Updated with new information.

BOSTON ( TheStreet) --The U.S. Food and Drug Administration has raised new concerns that chronic use of a class of powerful opioid constipation medicines may cause heart-safety problems.

Salix Pharmaceuticals ( SLXP) and Progenics ( PGNX - Get Report) disclosed Wednesday that FDA officials now want a large and long-term safety study conducted before their constipation drug Relistor will be approved for chronic use. Salix executives, speaking to investors and analysts on a conference call, questioned whether a safety study as requested by FDA can be conducted -- suggesting Relistor may never be approved for long-term use.

Nektar Therapeutics ( NKTR - Get Report), on Friday night, warned the FDA's heart-safety concerns cast new risks and uncertainties over the development of its constipation medicine naloxegol, also known as NKTR-118.

On Monday, Nektar partner AstraZeneca ( AZN - Get Report) reported positive results from two naloxegol phase III studies and said there were no "clinically relevant" imbalances in cardiovascular events between patients treated with naloxegol and placebo. But the phase III studies were relatively short, lasting only 12 and 24 weeks, respectively. A one-year safety study is still underway with results not expected until early next year.

Nektar shares were down 4% to $7.81 in Monday trading.

Also potentially affected is Cubist Pharmaceuticals ( CBST), which just began phase III studies of its own constipation medicine CB-5945.

All of these drugs are being developed to address stubborn constipation that affects about half of patients who take opioids for chronic, non-cancer pain relief. Opioids work by binding to mu-opioid receptors throughout the body. When these receptors located in the brain are blocked, pain is reduced. But when the same receptors in the gut are blocked, patients can suffer from severe constipation.

Relistor, naloxegol and CB-5945 -- administered by injection or as a pill -- work similarly by blocking the action of opioids in the gut, thereby relieving constipation. But these long-acting "mu-opioid antagonist" drugs are also designed not to get into the brain, so they don't interfere with the pain-relieving action of opioids.

The commercial market for opioid-induced constipation (OIC) drugs is potentially huge given the $15 billion spent annually on opioid drugs worldwide -- half of that in the U.S. and a quarter in Europe. Approximately 14 million chronic opioid users worldwide develop constipation that resists treatment with current prescription or over-the-counter drugs.

The FDA is now questioning the long-term safety of OIC drugs before any are approved.

In a meeting held in early October between Salix and the FDA regarding Relistor, regulators raised a concern about the potential risk associated with long-term use of OIC drugs in patients that take opioids for chronic pain, Salix disclosed Wednesday.

"So, the focus that starts to surface is the possibility of whether or not withdrawal or low-grade withdrawal might actually lead to a cardiovascular event," said Salix R&D chief Bill Forbes, further explaining FDA's safety concerns to analysts and investors on a conference call.

"In order to understand this potential risk, the Division FDA has communicated that a very large, well-controlled, chronic administration trial will have to be conducted to assess the safety of any mu-opioid antagonist prior to market approval for the treatment of patients with OIC who are taking opioids for chronic, non-cancer pain," Salix said.

Injectable Relistor was approved in 2008 but only for the limited indication of treating opioid-induced constipation in critically ill patients in hospice or palliative care. Relistor use beyond four months was not studied or approved.

In August 2011, Salix and Progenics filed an application with FDA seeking to expand Relistor's label to allow long-term treatment of OIC in all patients with non-cancer pain. The filing included data from a phase III, open-label safety study in which more than 1,000 patients were treated with Relistor for 48 weeks.

In July, FDA rejected Relistor and told Salix and Progenics that additional clinical work would be required before the drug could be approved for OIC. It was at an early October meeting to follow up on the rejection that FDA officials told Salix about the agency's concerns with the cardiovascular safety of the OIC drug class, the company said.

Salix admits that it has not conducted studies of Relistor designed to specifically measure the drug's risk to heart safety. However, data encompassing 4,000 patients treated with Relistor and 1,000 patients taking a placebo has not detected any such signal, said Forbes on Wednesday's conference call.

Forbes added that he's not sure a heart-safety trial of Relistor as requested by FDA is even possible to conduct given the relative paucity of cardiovascular events observed in patients to date. Salix continues to negotiate with the FDA but at this point, Relistor for OIC is in regulatory limbo. Clinical development of a Relistor pill, also for OIC, is also on hold.

Nektar can ill afford any delays in the development of its OIC drug naloxegol. Under a partnership agreement with AstraZeneca, Nektar expects to receive $95 million in cash when naloxegol is submitted for approval in the U.S. and Europe. AstraZeneca will pay Nektar another $140 million if naloxegol is approved and launched commercially.

Whether or not FDA intends to force Nektar and AstraZeneca to conduct another safety study of naloxegol is not clear.

On Friday, Nektar surprised investors with an early filing of its 10-Q for the third-quarter, which included a new risk statement regarding naloxegol:

"For example, we understand that the FDA is exploring whether there is any evidence of a potential cardiovascular class effect related to opioid withdrawal associated with mu-opioid antagonists and naloxegol is a mu-opioid antagonist. Although AstraZeneca is conducting comprehensive safety studies for naloxegol as part of the KODIAC development program, the health authorities retain significant discretion over regulatory requirements which remain very uncertain and difficult to predict prior to obtaining approval."

KODIAC refers to a series of phase III studies designed to determine the efficacy and safety of naloxegol in patients taking opioids for non-cancer pain. One of the KODIAC studies compares the safety of naloxegol versus "usual care" over one year but results won't be known until early next year. The two shorter efficacy studies of naloxogel reported positive results Monday.

"We do not comment on ongoing discussions with the FDA," said AstraZeneca spokesman Tony Jewell, in response to questions about how naloxegol might be affected by FDA's new safety concerns with OIC drugs.

Nektar executives declined to answer questions but the company is holding a conference call on Monday to review third-quarter results and the naloxogel study results.

FDA has not spoken publicly about why it's now concerned about the long-term safety of OIC drugs but it may have to do with a higher rate of heart attacks associated with Entereg, a drug sold by Cubist approved to speed the recovery of bowel function in patients following abdominal surgery.

Entereg is also a mu-opioid antagonist like the current class of OIC drugs in development. Entereg's FDA-approved label includes a warning about increased risk of heart attacks, although it's not clear if Entereg is the cause.

Last month, Cubist started a phase III program for its OIC drug candidate CB-5945. Enrollment of 1,400 patients in a one-year safety study has begun, with efficacy studies starting next year.

"We have had extensive discussions with the FDA on our phase III program including the design of the large and well controlled (placebo vs CB-5945) safety trial. We continue to believe that this large well controlled safety trial would be acceptable for approval," said Cubist spokesman Francis McLoughlin.

-- Reported by Adam Feuerstein in Boston.

Adam Feuerstein writes regularly for TheStreet. In keeping with company editorial policy, he doesn't own or short individual stocks, although he owns stock in TheStreet. He also doesn't invest in hedge funds or other private investment partnerships. Feuerstein appreciates your feedback; click here to send him an email.