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Is It the Next Analgesic?

Martin, Brian MD

doi: 10.1213/ANE.0000000000001024
Editorials: Editorial

From the Department of Anesthesiology, Baystate Medical Center, Springfield, Massachusetts.

Accepted for publication August 31, 2015.

Funding: None.

The author declares no conflicts of interest.

Reprints will not be available from the author.

Address correspondence to Brian Martin, MD, Department of Anesthesiology, Baystate Medical Center, 124 Cold Spring Lane, Suffield, CT 06078. Address e-mail to

An increasing number of procedures are performed using potent sedatives, without a protected airway.1 In some cases, nonanesthesia providers administer these medications and are not necessarily trained in airway management.2,3 In light of the recent media reports regarding propofol-related respiratory complications and death, the increased use of propofol for procedural sedation,1 and the narrow therapeutic window of sedatives when combined,1,3 the need for a nonsedating adjuvant appears legitimate. The recent national shortage of propofol is yet another impetus for an adjuvant for procedural sedation.2

Propofol, a potent IV anesthetic, quickly causes hypnosis.4 The combination of propofol with other sedatives, such as opioids, is synergistic1 and may quickly lead to clinical effects such as respiratory depression. In one review, propofol-induced hypoxemia occurred in 10% of patients who had an endoscopic procedure performed.1 Propofol combined with other sedatives led to respiratory depression and accounted for 33% of malpractice claims for sedation cases performed outside the operating room.3

The ideal adjuvant should probably be nonsedating, analgesic, inexpensive, readily available, and have a good safety profile. Propofol has very little to no analgesic properties at clinical doses but if combined with a nonsedating analgesic, the 2 drugs together should theoretically improve safety during procedural sedation, by allowing a decrease in the dose of propofol, yet still providing for patient comfort.

Could isovaline be this drug? In this month’s issue, Whitehead et al.5 describe the use of the amino acid, RS-isovaline hydrochloride, as a peripherally acting analgesic in mice. In this proof-of-principle, blinded study, they showed that isovaline combined with propofol produced general anesthesia (hypnosis and analgesia) and conscious sedation. The mice received intraperitoneal injections of saline, propofol, fentanyl citrate, and RS-isovaline chloride. The authors assessed hypnosis with the use of the loss-of-righting reflex test (the ability of the mice to rotate from the supine to the prone position) and the loss-of-response to light touch. Sedation was examined with the rotarod latency assay. In the rotarod assay, the authors trained the mice on the rotarod with a maximal cutoff time of 60 seconds. Isovaline did not reduce the rotarod latency time. Therefore, it did not lead to sedation or hypnosis even and at maximal doses.

Analgesia was assessed using the loss of response to tail clip test. In this study, implementing Haffner’s method, researchers applied an alligator clip to the tails of the mice. The Haffner’s method is an established, commonly used animal model for testing analgesia.6,7

They used the Dixon up-and-down method to evaluate efficacy and safety. They were able to demonstrate an analgesic effect when isovaline hydrochloride was administered to mice. The ED50 for isovaline-induced analgesia was also lowered when combined with propofol. Other interesting findings were the lack of isovaline-induced sedation when given alone and the absence of synergism for sedation when coadministered with propofol.

Although isovaline did not lower the dose for propofol-induced sedation, neither did fentanyl in this study. The authors noted that this might have been because of the wide confidence interval. The authors warn the reader to be cautious with this finding because the combination of fentanyl and propofol has been previously shown to be synergistic in causing sedation and respiratory depression.1,3

Isovaline is an isomer of the α-amino acid, valine.8 Isovaline (2-amino-2-methylbutanoic acid) structurally resembles the inhibitory neurotransmitter glycine.9,10 Glycine is partly responsible for inhibitory modulation of pain signals.9 Interestingly, isovaline was discovered in meteorites and is not 1 of the 20 proteinogenic amino acids found in living systems.8,9 Isovaline is a γ-aminobutyric acid (GABAB) agonist. It does not cross the blood-brain barrier and therefore has no central nervous system side effects when given peripherally.10

GABAB receptors are located on sensory neurons in the periphery, specifically Aδ and C fibers, which regulate nociception. Isovaline has also been shown to produce analgesia when administered directly into central nervous system tissue.9,10

If these results could be replicated in human studies, some pain-eliciting procedures requiring general anesthesia might be safely performed using sedation. There may be many other benefits if isovaline is demonstrated to be an effective nonsedating analgesic in humans. Health care costs may be reduced as a result of faster recovery from sedation and less time to discharge. Medical centers can improve patient and staff satisfaction. We may witness a sharp reduction in the number of sedation-related deaths and complications. Anesthesia providers may be able to decrease the dosage of propofol and might still be able to deliver care, despite propofol shortages. The dose of the sedating agent could be minimized because isovaline may theoretically provide effective relief from a painful stimulus without the sedating side effects. The risk involved in sedating patients with multiple comorbid conditions may be minimized because providers may be able to safely and minimally sedate these patients, while avoiding respiratory depression and excessive sedation.

More animal studies may have to be conducted to better understand the pharmacology of isovaline and any potential short-term and long-term side effects, as well as adverse reactions. The study by Whitehead et al.5 has sparked interest for the isovaline and other potential GABAB agonists. If such a drug class is efficacious for analgesia, the extensive array of clinical applications will be groundbreaking. Applications for pain may include peripheral nerve blockade, neuraxial anesthesia, multimodal analgesia, and chronic pain. I am elated about the potential for the implementation of GABAB agonists into clinical practice in the near future, and I hope that further research will achieve this goal!

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Name: Brian Martin, MD.

Contribution: This author wrote the manuscript.

Attestation: Brian Martin approved the final manuscript.

This manuscript was handled by: Markus W. Hollmann, MD, PhD, DEAA.

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