Basal sleepiness-alertness modulates drug effects. Sleepiness produced by sleep restriction leads to increased nociceptive sensitivity, suggesting opioid analgesia may also be modulated by sleepiness-alertness. This study compared thermal nociceptive sensitivity in sleepy versus nonsleepy participants after codeine or placebo. Twelve healthy normal adults, 18 to 35 years of age, had an 8-hr nocturnal polysomnogram (NPSG) followed by a Multiple Sleep Latency Test (MSLT; Carskadon and Dement, 1987). All had sleep efficiencies > 80% on their NPSG; 6 had average MSLT >or= 8 min (nonsleepy group) and 6 had latencies < 8 min (sleepy group). Participants were assessed following 8-hr time-in-bed with standard MSLT, and nociceptive assessments (using a radiant heat stimulation method) were conducted the following day with codeine 30 mg b.i.d. (0900 and 1300) or placebo b.i.d. Finger withdrawal latency (FWL) in seconds was measured to 5 different heat intensities randomly presented to the index finger pad of each hand. Mean +/- 1 SD MSLT values in the sleepy group were 4.72 +/- 1.83 min and 13.04 +/- 4.90 min in the nonsleepy group. As hypothesized, increased FWL (decreased nociception) was observed with lower heat intensities, codeine, and in the nonsleepy group. More important, there was a Group x Drug interaction with codeine increasing FWL in the nonsleepy, but not the sleepy, group. These data show the analgesic effects of codeine are diminished in sleepy versus nonsleepy individuals. They suggest clinical differences in response to analgesics are partly explained by basal state of sleepiness-alertness.