Greater coupling of pain intensity and opioid craving after delaying methadone dose among Veterans with opioid use disorder

Abstract: Aim: Individuals maintained on methadone commonly report greater pain between daily doses. Despite a strong theoretical link, little is known about the temporal relationship between pain and craving in the context of methadone treatment. Using a cross-over design, the current study evaluated the time course of pain measured via the Cold Pressor Task (CPT) and self-reported pain and craving as a function of the last methadone dose. Methods: Male Veterans (n=20) presented for the study in the morning and either received methadone dose as scheduled or delayed dose until the afternoon (i.e., 4 h). During the study visit, participants completed a series of tasks, including self-reported pain and craving at 0, 40, 70, 130, 160, and 240 minutes and a CPT at 15 min and 220 min. Results: Separate mixed model results demonstrated no effect of dosing condition on craving; however, there was a significant dosing condition by time interaction (F(5,209)=3.38, p=.006) such that pain increased over time in the delayed methadone, but not scheduled, condition. A mixed model predicting self-reported pain revealed a three-way interaction between dosing condition, craving, and time (F(5,197)=2.39, p=.039) explained by a positive association between craving and pain at each time point (except 240 min) in delayed condition (p-range=.004-.0001). Mixed models of CPT task revealed lower detection across time in both conditions (F(1,57)=10.54, p=.002) and a significant interaction between condition by time such that threshold was lower in the delayed condition (F(1,57)=4.01, p=.05), but not the scheduled condition. Conclusions: These findings highlight greater subjective and objective reports of pain and a stronger association between pain and opioid craving when a methadone dose is delayed. Though preliminary, these results suggest elevated vulnerabilities for relapse after missing a morning dose that could have implications for methadone clinic dosing policies.

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