Actiq, New Drug for Breakthrough Cancer Pain

Restricted Use, History of Hype

April 2, 1999 A new drug for treating "breakthrough" cancer pain is now available nationwide in the USA. An estimated one million patients suffer from cancer pain and 8 out of 10 experience breakthrough cancer pain.

The new drug is in the form of a small, white, sweet flavored lozenge that dissolves in the mouth while held by an attached handle. It delivers fast-acting relief by entering the patient's bloodstream through the lining of the mouth.

John Farrar, MD, assistant professor of anesthesia at the University of Pennsylvania, says the lollipop design "makes it nearly impossible for the patient to swallow whole." This is crucial "because, if that were to happen, it would make the drug's active ingredient less effective since it is poorly absorbed in the stomach."

Dr. Farrar and his colleagues participated in a double-blind placebo trial with 92 cancer patients. After building up to an effective dose, the patients in the randomized trial were given either the active drug or a placebo. They were instructed to take an additional "rescue medication" if their pain lasted for more than 30 minutes. The rescue medication consisted of the patients' previous breakthrough medication. The study found that Actiq was more than twice as effective as the placebo at relieving pain and was very safe when used by patients already taking other pain medications. These results were published in the June 17, 1998 issue of the Journal of the National Cancer Institute .

How It Works

The drug, Actiq^® (oral transmucosal fentanyl citrate) is an opioid narcotic more powerful than morphine. It is marketed by Anesta Corp. of Salt Lake City in partnership with Abbott Laboratories.

The United States Food and Drug Administration approved Actiq last November. In view of the lollipop-candy form, and a background of hype during the clinical trials period, the FDA is insisting on special precautions.

According to Anesta and Abbott, Actiq is "the first drug product specifically designed and studied for breakthrough cancer pain in patients who are already receiving, and tolerant to, opioid therapy for their underlying, persistent cancer pain." According to the clinical trial reports, the drug starts working within 5 minutes.

This should put cancer patients themselves in reach and control of the means of managing acute rapid onset pain. Breakthrough cancer pain is defined as a flare of severe cancer pain that "breaks through" other medication already administered around the clock at regular intervals for persistent cancer pain. According to Anesta, 50 per cent of cancer patients experience these flares.

Breakthrough cancer pain is hard to manage, the marketers say, because of its "severity, rapid onset and unpredictability." Pills to be dissolved in the stomach are liable to leave a "pain-relief gap" between onset of breakthrough pain and onset of pain relief.

Hype During Trials

The FDA is concerned about risk to other people who might get at this medication. They say that "Actiq may be fatal to children (as well as to adults not already taking opioid narcotics). They have approved Actiq under special regulations "that restrict distribution as defined in a comprehensive risk management plan." They say they "were extremely concerned that this product be packaged and marketed to minimize the opportunity for diversion, abuse, or access by children."

Unfortunately, Anesta hyped the drug while it was under development. In May 1998 the Division of Drug Marketing, Advertising, and Communications (DDMAC) found Anesta in violation of regulations against publicizing a drug while it is still being tested. DDMAC said Anesta was "disseminating press releases that make misleading promotional representations concerning the efficacy of Actiq."

DDMAC Branch Chief Thomas W. Abrams, R.Ph., M.B.A. complained that Dr. Paul Coluzzi, an investigator for Anesta, "presented statements about the safety and efficacy of Actiq in a promotional context." In the television program, Orange County Online, Dr. Coluzzi stated that with Actiq, patients may not get the "dopey effect" associated with other narcotic analgesics. "However," Dr. Abrams wrote to Patricia J. Richards, Director of Anesta's Regulatory Affairs division, "this statement contradicts the findings from the clinical trials where a high percentage of patients reported somnolence with the use of Actiq." [See Fax to Anesta for more on this].

Need is Severe

Of course what matters most is how Actiq works beyond the trials setting, in the real world -- in home, hospital, and nursing home use. Last year Giovanni Gambassi, M.D., visiting professor in the Center for Gerontology and Health Care Research at Brown University, found that "daily pain is prevalent among nursing home residents with cancer and is often untreated, particularly among older and minority patients."

HGambassi found that "26 percent of patients with daily pain received no analgesics, not even an aspirin or acetaminophen tablet." (These patients would not be able to take Actiq.) "Failure to prevent or to treat pain effectively is unacceptable and should be considered a first-line indicator of poor quality of medical care," he said. For more on this story, see Cancer Pain Widespread, Often Untreated.

Precautions

Patients who tested Actiq in clinical trials reported that the commonest side effects are sleepiness, nausea, vomiting and dizziness. Constipation, diarrhea, and edema were among other side effects. A list of all these should be made accessible to patients and caregivers by way of the full drug package insert. In addition, the latest Physician's Desk Reference is available for consultation in some public libraries.

Although Anesta seems to downplay side-effects in some press releases, and even avoid stating that this drug is an opioid, they do say that side effects were typical of those for opioid painkillers.
      Actiq carries risk of respiratory depression (slowed breathing). Actiq is not to be used for management of acute pain or for pain after a surgical operation (when slowed breathing and/or pneumonia are a risk). It must not be used in patients who cannot tolerate opioids. It is intended to be used only in the care of cancer patients by oncologists and pain specialists who are skilled in the use of Schedule II opioids to treat cancer pain.

Anesta and Abbott emphasize that special precautions must be taken to make sure that children or others don't treat this drug as candy. Abbott and Anesta say that they "have taken steps to protect against the accidental use or misuse of Actiq." "A comprehensive education program has been developed," they say, "to inform healthcare professionals, patients and their families of the proper use, storage, handling and disposal of Actiq. The program is designed to address potential risk situations involving the product, including accidental ingestion by children, improper patient selection and diversion or abuse."