General Pharmacology And Mechanism Of Action
Butorphanol is a mixed agonist-antagonist with low intrinsic activity at receptors of the μ-opioid type
(morphine-like). It is also an agonist at the κ-opioid receptors.
Its interactions with these receptors in the central nervous system apparently mediate most of its
pharmacologic effects, including analgesia.
In addition to analgesia, CNS effects include depression of spontaneous respiratory activity and cough,
stimulation of the emetic center, miosis, and sedation. Effects possibly mediated by non-CNS
mechanisms include alteration in cardiovascular resistance and capacitance, bronchomotor tone,
gastrointestinal secretory and motor activity, and bladder sphincter activity.
In an animal model, the dose of butorphanol tartrate required to antagonize morphine analgesia by 50%
was similar to that for nalorphine, less than that for pentazocine and more than that for naloxone.
The pharmacological activity of butorphanol metabolites has not been studied in humans; in animal
studies, butorphanol metabolites have demonstrated some analgesic activity.
In human studies of butorphanol (see Clinical Trials), sedation is commonly noted at doses of 0.5 mg or
more. Narcosis is produced by 10 to 12 mg doses of butorphanol administered over 10 to 15 minutes
Butorphanol, like other mixed agonist-antagonists with a high affinity for the κ-receptor, may produce
unpleasant psychotomimetic effects in some individuals.
Nausea and/or vomiting may be produced by doses of 1 mg or more administered by any route.
In human studies involving individuals without significant respiratory dysfuction, 2 mg of butorphanol
IV and 10 mg of morphine sulfate IV depressed respiration to a comparable degree. At higher doses,
the magnitude of respiratory depression with butorphanol is not appreciably increased; however, the
duration of respiratory depression is longer. Respiratory depression noted after administration of
butorphanol to humans by any route is reversed by treatment with naloxone, a specific opioid antagonist
(see Treatment in OVERDOSE).
Butorphanol tartrate demonstrates antitussive effects in animals at doses less than those required for
Hemodynamic changes noted during cardiac catheterization in patients receiving single 0.025 mg/kg
intravenous doses of butorphanol have included increases in pulmonary artery pressure, wedge
pressure and vascular resistance, increases in left ventricular end diastolic pressure, and in systemic
The analgesic effect of butorphanol is influenced by the route of administration. Onset of analgesia is
within a few minutes for intravenous administration, within 15 minutes for intramuscular injection, and
within 15 minutes for the nasal spray doses.
Peak analgesic activity occurs within 30 to 60 minutes following intravenous and intramuscular
administration and within 1 to 2 hours following the nasal spray administration.
The duration of analgesia varies depending on the pain model as well as the route of administration, but
is generally 3 to 4 hours with IM and IV doses as defined by the time 50% of patients required
remedication. In postoperative studies, the duration of analgesia with IV or IM butorphanol was similar
to morphine, meperidine, and pentazocine when administered in the same fashion at equipotent doses
(see Clinical Trials). Compared to the injectable form and other drugs in this class, butorphanol tartrate
nasal spray has a longer duration of action (4 to 5 hours) (see Clinical Trials).
Butorphanol tartrate injection is rapidly absorbed after IM injection and peak plasma levels are reached
in 20 to 40 minutes.
After nasal administration, mean peak blood levels of 0.9 to 1.04 ng/mL occur at 30 to 60 minutes after a
1 mg dose (see Table 1). The absolute bioavailability of butorphanol tartrate nasal spray is 60 to 70%
and is unchanged in patients with allergic rhinitis. In patients using a nasal vasoconstrictor
(oxymetazoline) the fraction of the dose absorbed was unchanged, but the rate of absorption was
slowed. The peak plasma concentrations were approximately half those achieved in the absence of the
Following its initial absorption/distribution phase, the single dose pharmacokinetics of butorphanol by
the intravenous, intramuscular, and nasal routes of administration are similar (see Figure 1).
Figure 1: Butorphanol Plasma Levels After IV, IM and Nasal Spray Administration of 2 mg Dose
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%.
The volume of distribution of butorphanol varies from 305 to 901 liters and total body clearance from
52 to 154 liters/hr (see Table 1).
Table 1: Mean Pharmacokinetic Parameters of Butorphanol in Young and Elderly Subjects*
||0.62 (0.32)‡ (0.15-1.50)§
||1.03 (0.74) (0.25-3.00)
||1.04 (0.40) (0.35-1.97)
||0.90 (0.57) (0.10-2.68)
||7.24 (1.57) (4.40-9.77)
||8.71 (2.02) (4.76-13.03)
||4.93 (1.24) (2.16-7.27)
||5.24 (2.27) (0.30-10.34)
||4.56 (1.67) (2.06-8.70)
||5.61 (1.36) (3.25-8.79)
||4.74 (1.57) (2.89-8.79)
||6.56 (1.51) (3.75-9.17)
||69 (16) (44-113)
||61 (25) (3-121)
|487 (155) (305-901)
||552 (124) (305-737)
|Total Body Clearance (L/hr)
||99 (23) (70-154)
||82 (21) (52-143)
|*Young subjects (n=24 ) are from 20 to 4 0 years old and elderly (n=24 ) are greater than 65 years of age.
†Time to peak plasma concentration.
‡Mean (1 S.D.)
§(range of observed values)
¶Peak plasma concentration normalized to 1 mg dose.
#Area under the plasma concentration-time curve after a 1 mg dose.
ÞDerived from IV data.
Dose proportionality for butorphanol tartrate nasal spray has been determined at steady state in doses up
to 4 mg at 6 hour intervals. Steady state is achieved within 2 days. The mean peak plasma concentration
at steady state was 1.8-fold (maximal 3-fold) following a single dose.
The drug is transported across the blood brain and placental barriers and into human milk (see PRECAUTIONS: Labor And Delivery And Nursing Mothers).
Butorphanol is extensively metabolized in the liver. Metabolism is qualitatively and quantitatively
similar following intravenous, intramuscular, or nasal administration. Oral bioavailability is only 5 to
17% because of extensive first pass metabolism of butorphanol.
The major metabolite of butorphanol is hydroxybutorphanol, while norbutorphanol is produced in small
amounts. Both have been detected in plasma following administration of butorphanol, with
norbutorphanol present at trace levels at most time points. The elimination half-life of
hydroxybutorphanol is about 18 hours and, as a consequence, considerable accumulation (~5-fold)
occurs when butorphanol is dosed to steady state (1 mg transnasally q6h for 5 days).
Elimination occurs by urine and fecal excretion. When H labelled butorphanol is administered to
normal subjects, most (70 to 80%) of the dose is recovered in the urine, while approximately 15% is
recovered in the feces.
About 5% of the dose is recovered in the urine as butorphanol. Forty-nine percent is eliminated in the
urine as hydroxybutorphanol. Less than 5% is excreted in the urine as norbutorphanol.
Butorphanol pharmacokinetics in the elderly differ from younger patients (see Table 1). The mean
absolute bioavailability of butorphanol tartrate nasal spray in elderly women (48%) was less than that in
elderly men (75%), young men (68%), or young women (70%). Elimination half-life is increased in the
elderly (6.6 hours as opposed to 4.7 hours in younger subjects).
In renally impaired patients with creatinine clearances <30 mL/min, the elimination half-life was
approximately doubled and the total body clearance was approximately one half (10.5 hours [clearance
150 L/h] as compared to 5.8 hours [clearance 260 L/h] in healthy subjects). No effect on Cmax or Tmax
was observed after a single dose.
After intravenous administration to patients with hepatic impairment, the elimination half-life of
butorphanol was approximately tripled and total body clearance was approximately one half (half-life
16.8 hours, clearance 92 L/h) compared to healthy subjects (half-life 4.8 hours, clearance 175 L/h). The
exposure of hepatically impaired patients to butorphanol was significantly greater (about 2-fold) than
that in healthy subjects. Similar results were seen after nasal administration. No effect on Cmax or Tmax
was observed after a single intranasal dose.
For further recommendations refer to PRECAUTIONS: Hepatic and Renal Disease, DRUG INTERACTIONS,
and Geriatric Use and to the CLINICAL PHARMACOLOGY: Individualization of Dosage.
The effectiveness of opioid analgesics varies in different pain syndromes.
Studies with butorphanol tartrate nasal spray have been performed in postoperative (general, orthopedic,
oral, cesarean section) pain, in postepisiotomy pain, in pain of musculoskeletal origin, and in migraine
headache pain (see below).
Use in the Management of Pain
The analgesic efficacy of butorphanol tartrate nasal spray was evaluated (approximately 35 patients per
treatment group) in a general and orthopedic surgery trial. Single doses of butorphanol tartrate nasal
spray (1 or 2 mg) and IM meperidine (37.5 or 75 mg) were compared. Analgesia provided by 1 and 2 mg
doses of butorphanol tartrate nasal spray was similar to 37.5 and 75 mg meperidine, respectively, with
onset of analgesia within 15 minutes and peak analgesic effect within 1 hour. The median duration of
pain relief was 2.5 hours with 1 mg butorphanol tartrate nasal spray, 3.5 hours with 2 mg butorphanol
tartrate nasal spray and 3.3 hours with either dose of meperidine.
In a postcesarean section trial, butorphanol tartrate nasal spray administered to 35 patients as two 1 mg
doses 60 minutes apart was compared with a single 2 mg dose of butorphanol tartrate nasal spray or a
single 2 mg IV dose of butorphanol tartrate injection (37 patients each). Onset of analgesia was within
15 minutes for all butorphanol tartrate regimens. Peak analgesic effects of 2 mg intravenous butorphanol
tartrate injection and butorphanol tartrate nasal spray were similar in magnitude. The duration of pain
relief provided by both 2 mg butorphanol tartrate nasal spray regimens was approximately 4.5 hours and
was greater than intravenous butorphanol tartrate injection (2.6 hours).
Migraine Headache Pain
The analgesic efficacy of two 1 mg doses 1 hour apart of butorphanol tartrate nasal spray in migraine
headache pain was compared with a single dose of 10 mg IM methadone (31 and 32 patients,
respectively). Significant onset of analgesia occurred within 15 minutes for both butorphanol tartrate
nasal spray and IM methadone. Peak analgesic effect occurred at 2 hours for butorphanol tartrate nasal
spray and 1.5 hours for methadone. The median duration of pain relief was 6 hours with butorphanol
tartrate nasal spray and 4 hours with methadone as judged by the time when approximately half of the
In two other trials in patients with migraine headache pain, a 2 mg initial dose of butorphanol tartrate
nasal spray followed by an additional 1 mg dose 1 hour later (76 patients) was compared with either 75
mg IM meperidine (24 patients) or placebo (72 patients). Onset, peak activity and duration were similar
with both active treatments; however, the incidence of adverse experiences (nausea, vomiting,
dizziness) was higher in these two trials with the 2 mg initial dose of butorphanol tartrate nasal spray
than in the trial with the 1 mg initial dose.
Individualization Of Dosage
Use of butorphanol in geriatric patients, patients with renal impairment, patients with hepatic impairment,
and during labor requires extra caution (see below and the appropriate sections in PRECAUTIONS).
The usual recommended dose for initial nasal administration is 1 mg (1 spray in one nostril). If adequate
pain relief is not achieved within 60 to 90 minutes, an additional 1 mg dose may be given.
The initial dose sequence outlined above may be repeated in 3 to 4 hours as required after the second
dose of the sequence.
For the management of severe pain, an initial dose of 2 mg (1 spray in each nostril) may be used in
patients who will be able to remain recumbent in the event drowsiness or dizziness occurs. In such
patients additional doses should not be given for 3 to 4 hours. The incidence of adverse events is
higher with an initial 2 mg dose (see Clinical Trials ).
The initial dose sequence in elderly patients and patients with renal or hepatic impairment should be
limited to 1 mg followed, if needed, by 1 mg in 90 to 120 minutes. The repeat dose sequence in these
patients should be determined by the patient’s response rather than at fixed times but will generally be
no less than at 6 hour intervals (see PRECAUTIONS).