Mixed Opiate Agonists/Antagonists

NOTE: Butorphanol is a schedule C-IV controlled substance.

Description: Butorphanol tartrate is a synthetic parenteral opiate agonist-antagonist. Although it is structurally related to morphine, butorphanol is more similar in action to nalbuphine, another agonist-antagonist. Butorphanol is available parenterally for treating moderate to severe pain and as a nasal spray that has been used to treat migraine. Although studies suggest equianalgesic parenteral doses are as effective as morphine, clinical response may indicate otherwise, perhaps due to the development of tolerance. Butorphanol does not offer significant advantages over pure opiate-agonists in the treatment of acute pain or cancer pain. Butorphanol is also used to provide preoperative sedation and analgesia, and to supplement surgical anesthesia. Butorphanol injection was approved by the FDA in 1978; the nasal spray was approved in 1991. Although butorphanol was not a controlled substance in the United States when it was originally introduced, the DEA recommended in June 1997 that both the injection and the nasal spray be classified as a controlled substance.

Mechanism of Action: Butorphanol is a mixed agonist-antagonist at opiate receptors. Butorphanol's actions at opiate receptors most closely resemble those of nalbuphine. Opiates are believed to exert their effects by stimulating specific opiate receptors, designated as µ (mu), kappa (kappa), and delta (delta), which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (µ). Mu-receptors are considered the classic morphine-receptor type, and stimulation at this receptor produces supraspinal analgesia, respiratory depression, euphoria, and physical dependence. Butorphanol is an agonist at kappa-receptors but is a weak antagonist at µ-receptors. Butorphanol mediates spinal analgesia via stimulation at kappa-receptors. Administration of a strong antagonist at the kappa-receptor, such as naloxone, would displace butorphanol from the receptor, producing a mild withdrawal. Butorphanol's antagonism at the µ-receptor is stronger than pentazocine's, but only 1/40th of naloxone's. In fact, butorphanol may exert no activity at all at the µ-receptor and may erroneously be considered a weak antagonist due to its inability to substitute for true µ-receptor agonists. Because of its lack of stimulation at the µ-receptor, butorphanol is believed to produce less respiratory depression and to pose a lower risk of physical dependence than morphine. The drug has little effect on bile duct flow and duodenal smooth muscle activity.

The pharmacologic effects observed after opiates bind to their receptors may involve a second messenger such as cyclic AMP, which is synthesized by adenylate cyclase. Opioid receptors are coupled to these second messenger systems through an inhibitory G-protein (guanine nucleotide-binding protein). G-proteins are located at the cell surface along with many other receptors, including opioid receptors. G-proteins are thought to interact with opiate receptors, giving the receptor a higher affinity for the opiate. Binding of the opiate stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case, the effector system is adenylate cyclase and cyclic AMP located at the inner surface of the plasma membrane. Opioid agonists effectively inhibit adenylate cyclase and cause a decrease in intracellular cyclic AMP levels. Other research has shown that µ-, delta-, and kappa-receptors are associated with ion channels and control the influx of cations into the cell. Mu and delta receptor stimulation is associated with increasing potassium influx and kappa receptor activity is associated with reducing calcium influx in cells located in various human and animal nerve systems. All of these effects appear to ultimately reduce transmitter release, and may also be mediated through G-proteins.

Pharmacokinetics: Although butorphanol is readily absorbed from the gut, it undergoes significant first-pass metabolism, so that only 17% of unchanged drug reaches the systemic circulation after oral administration. After an IM injection, analgesic effects begin within 15 minutes, peaking within 30—60 minutes. In contrast, an IV injection produces analgesia within 1 minute and peaks within 4—5 minutes. Onset of analgesia after intranasal administration occurs within 15 minutes, however, onset may be delayed if administered concurrently with or immediately following a nasal vasoconstrictor (e.g., oxymetazoline). The duration of action is 2—4 hours after IV administration and 3—4 hours after IM administration. Butorphanol and its metabolites are widely distributed. The drug crosses the blood-brain barrier and the placenta and is distributed into breast milk. Protein binding is 80%. Hepatic metabolism is extensive, primarily producing an inactive metabolite, hydroxybutorphanol. N-dealkylation and conjugation also occur. The metabolites produced during first pass have no analgesic activity. Sixty to 80% of a dose of butorphanol is excreted via the kidneys as inactive metabolites. Between 11% and 14% of a parenteral dose is excreted in the feces.

•Special Populations: In patients with creatinine clearance < 30 ml/min, the elimination half-life doubled and the total body clearance was approximately half compared to healthy subjects (10.5 hours vs. 5.8 hours, respectively). After intravenous administration to patients with hepatic impairment, the half-life of butorphanol tripled as compared to healthy subjects (16.8 hours vs. 4.8 hours, respectively). The exposure of hepatically impaired patients to butorphanol was 2-fold greater than that in healthy subjects. Similar results were seen after nasal administration.

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