Wales centre Jonathan Davies will miss the Six Nations because he must have knee surgery following the World Cup.
Davies is out of action for at least six months after picking up the injury during the World Cup against Fiji.
The 31-year-old British and Irish Lion missed the quarter-final against France but returned for the semi-final defeat against South Africa and bronze medal match against New Zealand.
Rhys Patchell is also out for at least three months after a shoulder injury.
The Scarlets fly-half, who was a replacement against the Springboks and started against the All Blacks, is expected to be out for three to four months as he also faces surgery.
Wales open their Six Nations campaign against Italy on Saturday, 1 February in Cardiff and finish against Scotland at the Principality Stadium on 14 March.
Saracens back Liam Williams is set to miss the start of the tournament with an ankle problem, while George North (hamstring), Tomas Francis (arm), Cory Hill (leg), Josh Navidi (hamstring) and Leigh Halfpenny (concussion) all finished the World Cup with injuries.
Davies suffered the knee injury while creating the hat-trick try for wing Josh Adams in the 29-17 win over Fiji in Japan.
He trained and played in Japan for the final few weeks with heavy strapping on his left leg.
Fellow Scarlets centre Hadleigh Parkes started six matches in Japan despite suffering a broken bone in his hand in the opening match against Georgia and also picked a shoulder problem against Uruguay.
Potential Six Nations replacements for Davies include Ospreys duo Owen Watkin and Scott Williams and Bath centre Jamie Roberts, although he would be ineligible to face the Barbarians on 30 November.
New Zealand-born Cardiff Blues centre Willis Halaholo is eligible for Wales through residency, while wings North and Owen Lane could be asked to move to fill the midfield position.
Blues coach John Mulivhill confirmed the national coaches had already spoken to Halaholo.
"His attack is right up there and his defence has improved this year - that's one of his big work-ons through the new Welsh coaches, who've spoken to him," said Mulvihill.
Patchell picked up his injury in the second-half of the 40-17 defeat by New Zealand and faces a race to be involved in any of Wales' Six Nations matches next year.
Sam Davies recall?
Wales are already without fellow fly-half Gareth Anscombe for the tournament after the Ospreys back picked up a knee injury in August.
Wayne Pivac will take charge of his first Wales game against a Barbarians team coached by Warren Gatland.
With Northampton fly-half Dan Biggar unavailable for this fixture because he plays his club rugby outside Wales, Cardiff Blues' Jarrod Evans would be the favourite to wear the Wales 10 jersey.
Sam Davies is the only other Wales capped fly-half with a Welsh region after moving from the Ospreys to the Dragons and is ready to rekindle his to rekindle his international career, according to the region's assistant coach Ceri Jones.
"I've been over the moon with Sam since he's come in," he said.
"He's given us real leadership on the field and been a massive asset to us. He's marshalled the game really well and I think he could do a fantastic job for Wales."