BUTORPHANOL

Absorption

Rapidly absorbed after intramuscular injection and peak plasma levels are reached in 20-40 minutes. The absolute bioavailability 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. Oral bioavailability is only 5-17% because of extensive first-pass metabolism.

Toxicity

The clinical manifestations of butorphanol overdose are those of opioid drugs in general. The most serious symptoms are hypoventilation, cardiovascular insufficiency, coma, and death.

Originator

Stadol,Bristol-Myers,US,1978

The Uses of BUTORPHANOL

Mixed opioid agonist-antagonist. Analgesic (narcotic); antitussive. Controlled substance.

Background

A synthetic morphinan analgesic with narcotic antagonist action. It is used in the management of severe pain.

Indications

For the relief of moderate to severe pain.

Definition

ChEBI: Levorphanol in which a hydrogen at position 14 of the morphinan skeleton is substituted by hydroxy and one of the hydrogens of the N-methyl group is substituted by cyclopropyl. A semi-synthetic opioid agonist-antagonist analgesic, it is sed as its (S,S)-tartaric acid salt for relief or moderate to severe pain.

Manufacturing Process

A mixture of 1.0 g (2.58 mmols) of N-cyclobutylmethyl-14-hydroxy-9- methoxymorphinan and 10 ml of 48% HBr was refluxed, under a nitrogen atmosphere, during five minutes. After cooling, the reaction mixture was diluted with water and made basic with aqueous ammonium hydroxide. The aquous basic mixture was extracted with chloroform and the combined chloroform extracts were dried over anhyrous sodium sulfate. After evaporation of the solvent, the residual oil (730 mg) was taken up in dry ether and the resulting solution filtered through celite-charcoal. The filtrate was treated with a saturated solution of hydrogen chloride in dry ether. The hydrochloride salt thus obtained was collected by filtration and recrystallized from a methanol-acetone mixture to yield 565 mg (56.5%)of Butorphanol hydrochloride crystals melting at 272°-274°C (decomposition).

brand name

Stadol (Bristol-Myers Squibb).

Therapeutic Function

Analgesic, Antitussive

Biological Functions

Butorphanol (Stadol) is chemically related to levorphanol but pharmacologically similar in action to pentazocine. As an opioid antagonist it is nearly 30 times as potent as pentazocine and has one-fortieth the potency of naloxone. It is a potent opioid analgesic indicated for the relief of moderate to severe pain. Its potency is 7 times that of morphine and 20 times that of pentazocine as an analgesic. Its onset of action is similar to that of morphine.The side effects and signs of toxicity are similar to those produced by pentazocine. It produces excitatory effects and sedation and precipitates withdrawal in opioid-dependent patients. Although generally administered parenterally because of its low bioavailability following oral administration, it is also unique in that a nasal spray formulation is available.The nasal spray is indicated for the relief of postoperative pain and migraine headache. The low molecular weight of butorphanol, its high lipophilicity, and its lack of vasoconstrictor effects make it particularly suitable for nasal administration.
Nasal administration of butorphanol decreases the onset of action to 15 minutes and decreases the firstpass effect of the drug, which increases bioavailability. Generally the patient sprays a set dose of 1 mg per hour for 2 hours. The duration of action is 4 to 5 hours. The convenience of such administration is a major advantage to patients requiring repeat dosing. The abuse potential following such administration has not been extensively studied, although it is thought to be small. Butorphanol is not a federally controlled (“scheduled”) drug, so physicians are not required to obtain the licenses and security safeguards required for other opioid analgesics.
Adverse effects, contraindications, and drug interactions are similar to those for pentazocine and morphine.

General Description

Structurally, butorphanol is a morphinan and shares the samecyclobutyl methyl group on the nitrogen as nalbuphine. Likenalbuphine, butorphanol is an agonist at the κ-receptor but atthe μ-receptor butorphanol is both a partial agonist and anantagonist. The affinity for opioid receptors in vitro is1:4:25 for the μ-, δ-, and κ-receptors respectively. Thehigh affinity for the κ-receptors is proposed to give butorphanolits analgesic properties and is also responsible for theCNS adverse effects such as hallucinations, psychosis, andparanoid reactions. Butorphanol binds with μ-receptors as apartial agonist, and administration to humans maintained onhigh-potency μ-agonists such as morphine may precipitatewithdrawal. Butorphanol was found to produce convulsionsin morphine-deprived, morphine-dependent monkeys.

Pharmacokinetics

Butorphanol is a synthetic opioid agonist-antagonist analgesic with a pharmacological and therapeutic profile that has been well established since its launch as a parenteral formulation in 1978. The introduction of a transnasal formulation of butorphanol represents a new and noninvasive presentation of an analgesic for moderate to severe pain. This route of administration bypasses the gastrointestinal tract, and this is an advantage for a drug such as butorphanol that undergoes significant first-pass metabolism after oral administration. The onset of action and systemic bioavailability of butorphanol following transnasal delivery are similar to those after parenteral administration. Butorphanol blocks pain impulses at specific sites in the brain and spinal cord.

Metabolism

Extensively metabolized in the liver. The pharmacological activity of butorphanol metabolites has not been studied in humans; in animal studies, butorphanol metabolites have demonstrated some analgesic activity.