A former Parker doctor, office manager and two pharmacists were arrested and charged with conspiracy and illegal distribution of prescription drugs that resulted in patients deaths.

The Special Agent in Charge of the Denver Field Division of the Drug Enforcement Agency told 9NEWS this is the biggest overall investigation of drug diversion in Colorado.

The indictment alleges at least two patients who received drugs from Dr. John Littleford, 70, died as a result. Littleford, currently lives in Manhattan, Kansas and was the owner of the Pain and Injury Clinic in Parker. He was arrested Tuesday morning in Kansas.

Dianna Smithling, 39, was the clinic office manager. She currently lives in Michigan and was arrested in that state. Stanley Callas, 63, and Scott Eskanos, 61, both of Parker, are the co-owners of Crown Point Pharmacy and Sky Ridge Pharmacy. They were arrested in Douglas County.

The defendants are alleged to have dispensed controlled substances such as pain killers and sedatives to patients in quantities that would lead to misuse or addiction. They face decades in prison for 34 federal offenses.

"It was a white collar drug enterprise," DEA Special Agent in Charge Barbra Roach said.

The four were indicted by a federal grand jury in Denver last week on charges relating to the illegal distribution of prescription medication and money laundering.

Callas and Eskanos appeared in U.S. District Court Tuesday afternoon in Denver where they were advised on the charges against them. The pharmacists will remain in custody until at least Friday, when they will appear in court for arraignment, discover and a detention hearing.

Roach said the investigation is years in the making. The DEA believes from April 2010 to November 2012, the co-conspirators agreed to dispense and distribute controlled substances to patients for other than legitimate medical purposes.

"This is not to be taken lightly," said Roach. "This is highly addictive and it's something that everyone has a responsibility, not only the patients but the doctors and the pharmacists."

Drug enforcement agents served search warrants at the Sky Ridge Pharmacy located in the medical office building on the Sky Ridge Medical Center campus. Sky Ridge spokesperson Linda Watson told 9NEWS the pharmacy is independently owned and operated and not associated with the hospital.

Special Agent in Charge Roach said the problem with the excessive distribution of opiates is that it leads to heroin use, addiction and often death.

The DEA along with the IRS Criminal Investigation continue to investigate this case and other people who might be involved.

"The case itself has tentacles all over the United States," Roach said.