Fletcher's men head to the Estadio Pepe Rojo, where most pundits anticipate them posting a cricket score.
Although Jonny Wilkinson remains absent because of an ankle injury, Newcastle team up England World Cup men Mathew Tait and Jamie Noon in midfield - with the former's brother Alex starting at full-back.
Tries will top the Falcons' agenda as they knuckle down to Pool Three business in a group which also includes Brive and Connacht.
Fletcher said: "On paper, you can say this should probably be our easiest game of the season.
"But this team are no mugs, and they will be playing for the whole of Spanish rugby when they meet us on Saturday.
"They gave Harlequins a hell of scare a couple of years ago, losing by just over one score, and they will be playing with a lot of passion on what is a huge occasion for them in front of their own crowd."
Like Newcastle, Worcester also find themselves in unfamiliar territory this weekend - travelling to Romania where Pool Two hosts Bucuresti await them on Saturday.
Warriors coach Mike Ruddock welcomes back number eight Kai Horstmann from injury - while back-division switches see youngster Chris Pennell at full-back, Loki Crichton wearing the number 12 shirt and Shane Drahm taking fly-half duties.
Bath include Springboks World Cup winner Butch James among a 24-man squad for the Pool One encounter away to Auch on Saturday night.
The fly-half arrived from South Africa earlier this week - and Bath head coach Steve Meehan has named him among a group which also includes England World Cup players Olly Barkley, Lee Mears, Matt Stevens and Steve Borthwick.
Premiership strugglers Leeds face a tough appointment with Pool Five visitors Castres on Friday night, although they are lifted by centre Rob Vickerman's likely return off the bench following 18 months out recovering from two knee reconstructions.
Leeds rugby director Stuart Lancaster said: "Rob has worked incredibly hard to get himself back to full fitness.
"While I am sure there have been dark times for him, he has never shown it and always displayed a positive mental approach."
Elsewhere on Friday night, Connacht travel to 1997 Heineken Cup winners Brive - while Bayonne host Padova, and Montauban are at home to GRAN Parma.