The opening encounter of a four-Test series will see England minus Flintoff (ankle), Ashes-winning captain Michael Vaughan (knee), pacemen James Anderson (back) and Simon Jones (knee) as well as left-arm spinner Ashley Giles (hip).
Meanwhile experienced swing bowler Matthew Hoggard is struggling with a freak hand injury sustained during a warm-up in last week's 'A' team draw against the tourists.
But as Stephen Harmison, set to be England's lone senior quick, observed it is Flintoff who will be the biggest loss for the hosts this week in a match where Andrew Strauss leads the team for the first time in a Test in the absence of the Lancashire hero.
"I can be replaced, everybody else can be replaced," the Durham quick said.
"But, at this moment in time, Fred (Flintoff) can't be replaced because we haven't got anybody else in the country who can bat at six, bowl at 90mph and stand at slip," Harmison insisted.
"I don't think you'll ever replace that."
England are set to bat Ian Bell at six and use his occasional medium-pacers, along with those of Paul Collingwood, to supplement Harmison, Liam Plunkett, Jon Lewis and left-arm spinner Monty Panesar, if Hoggard fails to overcome his right hand injury.
Harmison, a less obviously self-confident performer than Ashes ace Flintoff, insisted he could still be effective in the absence of his great friend despite bowling just 32 first-class overs this season because of a shin problem and struggling for rhythm during England's recent 5-0 one-day series thrashing by Sri Lanka.
"We are good mates but we are not totally inseparable. It's not like we sit in that corner and nine others sit in that corner. We are not like that.
"Anybody would miss him. You take 'Fred' out the team, we're not the same team. But we go with what we've got.
"The one thing we haven't been doing in recent times is nailing Test matches," Harmison explained. "We've got to get back to doing the basics well scoring 400 plus (in the first innings) and taking 20 wickets."
Pakistan too have their fair share of fitness problems. Spearhead quick Shoaib Akhtar is definitely out with an ankle problem and fellow pacemen Mohammad Asif (elbow) and Mohammad Sami (knee) are both battling injuries.
And Rana Naved, a star in English conditions for Sussex earlier in the season, has left the tour because of a groin injury with uncapped left-arm seamer Samiullah Niazi summoned as cover after an impressive domestic season.
"Asif is in pain but he is being treated by experts and might get fit for the first Test," said Pakistan tour manager Zaheer Abbas.
In leg-spinner Danish Kaneria Pakistan have one of the best slow bowlers in the world game. And during last year's 2-0 series win over England late last year, captain Inzamam-ul-Haq led from the front with 431 runs at an average of over 100.
The 'odd couple' of Inzamam and coach Bob Woolmer, the former England batsman, have created an unusually united side by recent Pakistan standards without losing the natural flair for which the country's players are renowned
Not since 1982 have England beaten Pakistan in a Test series in England. Ending that run may depend as much on their medics as their men in the middle.