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 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 10–12 mg doses of butorphanol administered over 10–15 minutes intravenously.
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 dysfunction, 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 OVERDOSAGE: Treatment).
Butorphanol tartrate demonstrates antitussive effects in animals at doses less than those required for analgesia.
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 arterial pressure.
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 30–60 minutes following intravenous and intramuscular administration and within 1–2 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 3–4 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, STADOL NS has a longer duration of action (4–5 hours) (see Clinical Trials).
STADOL Injection is rapidly absorbed after IM injection and peak plasma levels are reached in 20–40 minutes.
After nasal administration, mean peak blood levels of 0.9–1.04 ng/mL occur at 30–60 minutes after a 1 mg dose (see Table 1). The absolute bioavailability of STADOL NS is 60–70% 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 vasoconstrictor.
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 305–901 liters and total body clearance from 52–154 liters/hour (see Table 1).
|(a) Young subjects (n=24) are from 20 to 40 years old and elderly (n=24) are greater than 65 years of age.|
|(b) Time to peak plasma concentration.|
|(c) Peak plasma concentration normalized to 1-mg dose.|
|(d) Area under the plasma concentration-time curve after a 1-mg dose.|
|(e) Mean (1 S.D.)|
|(f) Derived from IV data.|
|(g) (range of observed values)|
|Table 1:||Mean Pharmacokinetic Parameters of Butorphanol in Young and Elderly Subjectsa|
|Parameters ||Young||Elderly ||Young ||Elderly|
|Tmaxb (h)||0.62 (0.32)e|
|Cmaxc (ng/mL)||1.04 (0.40)|
| 5.24 (2.27)|
|Half-life (h)||4.56 (1.67)|
| 4.74 (1.57)|
Dose proportionality for STADOL NS 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 5–17% 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 3H labelled butorphanol is administered to normal subjects, most (70–80%) 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 STADOL NS 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] 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 CLINICAL PHARMACOLOGY: Individualization of Dosage.
The effectiveness of opioid analgesics varies in different pain syndromes. Studies with STADOL Injection have been performed in postoperative (primarily abdominal and orthopedic) pain and pain during labor and delivery, as preoperative and preanesthetic medication, and as a supplement to balanced anesthesia (see below).
Studies with STADOL NS 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
Postoperative pain: The analgesic efficacy of STADOL Injection in postoperative pain was investigated in several double-blind active-controlled studies involving 958 butorphanol-treated patients. The following doses were found to have approximately equivalent analgesic effect: 2 mg butorphanol, 10 mg morphine, 40 mg pentazocine and 80 mg meperidine.
After intravenous administration of STADOL Injection, onset and peak analgesic effect occurred by the time of first observation (30 minutes). After intramuscular administration, pain relief onset occurred at 30 minutes or less, and peak effect occurred between 30 minutes and 1 hour. The duration of action of STADOL Injection was 3–4 hours when defined as the time necessary for pain intensity to return to pretreatment level or the time to retreatment.
The analgesic efficacy of STADOL NS was evaluated (approximately 35 patients per treatment group) in a general and orthopedic surgery trial. Single doses of STADOL NS (1 or 2 mg) and IM meperidine (37.5 or 75 mg) were compared. Analgesia provided by 1 and 2 mg doses of STADOL NS 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 STADOL NS, 3.5 hours with 2 mg STADOL NS and 3.3 hours with either dose of meperidine.
In a postcesarean section trial, STADOL NS administered to 35 patients as two 1-mg doses 60 minutes apart was compared with a single 2-mg dose of STADOL NS or a single 2-mg IV dose of STADOL Injection (37 patients each). Onset of analgesia was within 15 minutes for all STADOL regimens. Peak analgesic effects of 2 mg intravenous STADOL Injection and STADOL NS were similar in magnitude. The duration of pain relief provided by both 2-mg STADOL NS regimens was approximately 4.5 hours and was greater than intravenous STADOL Injection (2.6 hours).
Migraine headache pain: The analgesic efficacy of two 1-mg doses 1 hour apart of STADOL NS 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 STADOL NS and IM methadone. Peak analgesic effect occurred at 2 hours for STADOL NS and 1.5 hours for methadone. The median duration of pain relief was 6 hours with STADOL NS and 4 hours with methadone as judged by the time when approximately half of the patients remedicated.
In two other trials in patients with migraine headache pain, a 2-mg initial dose of STADOL NS 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 STADOL NS than in the trial with the 1-mg initial dose.
STADOL Injection (2 mg and 4 mg) and meperidine (80 mg) were studied for use as preanesthetic medication in hospitalized surgical patients. Patients received a single intramuscular dose of either STADOL Injection or meperidine approximately 90 minutes prior to anesthesia. The anesthesia regimen included barbiturate induction, followed by nitrous oxide and oxygen with halothane or enflurane, with or without a muscle relaxant.
Anesthetic preparation was rated as satisfactory in all 42 STADOL Injection patients regardless of the type of surgery.
STADOL Injection administered intravenously (mean dose 2 mg) was compared to intravenous morphine sulfate (mean dose 10 mg) as premedication shortly before thiopental induction, followed by balanced anesthesia in 50 ASA Class 1 and 2 patients. Anesthesia was then maintained by repeated intravenous doses, averaging 4.6 mg STADOL Injection and 22.8 mg morphine per patient.
Anesthetic induction and maintenance were generally rated as satisfactory with both STADOL Injection (25 patients) and morphine (25 patients) regardless of the type of surgery performed. Emergence from anesthesia was comparable with both agents.
The analgesic efficacy of intravenous STADOL Injection was studied in pain during labor. In a total of 145 patients, STADOL Injection (1 mg and 2 mg) was as effective as 40 mg and 80 mg of meperidine (144 patients) in the relief of pain in labor with no effect on the duration or progress of labor. Both drugs readily crossed the placenta and entered fetal circulation. The condition of the infants in these studies, determined by Apgar scores at 1 and 5 minutes (8 or above) and time to sustained respiration, showed that STADOL Injection had the same effects on the infants as meperidine.
In these studies, neurobehavioral testing in infants exposed to STADOL Injection at a mean of 18.6 hours after delivery showed no significant differences between treatment groups.
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).
For pain relief the recommended initial dosage regimen of STADOL Injection is 1 mg IV or 2 mg IM with repeated doses every 3 to 4 hours, as necessary. This dosage regimen is likely to be effective for the majority of patients. Dosage adjustments of STADOL Injection should be based on observations of its beneficial and adverse effects. The initial dose in the elderly and in patients with renal or hepatic impairment should generally be half the recommended adult dose (0.5 mg IV and 1.0 mg IM). Repeat doses in these patients should be determined by the patient’s response rather than at fixed intervals but will generally be no less than 6 hours (see PRECAUTIONS).
The usual preoperative dose is 2 mg IM given 60–90 minutes before surgery or 2 mg IV shortly before induction. This is approximately equivalent in sedative effect to 10 mg morphine or 80 mg of meperidine. This single preoperative dose should be individualized based on age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved.
During maintenance in balanced anesthesia the usual incremental dose of STADOL Injection is 0.5 to 1.0 mg IV. The incremental dose may be higher, up to 0.06 mg/kg (4 mg/70 kg), depending on previous sedative, analgesic, and hypnotic drugs administered. The total dose of STADOL Injection will vary; however, patients seldom require less than 4 mg or more than 12.5 mg (approximately 0.06 to 0.18 mg/kg).
As with other opioids of this class, STADOL Injection may not provide adequate intraoperative analgesia in every patient or under all conditions. A failure to achieve successful analgesia during balanced anesthesia is commonly reflected by increases in general sympathetic tone. Consequently, if blood pressure or heart rate continues to rise, consideration should be given to adding a potent volatile liquid inhalation anesthetic or another intravenous medication.
In labor, the recommended initial dose of STADOL Injection is 1 or 2 mg IM or IV in mothers with fetuses of 37 weeks gestation or beyond and without signs of fetal distress. Dosage adjustments of STADOL Injection in labor should be based on initial response with consideration given to concomitant analgesic or sedative drugs and the expected time of delivery. A dose should not be repeated in less than 4 hours nor administered less than 4 hours prior to the anticipated delivery (see 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 60–90 minutes, an additional 1-mg dose may be given.
The initial dose sequence outlined above may be repeated in 3–4 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 3-4 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 90-120 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).