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Butorphanol

Pharmacodynamic Properties

Following intranasal administration of butorphanol nasal spray, onset of analgesia is within 15-30 minutes, and peak analgesic activity generally occurs within 1-2 hours. The duration of analgesia varies depending on the pain model but is generally 3-6 hours with intranasal doses of 1-2 mg.

Pharmacokinetic Properties

The pharmacokinetics (including absorption times and peak blood levels) of a nasal spray dose and an intramuscular dose of butorphanol tartrate are similar. In addition, after an initial absorption phase, the pharmacokinetics of a nasal spray dose are also similar to those of an intravenous dose.

Butorphanol tartrate is rapidly absorbed without significant biotransformation following nasal administration. In both young and elderly normal volunteers, peak blood levels occur around one-half hour following nasal administration. Peak plasma concentrations after a 1 mg dose vary from a mean of 0.9 to 1.04 ng/mL (see table). Elderly subjects may have a somewhat decreased ability to eliminate butorphanol, with an apparent elimination half-life of 6.6 hours as opposed to 4.7 hours for younger subjects. The mean absolute bioavailability may be somewhat less for elderly women (48%) than for elderly men or younger subjects (75% and 69% respectively).

Mean Pharmacokinetic Parameters Of Butorphanol Tartrate Nasal Spray In Young And Elderly Subjectsa:

Parameter Young Elderly
Tmaxb (hr) 0.62 (0.50-2.00)e 0.75 (0.25-3.00)
Cmaxc (ng/mL) 1.04 (0.35-1.97) 0.90 (1.10-2.68)
AUC(inf)d (hrAng/mL) 4.93 (2.16-7.27) 5.24 (0.30-10.34)
Half-life (hr) 4.7 (2.89-8.79) 6.6 (3.75-9.17)
Absolute Bioavailability (%) 69 (44-113) 62 (3-121)
Volume of Distributionf (L) 487 (305-901) 552 (305-737)
Clearancef (L/hr) 98 (70-154) 82 (52-143)

a Young subjects (n=24) are from 20 to 40 years old (mean M/F, 25/30 years) and elderly subjects (n=24) are from 65 to 83 years old (mean M/F, 71 years).
b Time to peak plasma concentration, median values.
c Peak plasma concentration normalized to 1 mg dose.
d Area under the plasma concentration time curve after a 1 mg dose.
e (range of observed values).
f Derived from IV data.

The mean plasma half-life of butorphanol is 5.1 hours after a 2 mg intranasal administration.

Serum protein binding is independent of concentration over the range achieved in clinical practice (up to 7 ng/mL) with a bound fraction of approximately 80%. Butorphanol crosses the blood brain and placental barriers and is found in human milk.

The volume of distribution of butorphanol varies from 305-901 litres and total body clearance from 52-154 litres/hour.

Intranasal butorphanol pharmacokinetic studies determined that steady state plasma levels of butorphanol were dose proportional (in doses up to 4 mg every 6 hours). Steady state is achieved within 2 days, and plasma concentrations are approximately 1.8 times those following a single dose.

Butorphanol is extensively metabolized in the liver and is eliminated as oxidized and conjugated metabolites. Metabolism is qualitatively and quantitatively similar with nasal, intravenous, or intramuscular administration. Less than 5% of an intravenous dose is recovered in the urine as unchanged drug. Because of extensive first-pass metabolism, the bioavailability of oral butorphanol is less than 10%.

Hydroxybutorphanol is the main urinary metabolite of butorphanol (49% of dose); small amounts of norbutorphanol (<5%) are also excreted in urine. The analgesic activity of these two metabolites has not been determined in humans.

In Patients with Renal Insufficiency

Eighteen female volunteers (age 30-65 years) with normal or varying degrees of renal impairment were given single 1 mg intranasal doses of butorphanol. As shown below, the elimination half-life of butorphanol was prolonged, and the AUC increased, in patients with reduced creatinine clearance (CrCl). No effect, however, was observed on Cmax or Tmax.

 CrCl (mL/min) t½ (h) AUC (h·ng/mL)
Normal >705.75 4.32 (1.63)*
Moderately Impaired 30-60 8.55 6.49 (1.32)
Severely Impaired <30 10.48 7.41 (2.64)

* Standard Deviation

In Patients with Hepatic Disease

The pharmacokinetics and absolute bioavailability of a 1 mg dose of transnasal butorphanol tartrate was studied in 12 (8M, 4F) subjects with hepatic impairment, and 12 normal subjects matched for sex, age and weight. Compared to normal subjects, patients with hepatic impairment had on average a 3-fold increase in t½ and a 2 to 3-fold increase in AUC. Absolute bioavailability was 99% in the subjects with hepatic impairment compared to 73% in controls. Cmax and Tmax, however, remained unaltered regardless of the liver conditions.