Phenacetin was a pharmaceutical compound once widely used for its ability to relieve pain and reduce fever. Introduced to medical practice in the late 19th century, it gained significant popularity as a household analgesic. While it provided effective relief for many years, phenacetin is no longer in use today due to serious health concerns that emerged over time. Its history serves as a notable example of how scientific understanding of drug safety evolves.
Early Development and Applications
Phenacetin was first synthesized in 1887 and quickly became one of the earliest synthetic fever reducers and non-opioid pain relievers. It was initially considered a safer alternative to acetanilide, an earlier compound with similar properties but known for causing a bluish discoloration of the skin due to its effect on hemoglobin. For decades, phenacetin was widely adopted into medical practice and was a common ingredient in over-the-counter medications.
This compound often appeared in combination pain medications, frequently alongside other active ingredients such as aspirin and caffeine. These “APC” (aspirin-phenacetin-caffeine) formulations were popular for treating headaches, muscle aches, and other common ailments. Typical doses of phenacetin in these mixtures ranged from 150 to 300 mg per tablet or capsule, and it was used extensively until the mid-20th century.
How It Affected the Body
Phenacetin functioned as an analgesic and antipyretic, alleviating pain and reducing fever. Its pain-relieving effects acted on the sensory pathways within the spinal cord. It also influenced the brain’s temperature regulation center, the hypothalamus, to lower the body’s set point, reducing fever.
Phenacetin’s action involved its metabolism. It underwent a metabolic conversion, primarily in the liver, into paracetamol, also known as acetaminophen. This metabolite, paracetamol, is widely recognized today for its own pain-relieving and fever-reducing properties and is responsible for many of the therapeutic effects originally attributed to phenacetin.
Significant Adverse Health Impacts
Prolonged use of phenacetin was found to cause severe health problems. One of the most serious consequences was kidney damage, specifically a condition called analgesic nephropathy. This form of chronic kidney disease involved damage to the internal structures of the kidneys, which could lead to progressive kidney failure.
Phenacetin was also linked to various blood disorders. It could induce methemoglobinemia, a condition where an abnormal form of hemoglobin, methemoglobin, accumulates in the blood, reducing its oxygen-carrying capacity. This could lead to symptoms such as bluish skin discoloration and fatigue. Another associated blood issue was hemolytic anemia, characterized by the destruction of red blood cells.
Beyond kidney and blood issues, phenacetin was identified as a carcinogen. It was associated with an increased risk of certain cancers, particularly those affecting the renal pelvis and bladder. The International Agency for Research on Cancer (IARC) classified phenacetin as a Group 1 carcinogen, indicating sufficient evidence of its cancer-causing potential in humans.
Worldwide Withdrawal from Use
Mounting evidence of phenacetin’s severe adverse effects prompted regulatory bodies around the world to act. Various national health authorities began withdrawing the drug from the market due to its established risks. In the United States, the Food and Drug Administration (FDA) ordered the withdrawal of drugs containing phenacetin in November 1983.
This regulatory action was based on the drug’s demonstrated carcinogenic properties and its harmful effects on the kidneys. Consequently, phenacetin is no longer available for medicinal use in most countries globally. Its metabolite, paracetamol, which has a more favorable safety profile, largely replaced phenacetin as an analgesic and antipyretic.