Charles P. O'Brien

Conditioned responses in a methadone population ☆: A comparison of laboratory, clinic, and natural settings

The incidence of conditioned high, craving, and withdrawal in methadone-maintained patients was compared across three settings: an artificial laboratory setting, clinic extinction sessions, and in self-reports from the natural home environment. A significant proportion of methadone patients showed increased craving and withdrawal in response to drug-related stimuli, even in the artificial laboratory setting. As stimulus opportunities became more varied (clinic extinction sessions) and closer to those in the patients own home environment, the proportion of patients experiencing subjective craving and withdrawal increased. These results are discussed in terms of the nature of, and inter-relationships among, the conditioned responses found in opiate abusers and the potential role of these responses in relapse to drug use in the abstinent patient.

Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene

Plasma concentrations of propoxyphene (P) and its pharmacologically active metabolite norpropoxyphene (NP) were determined in normal subjects after single 130‐mg oral doses and during and after 13 consecutive oral doses of 130 mg P, and informer heroin addicts who were maintained on 900 to 1200 mg of P per day. The data were analyzed using a first‐pass elimination pharmacokinetic model. Both P and NP cumulated during repeated dosing to levels 5 to 7 times those after the first dose. In contrast, “maintenance” patients exhibited steady‐state trough plasma NP cumulation that exceeded that of P by a factor of 13. Several changes in P and NP kinetics occurred during repeated dosing with P to the normal subjects: P clearance decreased from 994 to 508 ml/min, NP clearance decreased from 454 to 210 ml/min, P half‐life (t½) increased from 3.3 to 11.8 hr, NP t½ increased from 6.1 to 39.2 hr, and area under the concentration time curves for P and NP were doubled. These changes in kinetics during repeated dosing resulted in more extensive cumulation of P and NP than would be predicted from the single‐dose kinetic profile. Changes in the extent of first‐pass elimination of P result in variability in plasma P and NP that may contribute to P‐induced toxicity.

Nondependent monkeys self-administer hydromorphone.

Four monkeys, 2 rhesus and 2 cynomolgus, were trained to perform a multiple fixed-ratio extinction (MULT/FR/EXT) schedule for banana pellets. Subsequently, all animals were given hydromorphone (HYM) self-administration training, which consisted of substitution of FR (fixed ratio) 2 cocaine for FR 80 banana pellets and substitution of FR 2 HYM for FR 2 cocaine. All of the animals acquired cocaine self-administration. They also acquired HYM self-administration when it was substituted for cocaine. Next, 50 HYM self-maintenance sessions were given. During these sessions, animals were allowed to self-administer a total cumulative dose of 1 mg/kg/day of HYM. The animals were observed for spontaneous withdrawal while they performed an operant for food 24 and 48 hr after their last maintenance dose of HYM. Because none of the monkeys showed signs of spontaneous withdrawal or disruption of the appetitive baseline during the first postmaintenance appetitive session, a 0.4-mg dose of naloxone was administered noncontingently to test for precipitated withdrawal. Naloxone disrupted appetitive responding for banana pellets in the 2 rhesus monkeys. Naloxone had no effect on responding for food in the cynomolgus monkeys. Because none of the monkeys showed signs of spontaneous withdrawal or disruption of their appetitive baseline during the second postmaintenance session, a HYM challenge dose of 1 mg/kg was given noncontingently to assess whether tolerance to the daily maintenance dose had been acquired. The bolus dose of HYM suppressed lever pressing for food in both species, a result indicating a lack of tolerance. These results suggest that the positive reinforcing properties of HYM are sufficient to maintain opioid self-administration and that tolerance and physical dependence are not necessary.