OPIOID SERIES:

You think ’10 was tough? Check out ’12

For the first time in two cycles, Democrats will have more seats up for grabs than the Republicans, and the party could see its shrunken majority erased altogether.

Several of the senators up for reelection came in on the 2006 Democratic wave, when the party picked up six GOP seats and won control of the chamber.

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Sens. Bob CaseyRobert (Bob) Patrick CaseyNow is the time to modernize the OTC monograph system Dems walk tightrope on Pompeo nomination Overnight Energy: Trump NASA pick advances after drama | White House office to investigate Pruitt's soundproof booth | 170 lawmakers call for Pruitt to resign MORE Jr. (D-Pa.), Claire McCaskillClaire Conner McCaskillOvernight Energy: Senate confirms Bridenstine as NASA chief | Watchdog probes Pruitt’s use of security detail | Emails shine light on EPA science policy changes Heitkamp becomes first Dem to back Pompeo for secretary of State Duckworth brings her baby to Senate vote, drawing a crowd MORE (D-Mo.), Sherrod BrownSherrod Campbell BrownOvernight Finance: Senate repeals auto-lending guidance, shattering precedent with vote | House passes IRS reform bills | Senate GOP fears tax cut sequel Dem Senator open to bid from the left in 2020 GOP Senate hopefuls race to catch up with Dems MORE (D-Ohio), Sheldon WhitehouseSheldon WhitehouseDem senators demand Trump explain ties to Koch brothers Overnight Energy: Senate confirms Bridenstine as NASA chief | Watchdog probes Pruitt’s use of security detail | Emails shine light on EPA science policy changes EPA inspector general to probe Pruitt's use of taxpayer-funded security detail on trips to Disneyland, Rose Bowl game MORE (D-R.I.), Jon TesterJonathan (Jon) TesterOvernight Defense: Congress poised for busy week on nominations, defense bill | Trump to deliver Naval Academy commencement speech | Trump administration appeals decision to block suspected combatant's transfer The Hill's Morning Report: 200 Days to the Election Koch network targets Tester with new six-figure ad buy MORE (D-Mont.) and Jim Webb (D-Va.) defeated GOP incumbents that year but will have to win reelection in 2012.

And two senators who won special elections Tuesday, Joe ManchinJoseph (Joe) ManchinDemocrats mull audacious play to block Pompeo Heitkamp becomes first Dem to back Pompeo for secretary of State Trump eyes Cold War statute to keep coal burning: report MORE (D-W.Va.) and Kirsten GillibrandKirsten Elizabeth GillibrandSchumer to introduce bill to decriminalize marijuana Navy, Marines chiefs say no morale issues with transgender troops Dem senators call on FCC to protect against robocalls MORE (N.Y.), will face voters again in two years.

 Democrats lost at least six Senate seats Tuesday, with results in Washington and Alaska undetermined as of press time, but they retained control.

That could change in two years, when Democrats have 21 seats up for grabs, compared to only 10 for Republicans. Also up for reelection are Sens. Joe Lieberman (Conn.) and Bernie SandersBernard (Bernie) SandersHannity snaps back at 'Crybaby' Todd: 'Only conservatives have to disclose relationships?' Chuck Todd lashes out at Fox, defends wife in radio interview Trump pressed Sessions to fire FBI agents who sent anti-Trump texts: report MORE (Vt.), the two Independents who caucus with Democrats — meaning the party has a total of 23 seats to defend.

“The numbers are really working against them, no question about it,” said Jennifer Duffy, a senior Senate analyst at The Cook Political Report. “It will come down to what it always comes down to: retirements and recruiting.”

Many of those Democratic seats up next cycle are in purple or red states, including those of McCaskill, Manchin, Tester, Webb and Sens. Kent Conrad (N.D.), Ben Nelson (Neb.) and Bill NelsonClarence (Bill) William NelsonOvernight Energy: Senate confirms Bridenstine as NASA chief | Watchdog probes Pruitt’s use of security detail | Emails shine light on EPA science policy changes Scott ramps up spending to million in Florida Senate race Overnight Energy: Trump NASA pick advances after drama | White House office to investigate Pruitt's soundproof booth | 170 lawmakers call for Pruitt to resign MORE (Fla.).

Webb saw several House Democrats in his state lose reelection Tuesday, and McCaskill saw her party lose a Senate pickup opportunity when Roy BluntRoy Dean BluntMcCaskill outpaces GOP opponent by more than million GOP senators raise concerns about babies on Senate floor Some doubt McCarthy or Scalise will ever lead House GOP MORE (R) won retiring Sen. Kit Bond’s (R-Mo.) seat.

Some senators could opt to retire in 2012. Among those observers will be watching are Ben Nelson and Sen. Herb Kohl (D-Wis.).Nelson is expected to face a difficult race, and Kohl saw his home-state colleague, Sen. Russ Feingold (D), lose on Tuesday.

Casey and Conrad also saw Democratic colleagues lose in their home states on Tuesday. And Sen. Dianne FeinsteinDianne Emiel FeinsteinSenate panel punts Mueller protection bill to next week Steyer endorses de León in bid to unseat Feinstein Amid struggle for votes, GOP plows ahead with Cabinet picks MORE (D-Calif.), who’s up in 2012, watched fellow California Democrat Barbara BoxerBarbara Levy BoxerThe ‘bang for the buck’ theory fueling Trump’s infrastructure plan Kamala Harris endorses Gavin Newsom for California governor Dems face hard choice for State of the Union response MORE fend off a tough challenge from the GOP. 

“It is certainly true that the landscape will be tilted in 2012 in terms of the seats at risk,” said Stuart Rothenberg, editor and publisher of The Rothenberg Political Report. “[Democrats] will be defending more seats, so they could have more losses. On the other hand, it depends on the mood of the public.”

 The other Democratic incumbents up next cycle are Daniel Akaka (Hawaii), Tom CarperThomas (Tom) Richard CarperGOP chairman probes Pruitt’s four email addresses Watchdog requests probe into relationship between top EPA aide and man investigating him Overnight Finance: Wells Fargo could pay B fine | Dems seek info on loans to Kushner | House to vote on IRS reform bills | Fed vice chair heading before Congress MORE (Del.), Jeff Bingaman (N.M.), Maria CantwellMaria Elaine CantwellLobbying World Interior won't lower offshore drilling royalty rates Watchdog: Zinke could have avoided charter flight after meeting with Las Vegas hockey team MORE (Wash.), Ben CardinBenjamin (Ben) Louis CardinThe Hill's 12:30 Report Dems give muted praise to Pompeo-Kim meeting Key Dem to oppose Pompeo nomination MORE (Md.), Amy KlobucharAmy Jean KlobucharOvernight Energy: Senate confirms Bridenstine as NASA chief | Watchdog probes Pruitt’s use of security detail | Emails shine light on EPA science policy changes Duckworth brings her baby to Senate vote, drawing a crowd GOP senators raise concerns about babies on Senate floor MORE (Minn.), Robert MenendezRobert (Bob) MenendezPoll: Menendez has 17-point lead over GOP challenger Russian attacks on America require bipartisan response from Congress Justice Dept intends to re-try Menendez in corruption case MORE (N.J.) and Debbie StabenowDeborah (Debbie) Ann StabenowSenators push HHS to negotiate lower prices on opioid overdose reversal drug Senators press administration on mental health parity Progressive groups launch M midterm initiative in three battleground states MORE (Mich.).

 The 10 GOP senators facing reelection are John BarrassoJohn Anthony BarrassoMajor GOP donor Friess to enter Wyoming governor race EPA to conduct 'full review' of information requests for Pruitt records Overnight Energy: Senate confirms Bridenstine as NASA chief | Watchdog probes Pruitt’s use of security detail | Emails shine light on EPA science policy changes MORE (Wyo.), Scott Brown (Mass.), Bob CorkerRobert (Bob) Phillips CorkerDemocrats mull audacious play to block Pompeo Judge blocks Trump administration from transferring unnamed enemy combatant Rand Paul under pressure as Pompeo hunts for votes MORE (Tenn.), John Ensign (Nev.), Orrin HatchOrrin Grant HatchSenate Finance leaders call on Commerce to improve the tariff-exclusion process GOP senators raise concerns about babies on Senate floor House passes series of bills to improve IRS MORE (Utah), Kay Bailey Hutchison (Texas), Jon Kyl (Ariz.), Richard Lugar (Ind.), Olympia Snowe (Maine) and Roger WickerRoger Frederick WickerLet's hold Facebook to the same standards as other players in the industry Cindy Hyde-Smith sworn in as Mississippi's latest senator Miss. Dem touts campaign poll saying he leads GOP candidates in Senate race MORE (Miss.). 

Of that list, the only senator who could be considered in a “dangerous” position is Brown, who represents Massachusetts, a blue state.

Hutchison could retire. She ran for Texas governor in 2010 but lost in the GOP primary. At the time, Hutchison hinted she could resign her seat; she never committed to running again in 2012.

Ensign could leave the Senate if he faces charges stemming from the fallout of an affair he had with a former staffer.

An unknown factor for the Republicans is the Tea Party. The grassroots movement took down several party favorites in GOP primaries this year and has threatened to do the same next cycle.

Already, Rep. Jason ChaffetzJason ChaffetzIngraham’s ratings spike a wake-up for advertisers Boehner to campaign for House GOP candidates Americans want to protect public lands, Congress should listen MORE (R-Utah), a Tea Party favorite, has said he’d consider challenging Hatch in the 2012 GOP primary.

Additionally, Republicans could always be doomed on pocketbook issues. If the economy rebounds, President Obama could be credited in the eyes of some voters. If it stays sluggish, voters could blame the GOP.

The top three Senate Democrats launched a strategy on that front on Wednesday, putting Republicans on notice that they expected cooperation now that the minority party is more powerful.

 “We have made the message very clear that we want to work with Republicans,” said Majority Leader Harry ReidHarry Mason ReidDems walk tightrope on Pompeo nomination The Memo: Teens rankle the right with gun activism Dems to party: Go on offense with Trump’s alleged affairs MORE (D-Nev.). “If they’re unwilling to work with us, there’s not a thing we can do about that, but the American people can see that like a very slow curveball.”

Curtis Gans, director of the Center for the Study of the American Electorate at American University, notes that the Republican revolution of 1994, ushered in by former House Speaker Newt Gingrich (Ga.), dealt a major blow to President Clinton — though Clinton won reelection in 1996.

“My thesis is, we’re going to have a miserable two years, but this time not all the blame will go to the president,” Gans said. “Nobody knows what the climate will be in 2012.”

 Rothenberg agreed, saying much depends on the messaging and issues that will dominate the political landscape over the next two years.

 “There’s probably not likely to be as stark of a choice in 2012 as this year — however, it’s also true that most people think the president’s party runs things. It’s not as easy for Democrats to just say, ‘They share responsibility, too.’ ”