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Azolosa JL, Stitzer ML, Greenwald MK. 
“Opioid physical dependence development: effects of single versus repeated morphine pretreatments and of subjects' opioid exposure history”. 
Psychopharmacology (Berl). 1994 Feb 08;114(1):71-80.
In acute dependence, signs and symptoms of opioid withdrawal are precipitated when an opioid antagonist (naloxone) is administered following acute (e.g. single dose) pretreatment with a mu agonist. This study examined the influence of amount of previous opioid exposure, both immediate and remote, on intensity of precipitated withdrawal effects in an acute dependence model. Two groups of subjects, opioid abusers (n = 20) and nonabusers (n = 20), received either one 15 mg/70 kg IM morphine pretreatment or two such pretreatments spaced 24 h apart. Naloxone challenge (30 mg/70 kg) followed 4.33 h after the second pretreatment. There were clear effects of morphine pretreatment condition (single versus repeated 15 mg) on the intensity of precipitated withdrawal responses elicited by naloxone. More intense effects were seen after the repeated pretreatment, suggesting that physical dependence escalates with repeated opioid exposures spaced at appropriate intervals. Subjects with an opioid abuse history reported greater liking of agonist drug effects than did nonabusers, whereas nonabusers reported more sedating effects. However, an opioid abuse history did not influence the intensity of precipitated withdrawal symptoms and signs. The latter finding suggests that a previous opioid exposure history does not dramatically modulate initial stages of physical dependence development during subsequent opioid exposure episodes.
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