSOCIATED CHALLENGES

As ~70–90% of HCC patients have cirrhosis, pain management with traditional analgesics in many patients with HCC presents a clinical challenge. Cirrhosis can alter drug pharmacodynamics by affecting changes in drug absorption, distribution, bioavailability, cytochrome P450 metabolism, and hepatic and renal clearance mechanisms.6 Prescription of improper drug classes or failing to closely monitor dosage and dose frequency can cause or worsen variceal hemorrhage, ascites, renal failure, and hepatic encephalopathy or even can precipitate liver failure.

Though nonhepatologists have warily regarded its use in patients with liver disease, acetaminophen is a safe and effective pain reliever as long as the patient does not consume alcohol.17 The Food and Drug Administration lists 4 g of acetaminophen as the maximum daily dose, though most hepatologists advise patients consume a maximum of 2 g/day. Previous survey data suggest a disparity between gastroenterologists and nongastroenterologists regarding over-the-counter analgesic clinician recommendations for cirrhotic patients;6 gastroenterologists were more likely to recommend acetaminophen over nonsteroidal anti-inflammatory drugs (NSAIDs), while nongastroenterologists were more likely to recommend the opposite. In practice, NSAIDs are contraindicated for all patients with cirrhosis due to risk for renal failure and gastrointestinal bleeding, even for patients with well-compensated liver disease.17 NSAIDs can also precipitate the development of ascites and nephrotoxicity, particularly in patients with portal hypertension.

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Opioids are effective for moderate-to-severe pain but should be used cautiously in patients suffering hepatic impairment. Some opioids must undergo biotransformation in the liver to become active metabolites, which can lead to clinical efficacy variability among those with HCC. The reduced analgesic effect exhibited by both tramadol and codeine can be attributed to these phenomena.6Conversely, meperidine bioavailability can increase up to 80% in cirrhotic patients due to a diminished first-pass effect and can cause CNS suppression and hepatic encephalopathy.18 Coupled with the risks posed by its neurotoxic metabolite normeperidine, meperidine should be avoided in all patients with cirrhosis. Clinicians may prefer to use opioids metabolized by glucuronidation, such as morphine and buprenorphine, rather than those metabolized by the cytochrome P450 system. Liver failure precipitates decreased clearance of opioids metabolized by the P450 system, thereby increasing their bioavailability. Glucuronidation reactions are altered less since glucuronidases are maintained in the setting of hepatic impairment. In light of this, if physicians choose to use medications metabolized via the P450 pathway, dosage should be modified accordingly. Fentanyl, methadone, and hydromorphone are metabolized by the P450 system and may therefore be safer options for cirrhotic patients since they do not produce toxic metabolites. Codeine is also metabolized via the P450 pathway but should be avoided, as its analgesic effects are considerably diminished and accumulation of its metabolite has been known to cause respiratory depression. All opioids should be administered carefully since they can cause or worsen hepatic encephalopathy. The European Association for the Study of the Liver (EASL) notes administering naltrexone along with opioids may help overcome the increased risk of constipation and hepatic encephalopathy in HCC patients treated with opioids.19 A pure opioid receptor antagonist with greater gastrointestinal rather than systemic activity, naltrexone, has been shown to alleviate these risks in populations susceptible to opioid-induced constipation.

For pain management in opioid-naïve cancer patients in general, the National Comprehensive Cancer Network (NCCN) recommends different routes of treatment based on pain intensity.20 Patients presenting with severe pain (7–10 on a 1–10 scale) should be given rapid titration of short-acting opioids while those presenting with moderate pain (4–6) should be provided slower titration of short-acting opioids. The NCCN recommends morphine as the starting drug of choice, although other pure agonists such as oxycodone, fentanyl, and hydromorphone are also commonly used and equianalgesic doses may be substituted. In addition to achieve quick analgesic effect, these medications are preferable because their short half-lives allow easier titration than long half-life analgesics such as methadone. Mild cancer pain should be treated first with acetaminophen and adjuvant analgesics such as anticonvulsants and antidepressants. If the pain persists, short-acting opioids may be considered. Anticonvulsants such as gabapentin and pregabalin are commonly used to treat neuropathic cancer-related pain; they may be especially helpful in patients with cirrhosis since these patients frequently experience neuropathies caused by factors such as alcoholism, diabetes, and nutritional deficiencies.20,21 Neither gabapentin nor pregabalin is metabolized by the liver, making them the preferred anticonvulsants in the setting of cirrhosis. Antidepressants are also regularly used to treat neuropathic cancer pain. Clinicians wishing to use tricyclic antidepressants (TCAs) should start HCC patients at low doses because of TCAs’ sedative effects and because patients may be more affected by anticholinergic adverse effects due to the altered metabolism precipitated by liver disease. Furthermore, clinicians should be vigilant about intestinal stasis as an adverse effect of TCA use since it can cause hepatic encephalopathy. Serotonergic antidepressants should be prescribed carefully since drug interactions pose the risk of serotonin syndrome. Tramadol and tapentadol should not be administered to any patients receiving selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or TCAs for this reason.

For pain management in opioid-tolerant patients reporting breakthrough pain ≥4, the NCCN advises administration of a “rescue” dose in addition to the patient’s chronic dose. This should be equivalent to 10–20% of the opioid amount taken by the patient in the preceding 24 hours. Patients should be continually monitored following rescue dose administration to determine efficacy and adverse effects; if the patient’s pain score remains unchanged, additional rescue doses at 50–100% the amount of the previous dose may be administered. Adjuvant analgesic therapies may also be considered for opioid-tolerant patients who are only partially responsive to their current medications. Table 1 provides an overview of clinical practice for common analgesics with regard to cancer patients and dosing modifications in the setting of cirrhosis. Given the complexity of treating chronic pain in cancer patients, it would be beneficial to consider consultation with a palliative care specialist to aid in pain management for patients with chronic or difficult-to-control pain.

(To view a larger version of Table 1, click here.)