Computational Opioid Prescribing: A Novel Application of Clinical Pharmacokinetics

Figures & data

FIGURE 1  One-compartment models. The intravascular administration model (left panel) is characterized by a single sampled compartment into which a dose of drug is administered. The triangle cuts into the sampled compartment. In these models, D_B represents the mass of drug in the body, V_d is the apparent volume of distribution of drug, and C represents the drug concentration, equal to D/V_d. k_e represents the first-order elimination rate constant (h⁻¹). Drug is eliminated in the urine unchanged and in metabolite form. In the extravascular administration model (right panel), a dose of drug is administered into a compartment from which the drug is transferred into the body via the gastrointestinal tract. F represents the drug's bioavailability. k_a is the first-order absorption rate constant. The steady-state plasma concentration of opioid over time for oral dosing is independent of k_a, so the path from D_GI to D_B equals Dose × F.

TABLE 1  Opioid Population Pharmacokinetic Parameter Estimates Using the Bootstrap

Opioids (N = 1000)	t½ (h)	ke (h^−1)	Vd (L/kg)	Cl (L/h/kg)
Morphine	3.9 ± 1.7	0.318 ± 0.126	4.5 ± 1.4	1.43 ± 0.69
	(3.7, 4.0)	(0.305, 0.329)	(4.4, 4.6)	(1.35, 1.52)
Tramadol	5.5 ± 0.7	0.132 ± 0.017	2.8 ± 0.1	0.37 ± 0.06
	(5.4, 5.6)	(0.127, 0.136)	(2.7, 2.8)	(0.3598, 0.3763)
Codeine	2.6 ± 0.8	0.377 ± 0.116	3.0 ± 0.3	1.23 ± 0.45
	(2.5, 2.7)	(0.3653, 0.3880)	(2.9, 3.0)	(1.21, 1.26)
Meperidine	3.5 ± 0.9	0.242 ± 0.061	4.0 ± 0.1	0.98 ± 0.27
	(3.4, 3.6)	(0.234, 0.251)	(3.9, 4.0)	(0.97, 1.00)
Hydrocodone	6.1 ± 1.5	0.141 ± 0.036	4.0 ± 0.4	0.61 ± 0.20
	(6.0, 6.2)	(0.135, 0.148)	(3.9, 4.1)	(0.5938, 0.6230)
Oxycodone IR	4.5 ± 0.9	0.174 ± 0.034	2.8 ± 0.5	0.42 ± 0.003
	(4.4, 4.6)	(0.167, 0.180)	(2.7, 2.8)	(0.41, 0.42)
Oxycodone CR
Phase I	33.5 ± 2.1 min	0.021 ± 0.001 min^−1	2.8 ± 0.5	0.06 ± 0.01 L/min/kg
Phase II	(33.34, 33.66)	(0.0194, 0.0219)	(2.7, 2.8)	(0.055, 0.063)
	4.6 ± 0.6 h	0.160 ± 0.022 h^−1	2.8 ± 0.6	0.58 ± 0.08 L/h/kg
	(4.5, 4.7)	(0.156, 0.165)	(2.7, 2.8)	(0.57, 0.59)
Hydromorphone	6.0 ± 1.7	0.154 ± 0.045	3.0 ± 0.6	0.54 ± 0.22
	(5.0, 6.1)	(0.147, 0.161)	(2.9, 3.1)	(0.52, 0.55)
Oxymorphone	8.0 ± 2.3	0.115 ± 0.033	3.0 ± 0.6	0.40 ± 0.17
	(7.8, 8.2)	(0.109, 0.122)	(2.9, 3.1)	(0.39, 0.42)
Methadone	35 ± 11.7	0.029 ± 0.009	5.5 ± 0.89	0.19 ± 0.08
	(34.6, 35.4)	(0.0258, 0.0323)	(5.4, 5.6)	(0.18, 0.20)
Fentanyl	7.5 ± 2.6	0.144 ± 0.049	5.5 ± 1.4	1.32 ± 0.73
	(7.3, 7.7)	(0.137, 0.152)	(5.4, 5.6)	(1.29, 1.35)
Buprenorphine	33.5 ± 8.7	0.026 ± 0.007	3.8 ± 1.5	0.13 ± 0.07
	(33.2, 33.8)	(0.023, 0.029)	(3.7, 4.0)	(0.12, 0.14)

*Values are bootstrap (49) mean ± SD; values in parentheses are bootstrap bias-corrected and -accelerated (50) 95% confidence intervals.

^†All values computed from pooled literature values reported in the literature (see Methods) using the bootstrap (51) with N = 1000.

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