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) 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), 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) 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.