Update on Anesthesia Drugs

New anesthetic drugs may help your anesthesiologist or nurse anesthetist achieve a smoother and quicker induction and recovery, offer better post-op pain management and decrease costs. Like all drugs, however, most of the new ones incorporate trade-offs that render them less than perfect. In this article we'll review five relatively new medications that you may or may not have tried in your facility, and attempt to help you determine if they could be of benefit to you.

Alternative Propofol
For years, propofol, manufactured under the brand name Diprivan by Astra Zeneca, has been a popular IV drug for inducing and/or maintaining anesthesia. In April 1999 Baxter Pharmaceutical released a substitute deemed by the FDA to be "therapeutically equivalent" to Diprivan.

Since Baxter PPI's propofol incorporates the same active ingredient as Diprivan, but is not the exact same formulation, it is not considered to be a generic version; its preservatives and pH are different. Diprivan is formulated at a pH of 7.0 to 8.5, and uses EDTA as a preservative. Baxter's product, formulated at a pH of 4.5 to 6.4, uses sodium metabisulfite as a preservative.

These two items may be significant. Drugs containing sulfites have been known to induce anaphylactic reactions and serious asthmatic episodes in certain susceptible people. Theodore Stanley, MD, a professor of anesthesiology at the University of Utah, also is concerned about the stability of the Baxter drug. He reports that under excessive or severe conditions such as extreme heat or cold, the lower pH required for sulfites could cause the lipid droplets in the propofol emulsion to coalesce and make larger lipid droplets. These larger droplets have the potential to cause emboli, he says.

Most of the anesthesiologists we interviewed consider these to be relatively minor issues, however. Larry Grossman, MD, of Synergy Health Care Systems in Ft. Washington, Pa., agrees that "Many anesthesiologists are concerned about potential complications and so will only use Diprivan." However, he reports that he has used both Diprivan and Baxter's version, and finds them "comparable" in function if not in cost. Denis McNicholl, a spokesperson for drug distributor Physicians Formulary, says that 25 20-ml vials of Diprivan retail for $365; if purchased on contract, the price can drop to $225. In contrast, 25 20-ml vials of Baxter's propofol retails for $280, but can sell for as little as $190 on contract.

Thomas Cutter, an associate professor of anesthesiology at the University of Chicago, says that though the reports of potential hazards associated with use of Baxter's propofol have been well publicized, few of his colleagues seem to feel that the threat is very serious. "Most of the hesitation on the part of anesthesiologists to use the generic is more a result of the threat of a complication and less the result of conclusive scientific data," says Brent Burke, MD, the Associate Director of Anesthesia at Indiana Surgery Center East in Indianapolis.

A reasonable course, suggests Dr. Grossman, may be to use the drugs interchangeably for uncomplicated cases, but to choose the brand-name version for "potentially susceptible patients such as asthmatics."

Generic Midazolam
The sedative and amnesiac midazolam, frequently used in outpatient surgery facilities for intramuscular or IV injection, is now off patent. A new generic version available from Bedford Laboratories is significantly less expensive than Versed. Mr. McNicholl says a "street price" for ten 10 ml vials of Versed, 1 mg/1 ml, would cost about $205, whereas the same quantity of generic midazolam would cost about $54.

In addition to lower price, Bedford also offers a preservative-free version of the drug. A Bedford spokesperson says the company believes many anesthesia professionals may prefer this to Versed, which is preserved with benzyl alcohol. However, the value of this benefit is more difficult to quantify than the price benefit. A literature search turned up no studies suggesting any harmful effects of benzyl alcohol. Morever, the anesthesiologists we interviewed say that while they have seen adverse effects from midazolam, such as a greater potential for respiratory depression when the drug is given in combination with other sedatives, patients have not to their knowledge experienced any adverse effects from the preservative.

Bedford's generic is available in seven presentations. Four of the vials are measured for single dose and are preservative-free. These include a 1mg/mL 2mL vial, a 1mg/mL 5mL vial, a 5mg/mL 1mL vial, and a 5mg/mL 2mL vial. The other three available presentations contain multiple doses and do contain preservatives.

Bupivacaine alternatives
Two relatively new regional blocks may provide benefits over bupivacaine. Levobupivacaine, which Purdue Pharma markets under the name Chirocaine, is approved for local or regional anesthesia for surgery. A number of studies indicate that Chirocaine produces analgesic and anesthetic results similar to bupivacaine at equal concentrations and volumes. However, it is less likely to produce cardiovascular toxicity (a relatively rare event) than bupivacaine. Levobupivacaine contains only one isomer, while bupivacaine contains two. Bupivacine's two isomers are more likely to bind to cardiac tissue than levobupivacaine's single isomer.

In two studies, one examining the toxicity of bupivacaine and the other examining the toxicity of levobupivacaine, the latter was found to produce fatal cardiac toxicity in sheep at 277 +/- 51 mg, while only 156 +/- 31 mg of bupivacaine resulted in cardiac fatality. In a clinical study involving 88 patients who received levobupivacaine, the most common adverse event was intra-operative hypotension, but the researchers encountered no serious arrhythmia. Cardiac problems are generally quite rare with bupivacaine, but they can occur in the event of an accidental intravascular injection.

The FDA has also approved levobupivacaine for post-operative pain management, a distinction bupivacaine does not enjoy. When administered as a peripheral nerve block, the effects of levobupivacaine appear to last some two hours longer than those of bupivacaine. The motor block is about the same or even a little less, meaning that the drug may allow patients to go home earlier with less pain. The only possible disadvantage is price-Chirocaine can cost up to five times what bupivacaine does-but this may be a significant issue. So far, opines Dr. Stanley "Levobupivacaine is not producing much change in what clinicians do."

Another possible alternative to bupivacaine is ropivacaine. Manufactured as Naropin by AstraZeneca, this drug has been shown to be less toxic than bupivacaine to the central nervous system and cardiovascular system. On average, a 100-200 mg epidural injection achieves sensory and motor block in ten minutes. The average duration is four hours, the company reports. Like levobupivacaine, ropivacaine costs approximately four to five times as much as bupivacaine. Unfortunately, none of the anesthesiologists with whom we spoke had any clinical experience with Naropin, but a literature search suggests that the benefits of the drug are similar to Chirocaine.

Remifentanil
Remifentanil, an analog of the opioid fentanyl, is said to metabolize more quickly than its cousin, providing both faster onset and significantly faster recovery. It's marketed as Ultiva by Glaxo-Wellcome.

Many of the anesthesiologists with whom we spoke give this drug high ratings. Dr. Stanley, who calls it "exciting," explains that "Its onset is approximately 90 seconds with total recovery in a matter of minutes," making it easy to titrate the drug to the desired depth of anesthesia.

Dr. Burke concurs: "This is a great drug for fast-tracking to provide rapid emergence in outpatient anesthesia. For procedures that last less than an hour, patients can be relatively clear headed within five minutes of turning off the infusion and hypnotic," he says.

However, the rapid emergence feature also poses a problem, Dr. Burke adds. If the patient needs post-op analgesia, the anesthesiologist must maintain an infusion or quickly switch drugs before surgery ends. Otherwise, Dr. Burke warns, the patient can wake up with severe pain.

Another problem may be PONV. Dr. Cutter uses the drug, but says that in his experience, if it is used alone, it can cause "significant side effects such as hypotension and increased nausea and vomiting." He says it's also more expensive.

In general, however, Dr. Burke feels that remifentanil's advantages outweigh its disadvantages, especially for shorter cases such as endoscopic sinus surgery or short laparoscopic procedures. Although these procedures are associated with considerable pain, Dr. Burke believes that supplementing remifentanil with another drug towards the end of the procedure is preferable than simply using only one drug for the whole procedure. "Other drugs that may provide better analgesia post-operatively tend to stay in the patient's system longer if you use them throughout a procedure. This can make patients drowsy and increase their recovery time," says Dr. Burke.

Dr. Maurer says his facility sometimes uses the drug in an interesting way. A very small segment of the patient population prefers to be aware of what occurs during their procedures, he says. It is not uncommon that these patients request that their surgeries be videotaped so that they can see firsthand what happens.

With these patients in mind, the Cleveland Clinic sometimes uses remifentanil to "consciously narcoticize" patients. The anesthesia provider can induce this state (in which the patient remains fully conscious but less susceptible to pain) by administering a milligram of midazolam in combination with a continuous remifentanil drip.

Conscious narcoticization may also be useful for arthroscopic procedures and for treating recurring pelvic pain through pain mapping. Pain mapping is a technique where the surgeon uses a microlaparoscope to touch different structures in the pelvis while the patient is awake to pinpoint areas of chronic pain. "Although remifentanil deadens the pain sensations, enough feeling remains for the patient to help the physician pinpoint the problem area," Dr. Maurer reports.

Rapacuronium bromide
Rapacuronium, approved in August 1999 and manufactured as Raplon by Organon Inc., is an amino-steroid, non-depolarizing neuromuscular blocking agent designed to be used as an adjunct to general anesthesia to facilitate tracheal intubation. The drug is designed to offer an alternative to succinylcholine, which can cause severe immune-system mediated side effects, including tachycardia, bronchospasm, myalgia and renal complications.

Clinical studies have indicated that an intravenous bolus at the recommended dose of 1.5 mg/kg has a rapid onset of approximately 1.2 to 1.8 minutes and a short duration of action of 15 to 25 minutes, similar to succinylcholine.

Our anesthesiologists say they like the drug's safety profile. Reports Dr. Cutter: "I use this product a lot."

The drug does incorporate two significant drawbacks, however. First, it's more appropriate for longer cases than shorter cases, our anesthesiologists agree. Dr. Burke says in his experience, the drug's effects do not typically wear off as quickly as the clinical studies indicate they do. Both he and Adam Dorin, MD, Medical Director and Chief of Anesthesia for The Surgery Center of Chevy Chase in Maryland, say that using Raplon for cases that last less than an hour necessitate using a reversal agent. Dr. Burke adds that he tries to avoid reversal agents, since they can leave patients feeling weak, and cause them to have difficulty with breathing. He reports that "Patients commonly can not cough and swallow effectively, they can't maintain their own airway, when reversal agents are used." By comparison, succinylcholine-induced blocks wear off in about five minutes and typically do not require reversal, he says.

Raplon is also significantly more expensive than succinylcholine. Dr. Burke says at his facility, succinylcholine costs only about 50 cents per dose, whereas Raplon costs $15 to $20 per case. Because of the cost and the slower recovery, he says he still uses the former drug for short cases.