Johnny Sexton has been ruled out of Ireland's Six Nations opener against Scotland with a calf injury.
The Leinster fly-half did some light running in training on Tuesday but was still feeling some tightness in his calf and will not be considered for Saturday's trip to Murrayfield.
Flanker Peter O'Mahony will also miss the Scotland clash after suffering a hamstring strain, but Ireland will feel the loss of linchpin Sexton most acutely.
"We felt it right not to push him through the week and risk potential further damage," said Ireland forwards coach Simon Easterby.
"He's obviously had a lot of lower limb injuries, a hamstring injury which we've managed with Leinster in the pre-Christmas period.
"As a result of his calf strain and the fact we don't want to compromise his calf any further, we feel it best to leave him out this week and make sure he's right for upcoming games."
Paddy Jackson is in line to wear the No 10 shirt against Scotland with the uncapped Rory Scannell and late squad addition Ian Keatley providing cover.
While 19-cap Jackson has the experience to cope with the starting jersey, Keatley boasts just four caps - and has not featured since Ireland's 26-3 win in Italy on February 7, 2015.
Easterby defended the decision to overlook Bordeaux fly-half Ian Madigan as Ireland bosses continue to favour home-based stars for Test match selection.
"What's the alternative? Is he the first choice for Bordeaux?" said Easterby. "Unfortunately he couldn't be with us last weekend anyway because he was on the bench for Bordeaux against Clermont. So it compromises his position with us when he's not playing in Ireland.
"We're trying to support the guys who are staying here and on the whole that will be the case.
"Circumstances may allow us to look outside of that, but as it happens at the moment we've got three guys in.
"Mads hasn't been selected in the squad. He couldn't be involved last week so that didn't help his cause."
Ulster wing Andrew Trimble is struggling will a groin problem and will be monitored closely, but Keith Earls and Sean O'Brien both took a full part in training on Monday and Tuesday and are available for selection.