It is a commonly held clinical belief that people with red hair respond to medications differently from those with other hair colors. "Redheads are a 'tough knockout'" is a commonly heard aphorism among anesthesiologists. Now, there is valid evidence that the saying is true. A study published in the August issue of Anesthesiology[1] attempted to put this belief to the test. Researchers from the University of Louisville, Kentucky, studied the anesthetic response of women with red hair compared with a control group with dark hair color. Twenty healthy female volunteer subjects (10 with red hair and 10 brunettes) were given a standard general anesthetic using desflurane, a commonly used inhalation gas. Only women were studied to rule out any possible confounding related to different anesthetic responses between the sexes. Moreover, all subjects were in roughly the same phase of the menstrual cycle to avoid known hormonal differences in anesthetic responsiveness. After a stable level of anesthesia was obtained, an electric shock of calibrated intensity was delivered to the leg. According to the researchers, the intensity of the shock was one that would be "intolerable" to an awake, alert person. If movement was detected in response to the shock, the level of inhalation anesthetic was increased until no further movement was detected with subsequent shocks. The researchers determined that roughly 20% more anesthetic was required, on average, for the redheads compared with the women of other hair color -- a finding that was highly statistically significant.

The authors point out that red hair is associated with specific mutations on the melanocortin-1 receptor gene (MC1R) that encodes melanocyte-stimulating hormone, which is involved in melanogenesis. These mutations result in loss of function or diminished function of the gene, which leads to increased expression of the red pigment pheomelanin and relatively decreased production of eumelanin, the pigment responsible for dark hair color. As a possible explanation for their findings that redheads had an increased requirement for anesthesia, the authors propose that the MC1R gene may be involved with complex neuromodulatory regulation within the central nervous system.

Further investigation into the mechanism of this observation by another team of researchers, also from the University of Louisville, was provided in another article in the same issue of the journal.[2] This team conducted a study in mice with a particular MC1R mutation  a knockout mutation that results in loss of gene function. Under carefully controlled laboratory conditions, the anesthetic requirements were compared between these mice (who have light hair) and a control group of phenotypical and genotypical normal (dark-haired) mice. This laboratory investigation confirmed a higher anesthetic requirement in the knockout mice.

The clinical implications of a 20% difference in anesthetic requirements may be minimal in terms of the conduct of most anesthetics delivered for typical surgical procedures. However, the broader implication of this finding is that different genotypes and phenotypes can and do manifest different responses to common drugs. We have all heard people who say, "the dentist always has to inject me 3 times before I get numb" or "Tylenol just doesn't seem to work for me" or similar comments. Perhaps there are indeed genetic explanations for these observations. The concept of "pharmacogenetics" is an emerging field, and many drugs are now known to manifest altered responses in genotypically different subjects. This important topic has many clinical implications that will be revealed as investigators continue these lines of investigation.