Flexible dosing of tincture of opium in the management of opioid withdrawal: pharmacokinetics and pharmacodynamics

Abstract

Aims: 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.

Conclusion: The management of opioid withdrawal can be achieved, with minimal adverse effects, by using flexible dosing of TOP.

Figure 1

Mean plasma morphine concentration–time profiles for 32 patients maintained on twice-daily Tincture of Opium (TOP). Thirteen patients received 10 ml (dose 1), eight patients 20 ml (dose 2) and 11 patients 30 ml (dose 3) of TOP twice daily. TOP was administered at time zero. Values are mean ± SD. *P < 0.05 significant difference between dose 1 and dose 3. Dose 1 (); Dose 2 (); Dose 3 ()

Figure 2

Mean ± SD systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg) in patients maintained on either 10 ml (dose 1), 20 ml (dose 2) or 30 ml (dose 3) of Tincture of Opium twice daily. SBP (Dose 1) (); SBP (Dose 2) (); SBP (Dose 3) (); DBP (Dose 1) (); DBP (Dose 2) (); DBP (Dose 3) ()

Figure 3

Mean ± SD respiratory rate (breaths per minute) for patients maintained on either 10 ml (dose 1), 20 ml (dose 2) or 30 ml (dose 3) of Tincture of Opium twice daily. Dose 1 (); Dose 2 (); Dose 3 ()

Figure 4

(A,B) Withdrawal scores for 32 patients maintained on twice-daily Tincture of Opium. Thirteen patients received 10 ml (dose 1), eight patients 20 ml (dose 2) and 11 patients 30 ml (dose 3) of Tincture of Opium twice daily. (A) Mean ± SD withdrawal scores (maximum score 16). Dose 1 (); Dose 2 (); Dose 3 () (B) Log withdrawal scores adjusted for prior daily opium use and plasma morphine concentration at each time point for all subjects. *P < 0.05; time point 1 h vs. 3 h