Seven doctors and 41 others in four Southern states were arrested Wednesday in raids by Drug Enforcement Administration agents, officials said, part of what the agency called its largest operation against illegal trafficking of prescription drugs. The raids came after a 15-month investigation by the agency, which focused on the illegal sale and distribution of painkillers including oxycodone and hydrocodone and the tranquilizer Xanax.

At a news conference, officials said the arrests were in addition to 230 others made during the investigation, which targeted doctors, pharmacists, street-level dealers and others. The arrests Wednesday were made in Alabama, Arkansas, Louisiana and Mississippi. In Mobile, Ala., two doctors who ran two pain clinics and also owned a pharmacy were arrested and charged with dispensing controlled substances outside the usual course of medical practice, and for health care fraud.

A pain clinic in Little Rock, Ark., that was raided on Wednesday was the source of hundreds of prescriptions a day written without proper examinations, said Keith Brown, the D.E.A. agent in charge of the New Orleans division.

One Arkansas pharmacist used fake prescriptions to sell 93,000 hydrocodone pills for about $500,000 in 2013, Christopher R. Thyer, the United States attorney for the Eastern District of Arkansas, said at the news conference.