Beware the Redheaded Patient: Fact or Fiction in Cosmetic and Surgical Dermatology?

Do redheads require more anesthesia? Anecdotal experience among dermatologists supports the notion that redheads exhibit decreased pain tolerance and require more subcutaneous lidocaine during routine procedures. The topic of red hair and pain tolerance has been explored extensively in anesthesia, general surgery, and endodontic literature, but largely has been neglected within dermatology literature. Here, we review results from basic science research as well as clinical studies on melanocortin 1 receptor (MC1R) expression and pain responsiveness in mouse models; MC1R variability and human hair color; and differences in inhalational, topical, and subcutaneous anesthetic requirements as well as altered pain and temperature thresholds in redheads versus the general population.

A PubMed literature search was conducted using the terms “redhead,” “red hair,” “pain,” “anesthesia,” “melanocortin-1 receptor,” “MC1R,” “lidocaine” in various combinations. All relevant scientific or otherwise related papers identified were selected for review.

LITERATURE REVIEW

The MC1R is expressed on the surface membrane of melanocytes. When stimulated by its ligand alpha melanocyte stimulating hormone, MC1R activates a cyclic AMP mediated signaling pathway, which ultimately results in transcriptional activation. One of the results is that melanin production shifts from the baseline yellow-red pheomelanin production to that of the darker eumelanin pigment. The MC1R has a number of biological roles; it is responsible for pigmentation, response to UV radiation, and it also appears to exert anti-inflammatory effects via attenuation of proinflammatory cytokines. The red hair phenotype is characterized by fair skin color, freckles, increased UV sensitivity, and red hair color—all of which result because a less efficient MC1R favors default production of pehomelanin. Patients with freckles have an 85 percent chance of having one mutant MC1R allele. Mutations in the MC1R gene are quite frequent in Northern European populations, with overall carrier prevalence of 50 percent in the United Kingdom and 25 percent overall in the United Staes. Three variant alleles are found in 93 percent of redheads; and the overwhelming majority of redheads have either homozygous mutations or compound heterozygote mutations. Whatever the variant, the end result is a dysfunctional MC1R with reduced cAMP signaling in response to alpha MSH stimulation. The connection between the MC1R gene and the red hair phenotype is well established in the literature.

The MC1R also plays a role in analgesia. Alpha MSH has anti-opioid effects. Often these responses are sexually dimorphic. Female mice with variant MC1R genes demonstrate increased sensitivity to kappa- and mu-opioid agonists. In a 2003 article in Proceedings of the National Academy of Sciences, Mogil and colleagues demonstrated that women with two variant MC1R alleles display significantly greater analgesia to kappa-opiate pentazocine compared to women with one or no variant allele. In a follow up study, Dr. Mogil's team showed greater sensitivity to the morphine-6-glucuronide, a potent mu agonist, among human MC1R mutants of both sexes.

In the surgical literature, Dixon up and down method to assess desflurane requirements (P50) to attenuate motor response to noxious electrical stimulation in redhead vs. dark-haired females populations found desflurane requirement in redheads was significantly greater than in dark haired women (P = 0.0004). On average, redheads required 19 percent more desflurane than those with dark hair. Subcutaneous lidocaine was also found to be significantly less effective in redheads (e.g., one study found pain tolerance threshold at 2,000-Hz stimulation in redheads was 11.0 [8.5-16.5] vs. > 20.0 (14.5 to > 20) mA in others; P = 0.005). Redheads are more sensitive to thermal pain.

Dental and endodontic literature show women with two MC1R variants have significantly more dental anxiety, no difference in inferior alveolar nerve block success rate, and significantly greater pain on needle insertion. In both sexes, patients with two MC1R variants have more dental anxiety, more fear of dental pain, and are twice as likely to avoid dental care.

Review of surgical literature found no association between red hair and delayed post-tonsillectomy hemorrhage; red-haired women report slightly more post-op bruising but have normal coagulation tests; there is no data linking red hair and hernia formation; and red hair is linked to brittle cornea syndrome (both on chromosome 16q24).

CONCLUSION

Numerous studies across various disciplines have demonstrated that there are significant differences between redheads and the general population with respect to pain and analgesia. When performing procedures on redheaded patients, practitioners should anticipate decreased response to topical and local anesthetics and should be prepared for increased sensitivity to thermal pain during procedures such as cryosurgery, cryolipolysis, electrosurgery, radiofrequency, microwave technologies, and ablative resurfacing. Finally, the increased efficacy of opioids in redheads may be beneficial in pain management. Further studies will help delineate the best approach to these patients.

Dr. Shaughnessy is with the Medical College of Georgia Division of Dermatology, Augusta, GA. She has no financial disclosures and no conflicts of interest

To learn more about Cosmetic Surgery Forum, visit cosmeticsurgeryforum.com

1. Liem EB, Joiner TV, Tsueda K, Sessler DI. Increased Sensitivity to Thermal Pain and Reduced Subcutaneous Lidocaine Efficacy in Redheads. Anesthesiology 2005;102:509-14.
2. Liem EB, Lin CM, Suleman MI, Doufas AG, Gregg RG, Veauthier JM, Loyd G, Sessler DI. Anesthetic Requirement is Increased in Redheads. Anesthesiology 2004;101:279-83.
3. Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KVS, Lariviere WR et al. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci USA 2003;100:4867-72.
4. Mogil JS, et al. Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans. J Med Genet 2005;42:583-7.
5. Droll B, Drum M, et al. Anesthetic Efficacy of the Inferior Alveolar Nerve Block in Red-haired Women. J Endo 2012;38:15564-9.
6. Brinkley CJ, Beacham A, Neace W, Gregg RG, Liem EB, Sessler DI. Genetic variations associated with red hair color and fear of dental pain, anxiety regarding dental care and avoidance of dental care. J Am Dent Assoc 2009;7:896-905.
7. Andresen T, Lunden D, Drewes AM, Arendt-Nielsen L. Pain sensitivity and experimentally induced sensitization in red haired females. Scandanavian Journal of Pain 2010;2:3-6.
8. Kumar VV, Kumar NV, Isaacson G. Superstition and Post-Tonsillectomy Hemorrhage. Laryngoscope 2004;114:2031-3.
9. Cunningham AL, Jones CP, Ansell J, Barry JD. Red for danger? The effects of red hair in surgical practice. BMJ 2010;341:1304-5.
10. Liem EB, Hollensead SC, Joiner TV, Sessler DI. Women with red hair report a slightly increased rate of bruising but have normal coagulation tests. Anesth Analg 2006;102:313-8.