In most cases and when taken properly for pain, these drugs are very safe. That's why they're sold over-the-counter in the first place. But there are some situations where you can put yourself at risk by using these pain drugs improperly. Acetaminophen and Risk of Liver Damage. One of the most well-known risks of painkillers is liver damage from acetaminophen. Although [acetaminophen] has been used for years and overall is extremely safe, liver toxicity can occur with use of more than 4,000 milligrams in a day, says Dr. Glaser.