Arian Foster, Darren McFadden and Darren Sproles all went down with injuries on a painful day for some of the NFL's most versatile running backs.
After missing practice during the week with a hamstring injury, Foster started for the Houston Texans on Sunday night but quickly injured his back and was ruled out for the rest of the game against Indianapolis.
Foster played on Houston's first series, but did not have a carry. He soon left the field and was taken to the locker room.
A blowout loss was extra painful for the Oakland Raiders because of injuries to a pair of top players on offense.
McFadden left with a hamstring injury early in the second quarter of a 49-20 defeat against Philadelphia, and quarterback Terrelle Pryor came out in the fourth with a knee problem that he does not believe is serious.
The injury-prone McFadden had five carries for 12 yards and one catch for three yards before re-aggravating a hamstring that kept him out of one game already this season.
New Orleans also lost a slippery back when Sproles left a 26-20 loss to the New York Jets with a concussion and didn't return.
Sproles headed to the locker room early in the first quarter, and the Saints announced he was out for the rest of the game shortly before halftime.
It was unclear when the injury occurred, but Sproles had a 2-yard catch and was hit hard by Antonio Allen before leaving. He was replaced by Travaris Cadet on kickoff returns and Lance Moore on punt returns.
''What it does is it eliminates a handful of your plan that he's going to be involved in,'' Saints coach Sean Payton said. ''You just have to quickly be able to say, 'All right, here's what we're going to get to, and here's how much we'd like to do with Cadet that we might normally have done with Darren.'''
A key player on New York's offense went down as well: Leading receiver Jeremy Kerley was knocked out of the game with an elbow injury in the second quarter.
Allen left in the third quarter with a possible head injury, and linebacker Garrett McIntyre also didn't return after leaving with a knee injury. Jets linebacker Calvin Pace left the game late, but said he was just ''banged up'' and was fine.
Cleveland quarterback Jason Campbell briefly left in the first half with a rib injury before returning to lead the Browns past Baltimore 24-18.
Seattle center Max Unger left in the fourth quarter with a concussion, but the Seahawks rallied to beat winless Tampa Bay 27-24 in overtime.
Buffalo has more injuries to contend with on offense after rookie receiver Robert Woods hurt his lower left leg during a 23-13 loss to unbeaten Kansas City.
Bills coach Doug Marrone had no definitive update on Woods' status following the game except to say tests were negative. The second-round pick was hurt late in the third quarter when he dived for a pass and tumbled into the right sideline.
Woods had difficulty putting any weight on his leg while being escorted to the locker room.
Fellow rookie receiver Marquise Goodwin did not return after hurting his hamstring late in the game.
Buffalo is already down two quarterbacks, rookie starter EJ Manuel (sprained right knee) and backup Thad Lewis (bruised ribs).
Raiders right tackle Matt McCants injured his foot and was replaced by rookie Menelik Watson in his first action of the season.
Carolina lost starting right guard Chris Scott and backup Jeff Byers to injuries, forcing the Panthers to use former defensive tackle Nate Chandler at that spot during a 34-10 win over Atlanta.
Three Patriots players didn't return after being injured in New England's 55-31 win over Pittsburgh - defensive end Rob Ninkovich (foot), safety Steve Gregory (thumb) and wide receiver Austin Collie (knee). The team provided no update on their conditions. For the Steelers, linebacker Vince Williams and cornerback Ike Taylor sustained concussions and right tackle Marcus Gilbert had an ankle injury.
AP NFL website: www.pro32.ap.org