The withdrawal/negative affect stage consists of key motivational elements, such as chronic irritability, emotional pain, malaise, dysphoria, alexithymia, states of stress, and loss of motivation for natural rewards. Across all major drugs of abuse, this stage is characterised in laboratory animals by elevations in reward thresholds (ie, decreased reward) during withdrawal. In animal models of the transition to addiction, elevations in brain reward thresholds occur that temporally precede and are highly correlated with escalation in drug intake.20 During acute and protracted withdrawal from chronic administration of all drugs of abuse, increases in stress and anxiety-like responses also occur that contribute greatly to the malaise of abstinence and protracted abstinence (table 1).66 Human brain imaging studies have reported decreases in the sensitivity of brain reward circuits to stimulation by natural rewards during the withdrawal/negative affect stage.67
