Flexible dosing of tincture of opium in the management of opioid withdrawal: pharmacokinetics and pharmacodynamics.
OBJECTIVE
The aim was to evaluate the clinical effectiveness, pharmacodynamics and pharmacokinetics of a range of Tincture of Opium (TOP) doses in the management of opioid withdrawal.


METHODS
Forty-five opium-dependent Thai subjects were allocated to three dosing groups (6.66, 13.3 and 20 mg morphine equivalents, twice daily) depending on their self-reported prior opium use. On day 5 of dosing subjects underwent an interdosing interval study where blood, withdrawal scores, heart rate and blood pressure (BP) were collected at 0, 1, 3 and 8 h. Plasma morphine concentrations were quantified by high-performance liquid chromatography, and plasma morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations by LCMS.


RESULTS
Thirty-two subjects completed the study. Withdrawal scores were low for all subjects (range 9-23% of maximum response). There were dose-dependent changes in both systolic and diastolic BP (P = 0.021 and P = 0.01, respectively), but these were not considered clinically significant. There were no effects of dose on respiratory rate. Plasma morphine concentrations changed significantly across the interdosing interval (P = 0.0001), rising to a maximum at 1 h after dosing. Plasma morphine concentrations also differed according to dose (P < 0.05). The mean ratios of the morphine glucuronides were found to be: M3G/M6G = 7.7, M3G/morphine = 35.6 and M6G/morphine = 4.9, values comparable to those previously reported.


CONCLUSIONS
The management of opioid withdrawal can be achieved, with minimal adverse effects, by using flexible dosing of TOP.
Somogyi
Andrew A
AA
Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia. andrew.somogyi@adelaide.edu.au
Larsen
Mie
M
Abadi
Reza M
RM
Jittiwutikarn
Jaroon
J
Ali
Robert
R
White
Jason M
JM
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D009021:Morphine Dependence / Q000097:blood / Q000188:drug therapy*; D009022:Morphine Derivatives / Q000097:blood; D009294:Narcotics / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D012119:Respiration / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000517:prevention & control*; D013785:Thailand; D016896:Treatment Outcome; D055815:Young Adult
D009022:Morphine Derivatives; D009294:Narcotics; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide