LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

The opioids are a large class of medications related in structure to the natural plant alkaloids found in opium that are derived from the resin of the opium poppy, Papaver somniferum. The natural alkaloids are also referred to as opiates and include morphine and codeine. Synthetic derivatives include heroin, fentanyl, hydromorphone, methadone, buprenorphine and others. The opioids are highly potent and effective analgesics, but most have a high potential for dependency and abuse. Opioids act by engagement of specific cell surface receptors; the opiate receptors, which are designated µ [mu], κ [kappa] and δ [delta]. These receptors are found predominantly in the central nervous system, brain and spinal column, but are also present on vascular, cardiac, lung, gut and even peripheral blood mononuclear cells. Engagement of the opiate receptors generates a series of intracellular signals, including inhibition of adenylate cyclase, decreased opening of calcium channels, increased potassium currents and activation of protein kinase C (PKC). The major effect of these pathways is reduction in cell excitability and neurotransmission. The natural ligands for the opiate receptors are the so-called endogenous opioid peptides such as the enkephalins, endorphins and endomorphins. The opioids have a variety of clinical effects, but are predominantly known and used for their profound pain relieving effects. Other effects that are often linked to opiate analgesia include euphoria, changes in mood, drowsiness and mental clouding. However, the distinctive feature of the analgesia induced by the opioids is the lack of loss of consciousness. The pain is often described as less intense, but still present although better tolerated. Thus, the opioids do not decrease or treat the cause of the painful stimulus, but rather decrease its perception. Other effects of opioids include respiratory depression, decreased gastrointestinal motility, sedation, nausea, vomiting, constipation and intestinal bloating. Opioids also have direct cardiovascular effects, decreasing blood pressure, causing vasodilation and decreasing cardiac work. Most opioids have similar effects and side effects, although pharmacokinetic differences, tissue distribution, and receptor type specificity probably account for the variation in effects of the various synthetic and semisynthetic derivatives of morphine. Morphine is considered the prototype opiate, against which other agents are measured for their analgesic effects as well as adverse side effects. The opioids can be categorized into subclasses on the basis of their chemical structure as opium alkaloids (opiates: codeine, morphine), semisynthetic derivatives of the natural alkaloids (hydrocodone, hydromorphone, oxycodone, buprenorphine), and various classes of synthetic opioids such as the anililopiperidines (fentanyl, alfentanil, sufentanil, remifentanil), diphenylpropylamine derivatives (propoxyphene, dextropropoxyphene, methadone, diphenoxylate, loperamide), and others (pentazocine, butorphanol, nalbupine, levorphanol, tramadol), and, the opioid antagonists (nalmefene, naloxone and naltrexone). They can also be informally classified based upon their major use such as anesthesia (fentanyl, alfentanil, remifentanil, sufentanil), severe pain (morphine, hydromorphone, levorphanol, merperidine), moderate to severe acute or chronic pain (transdermal or transbuccal fentanyl, codeine, oxycodone, hydrocodone, levorphanol, methadone), diarrhea (loperamide, diphenoxylate), and cough (codeine, hydrocodone). Finally, opioids can be categorized on the basis of their action as full agonists, partial agonists or mixed agonists/antagonists, and antagonists of opiate receptors. Opioid receptor antagonists are used to reverse the effects of opioids and are invaluable in the management of opioid overdose (naloxone, naltrexone, nalmifene). Specialized opioid antagonists can be used to reverse unwanted opioid effects, such as constipation in patients with chronic pain on long-term opioids. These agents (naldemedine, naloxegol) are generally modified so as not to cross the blood brain and reverse the central nervous system effects of opiates. Opioids are rare causes of drug induced liver disease and are not mentioned in large case series of clinically apparent liver injury caused by medications. In physiological, pain relieving doses, opioids have not been implicated in causing clinically apparent liver injury, acute liver failure, chronic hepatitis or vanishing bile duct syndrome. However, overdoses of the more potent opioids have been linked to cases of acute liver injury, usually with a precipitous onset and pattern of acute toxicity with marked elevations in serum aminotransferase levels and early onset of signs of hepatic failure. This syndrome has been best characterized after buprenorphine overdose or abuse, but likely occurs with others. It is possible that the implicated opioids are not directly toxic to the liver, but cause ischemic liver injury due to respiratory failure, cardiovascular collapse, shock and anoxia that can occur with severe opioid overdose. The clinical syndrome resembles acute hepatic necrosis and liver failure, but is rapidly reversible and rarely the primary cause of death from overdose. A special form of liver injury linked to opioid use occurs with their fixed drug combinations with acetaminophen. These combinations are commonly used for moderate to moderately severe pain and can lead to abuse. If taken too frequently, acetaminophen doses may reach toxic levels, particularly with overuse for several days in the face of malnutrition, alcohol abuse or intercurrent illness. These other stresses can lower hepatic glutathione levels and predispose to acetaminophen hepatotoxicity. This constellation of events is referred to as inadvertent or unintended acetaminophen overdose or more colloquially as a “therapeutic misadventure”. For this reason, the FDA has recommended that physicians not use opioid combinations in which the dose of acetaminophen is greater than 325 mg per tablet or unit dose. References to the safety and hepatotoxic potential of the various opiate agonists are given together at the end of this Overview section. References to the opioids and the opiate antagonists used to treat substance abuse are given separately with each agent (buprenorphine, methadone, nalmefene, naloxone, naltrexone). The opioids are discussed individually or as groups of agents and links to each are given below. Full and partial agonists: Alfentanil. Butorphanol. Codeine. Diphenoxylate. Fentanyl. Heroin. Hydrocodone. Hydromorphone. Levorphanol. Loperamide. Meperidine. Methadone. Morphine. Opium. Oxycodone. Oxymorphone. Pentazocine. Remifentanil. Sufentanil. Tramadol. Opiate antagonists: Naldemedine. Nalmefene. Naloxegol. Naloxone. Naltrexone.