From the opening match of the championship, the Irish have been forced to contend with an ever-growing number of casualties that robbed them of six key personnel for Saturday's 13-13 draw with France alone.
O'Brien, the Six Nations' leading ball carrier, believes that Ireland will always trail some of their rivals in terms of sheer mass due to their genetics, but denies that is affecting their game. "I'm not sure that the size disadvantage is hampering our performances," the Leinster openside said.
"You could go back and look at the whole championship - our discipline let us down in one game and we weren't patient enough in another. We're matching teams physically, but obviously with our genetics, we're not a big race. If you compare us to Argentina or South Africa, they're just big men naturally and when they start to lift weights and whatnot they get bigger.
"I don't think it has hampered us. We've had a lot of injuries to big players, physical players. I won't use that as an excuse for us in this campaign, but it could be a cause of the injuries.
"But when we won the Grand Slam in 2009, no-one got injured, so what's the difference? They were as committed back then as they are now. Sometimes you just get unlucky with injuries, get a run of injuries, and that leads on to different things, but I still think we're able to mix it with the best of them."
One final assault awaits a team that has infuriated since the opening 45 minutes against Wales in what has become an anti-climatic Six Nations. Even allowing for the vast number of injuries to have depleted their ranks, their inability to turn winning positions against England, Scotland and France into victories has been deeply frustrating.
Standing between them and a possible third-place finish, which would represent a reasonable outcome given the difficulties they have faced, is a battle-hardened pack led by Sergio Parisse that carried the fight to England at Twickenham last Saturday.
"Italy's forwards are going well and it's going to be another massive, physical challenge this weekend," O'Brien said.
"Parisse is one of the best players in the world, he has an all-round game. He's good in the air, he's good at carrying, good defensively and is able to poach. He's an all-round back row and is a go-to man for Italy. If you keep him quiet it's good because most of the good things they do revolve around him. He's one of their best players and a real leader."