, Volume 50, Issue 1, pp 157–175 | Cite as

Transnasal Butorphanol

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Acute Pain Management
  • Jane C. Gillis
  • Paul Benfield
  • Karen L. Goa
Drug Evaluation



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.

The analgesic efficacy of transnasal butorphanol was generally superior to that of placebo in clinical trials in patients with moderate to severe postoperative pain or migraine headache. Results from single trials indicate that transnasal butorphanol provides pain relief comparable to that of intramuscular pethidine (meperidine) in postsurgical pain and comparable to or greater than intramuscular methadone in migraine headache. Moderate to severe musculoskeletal pain also appears to be responsive to transnasal butorphanol on the basis of results from 1 small noncomparative study. Tolerability of transnasal butorphanol parallels that of the injectable form, with somnolence, dizziness, nausea and/or vomiting reported most frequently.

Thus, transnasal butorphanol is a novel formulation of an established analgesic which appears suitable for the short term treatment of moderate to severe pain, especially in an ambulatory setting. Transnasal butorphanol is likely to provide an alternative to oral opioid analgesics, particularly in the presence of nausea or vomiting, or to parenteral opioids when the oral route of administration is not appropriate.

Pharmacodynamic Properties

As might be expected, the pharmacodynamic profile of transnasal butorphanol is similar to that of the injectable formulation. Butorphanol is an opioid agonist-antagonist drug with intrinsic agonist activity at the Κ opioid receptor and antagonist activity at the μ opioid receptor. The analgesic potency of butorphanol is approximately 4 to 8 times that of morphine, 30 to 40 times that of pethidine (meperidine) and 16 to 24 times that of pentazocine. Investigation of transnasal butorphanol versus intramuscular pethidine showed a potency ratio consistent with values derived from parenteral administration studies.

Respiratory depression produced by morphine and other potent μ receptor agonists increases in a dose proportional fashion; in contrast, there is a ‘ceiling’ on the degree of respiratory depression induced by butorphanol. Increasing butorphanol doses beyond 2mg does not result in a corresponding increase in degree of respiratory depression; however, the duration of respiratory depression increases with higher doses.

No changes in vital signs were reported in healthy volunteers receiving trans-nasal butorphanol 1 to 4mg for 16 days. Clinical studies with intravenous butorphanol in patients undergoing cardiac catheterisation indicate that it may increase cardiac workload, as demonstrated by elevated values for cardiac index, stroke volume and left ventricular end diastolic pressure. A significant increase in pulmonary artery pressure has also been measured after intravenous butorphanol administration.

Results with transnasal butorphanol support the generally accepted finding that opioid agonist-antagonist drugs have less propensity for development of tolerance, physical dependence, or abuse potential than pure agonists.

Pharmacokinetic Properties

With oral administration, butorphanol undergoes significant hepatic first-pass metabolism and bioavailability is only about 5 to 17%; with transnasal administration, butorphanol bioavailability is approximately 48 to 70%. Intravenous, intramuscular and transnasal administration of butorphanol 2mg result in similar plasma concentration-time curves, indicating that transnasal butorphanol is not subject to first-pass hepatic metabolism or metabolism in the nasal mucosa. In healthy volunteers, transnasal butorphanol shows linear pharmacokinetics over a dose range of 1 to 4mg every 6 hours. Transnasal administration of butorphanol results in rapid absorption and an onset of analgesia within 15 minutes. Peak plasma butorphanol concentrations were reached 30 to 60 minutes after transnasal administration of a 1mg dose. Steady-state is achieved within 48 hours, at which time plasma butorphanol concentrations are about 1.8 times those seen after a single dose.

Data from animal studies show that [3 H]-butorphanol is distributed widely to highly perfused organs and excretory organs. After intravenous administration of butorphanol to humans the volume of distribution is estimated to be 300 to 900L and the extent of plasma protein binding is approximately 80%. Following intramuscular administration of butorphanol to prepartum women, the drug is detected in neonatal serum; it is also found in negligible amounts in breastmilk after intramuscular injection to postpartum women.

Butorphanol is extensively metabolised in the liver and excreted primarily via the kidneys. The mean elimination half-life after transnasal administration of butorphanol to healthy volunteers is 4.7 to 5.8 hours; this is prolonged in the elderly (older than 65 years) [6.6 hours] and in patients with renal impairment (8.6 to 10.5 hours).

Therapeutic Potential

In clinical studies, mainly in patients with moderate to severe postsurgical pain, short term treatment (3 days or less) with transnasal butorphanol in doses of 1 to 2mg was usually associated with better analgesia than placebo. Analgesia occurred within 15 minutes and lasted approximately 3 to 5 hours. Comparative studies of transnasal butorphanol versus other opioid analgesics in postsurgical pain are limited to 1 comparison with intramuscular pethidine, which reported no significant differences in pain relief between treatments. Preliminary results also indicate that transnasal butorphanol 1 to 3mg, administered over a 2 hour period, is effective in the management of moderate to severe musculoskeletal pain.

Acute migraine pain responded better to transnasal butorphanol lmg, followed by lmg 30 to 90 minutes later, than to placebo. In 1 trial, transnasal butorphanol provided greater pain relief than intramuscular methadone (10mg) 1.5 and 2 hours following drug administration and similar pain relief throughout the remainder of the 6-hour assessment period. However, comparative trials of transnasal butorphanol with more conventional first-line agents in the treatment of acute migraine are needed to help establish its relative role in this condition.


Adverse events occur frequently with transnasal butorphanol, but are generally mild to moderate in severity. The profile of short term (3 days or less) use of transnasal butorphanol is qualitatively similar to that of the injectable formulation, with somnolence, dizziness, nausea and/or vomiting reported most often. The extent of dizziness and drowsiness appears to be dose-related and is minimised by administration of transnasal butorphanol 2mg in divided doses of 1mg at 60 minute intervals. In 1 trial, butorphanol was better tolerated when administered to patients by the transnasal, rather than the intravenous, route.

The incidence of nasal adverse effects appears to be related to duration of transnasal butorphanol use. Nasal mucosa integrity was generally unaffected by short term use, whereas with long term use nasal congestion, nasal irritation, rhinitis and epistaxis have been noted. Transnasal butorphanol has also been associated with infrequent reports of dysphoria or psychotomimetic effects.

Dosage and Administration

The usual recommended dose of transnasal butorphanol is lmg (1 spray) in one nostril; if satisfactory analgesia is not obtained in 60 to 90 minutes an additional lmg dose may be administered. In severe pain, an initial dose of 2mg (1 spray in each nostril) may be used in patients able to remain lying down in the event drowsiness or dizziness occurs. Three to 4 hours should elapse between administration of doses totalling 2mg.

In the elderly, the initial dose should not exceed lmg and patients should wait 90 to 120 minutes before readministration, if required. The recommended dose interval in the elderly and patients with hepatic or renal impairment should be on the basis of patient response and generally will be 6 to 8 hours.

It is essential that patients receive proper instruction on priming the nasal spray unit, correct drug administration technique and expectations as to adverse events.


Migraine Morphine Pethidine Pentazocine Butorphanol 
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Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Jane C. Gillis
    • 1
  • Paul Benfield
    • 1
  • Karen L. Goa
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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