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 k-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 k-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.

Pharmacodynamics

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).

Pharmacokinetics

STADOL Injection is rapidly absorbed after IM injection and peak plasma levels are reached in 20-40 minutes.

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