From Volume 51, Issue 8, September 2024 | Pages 557-560
Dentists have historically approached redheaded patients with some caution owing to their reputation for heightened bleeding, lower pain tolerance and increased requirement for anesthesia and pain relief. This article examines the evidence and dispells any misconceptions.
Hair colour is a genetic and physiologically complex phenotype. Approximately 2% of the global population possesses the red hair phenotype, with an increase to 6% in Scotland and 10% in Ireland.1
This phenotype is often characterized by fair skin, freckles and light-coloured eyes. This is attributable to the elevated red pigment, pheomelanin, and the reduced levels of the dark pigment, eumelanin. The genetic basis of red hair was identified in 1995 in association with the melanocortin-1 receptor (MC1R) located on chromosome 16. Additionally, individuals with red hair tend to be sensitive to UV light.2,3 The MC1R gene-encoded protein is made up of 317 amino acids, and over 35 polymorphic sites on the gene have been identified, only a small number of which cause red hair. The underlying genotype for the red hair phenotype is the MC1R mutation.
The MC1R gene is recessive, and to have red hair means that two copies of the recessive gene, one allele from each parent, have been inherited (Figure 1). A carrier of the gene may have dark hair, but possess the same genetic characteristics and predispositions of redheads.4
Red hair is considered one of the most ancient hair colours in human history, with the corresponding MC1R mutation dating back to prehistoric eras.5 Throughout various cultures, red hair has captivated people's interest and inspired superstitions, often associating individuals who possessed it with notions of enchantment and mysticism.6
Typical perceptions and stereotypes include fiery tempers and sharp tongues. There has always been prejudice and discrimination against redheads and there is no explicit protection provided by the equality act of 2010.7
Numerous anecdotes have been shared regarding the clinical characteristics of individuals with red hair.8
Individuals with red hair frequently exhibit pale skin and freckles. Pale skin is linked to a heightened susceptibility to skin cancer owing to the fact that eumelanin, which provides protection against harmful ultraviolet (UV) light – a known skin cancer risk factor, is significantly lower in redheads compared to individuals with darker skin tones.9
Alterations in the MC1R gene play a role in the development of pale, non-tanning skin and heightened sensitivity to UV radiation, consequently elevating the risk of skin cancer.10,11 These modifications can impact the body's ability to shield itself from UV light and repair DNA damage caused by UV exposure. Research indicates that the most prevalent MC1R gene variants linked to red hair, pale skin, and freckles are associated with a potential four-fold increase in the lifetime risk of developing skin cancer.11 However, the precise molecular mechanisms behind this association remain inadequately understood.
A 2013 study revealed that the MC1R variants identified in redheads are incapable of binding to PTEN, a tumour-suppressor gene. This malfunction leads to heightened activity in a cancer-promoting signalling pathway, subsequently increasing the risk of cancer development.12 Moreover, when combined with a mutation in the BRAF gene on chromosome 7, the risk escalates further. BRAF mutations are present in as many as 70% of all melanoma cases.13
This tendency to sunburn easily and an elevated risk of skin cancer in individuals with red hair means they should exercise particular caution when it comes to sun exposure and consistently use a high sun protection factor (SPF) sunscreen.
There is evidence to suggest that some individuals with red hair may experience heightened sensitivity to pain owing to alterations in pain perception associated with MC1R gene variants. Redheads have a demonstrated increased sensitivity to pain induced by heat or cold, as well as reduced responsiveness to pain relief from subcutaneous lidocaine.14 Additionally, limited research has indicated that redheads may require higher doses of anaesthesia.15 Furthermore, women possessing two variant MC1R alleles have exhibited enhanced pain relief with the opioid pain medication, pentazocine, compared to other groups.16
A 2021 study conducted on mice further reinforces the role of MC1R variants in pain sensitivity. Researchers examined red-haired mice carrying a loss-of-function MC1R variant also found in human redheads. They discovered that these mice displayed a higher pain tolerance level that was influenced by the number of melanocytes, rather than the quantity of melanin present.17,18 The MC1R loss of function in melanocytes resulted in reduced levels of a protein known as pro-opiomelanocortin. This, in turn, affected the levels of hormones involved in pain regulation, namely the pain-blocking hormone (beta-endorphin) and the pain-sensitizing hormone (melanocyte-stimulating hormone or MSH). These hormones work in tandem to balance receptors responsible for pain inhibition (opioid receptors) and pain sensitivity (melanocortin 4 receptors). In the red-haired mice, despite reduced levels of both hormones, the MC1R variants appeared to favour opioid receptors that inhibit pain, thereby increasing the pain threshold. However, it is worth noting that red-haired mice also possess additional factors, unrelated to melanocytes, that activate pain inhibition receptors, contributing to an overall heightened pain threshold.17,19
The evidence is somewhat contradictory, but it indicates that MC1R variants and pigmentation levels do impact the pain threshold, which carries implications for pain management in individuals with red hair. Moreover, alterations in the pathways involved in regulating hormone levels resulting in decreased plasma MSH may also account for variations in pain perception among individuals without red hair.20 More specific high-quality research is required in this area to provide a more definitive conclusion.
The potential connection between Parkinson's disease and an elevated occurrence of melanoma has prompted researchers to investigate the influence of MC1R gene variants in Parkinson's disease. Several studies have reported an association between red hair and Parkinson's disease. For instance, one study explored the relationship between hair colour and Parkinson's disease risk in a sample of over 130,000 participants from two extensive American studies: the Health Professionals Follow-up study and the Nurses' Health study.21 This investigation revealed that the relative risk of developing Parkinson's disease increased as hair colour became lighter, with individuals sporting red hair having a two-fold higher risk of Parkinson's disease compared to those with black hair. Notably, this association was particularly robust among individuals under the age of 70 years.
Furthermore, researchers observed that individuals homozygous for a specific MC1R variant allele exhibited a significantly elevated risk of Parkinson's disease.21 Studies conducted on mice carrying loss-of-function MC1R variants similar to those found in some redheads showed an increased susceptibility to dopaminergic toxins and the development of dopaminergic deficits in adulthood.22 This aligns with Parkinson's disease in humans, where the condition is characterized by low dopamine levels, typically manifesting later in life.
It remains unclear whether MC1R variants contribute to the heightened risk of Parkinson's disease solely through their impact on pigmentation, or if other mechanisms are at play. Nevertheless, some research hints at the possibility of MC1R playing a neuroprotective role.22 Again further research is required to substantiate a link.
There have been reports of a potential heightened risk of endometriosis among women with red hair, but this association may be influenced by fertility status. A study involving 90,065 women, published in 2006, indicated that non-infertile women with red hair were more likely to have endometriosis compared to women with different hair colours. In contrast, women with natural red hair who experienced infertility showed a reduced incidence of endometriosis.23 There is currently insufficient evidence to confirm the link.
In an effort to establish a connection between red hair and post-tonsillectomy bleeding (alongside factors such as full moons and Friday the 13th), one study was conducted. This study revealed that the occurrence of post-tonsillectomy bleeding was nearly 7%, which was statistically similar to the rate found in the control group.24
Another study examined the bleeding tendencies of 50 women, with half having red hair and the other half having black or brown hair, using objective coagulation tests, and no significant differences were observed.25
Another study showed that the presumed increased bleeding tendency in red-haired individuals is not associated with Willebrand factor antigen levels.26
In conclusion, the evidence available does not support the belief that having red hair causes excessive bleeding.
However, could there be another underlying reason for the bias against redheads when it comes to bleeding? It is possible that this bias is rooted in the automatic association of red hair with ginger, specifically the Zingiber officinale variety. Ginger is not only a common spice, but is also employed by herbalists to address various symptoms such as coughs, abdominal pain, diarrhoea, nausea and motion sickness. Of particular relevance is the fact that ginger can contribute to a propensity for bleeding. Ginger has the potential to interact with the anticoagulant warfarin, hinder platelet aggregation (by inhibiting thromboxane production from arachidonic acid), and enhance fibrinolysis. Thus, it seems that there is indeed a connection between ginger and bleeding.27
One small study reported more bruising in female redheads but no objective evidence for an underlying coagulopathy. Coagulation factor and platelet function were comparable in red haired and dark-haired women.28 Another study found no differences in coagulation parameters between red haired vs black haired males.29 It may be that because the skin is fairer the bruises may appear more prominent. The weak evidence from these small studies showed increased incidence of bruising.
One specific study delved into the elevated anaesthesia needs of patients with red hair during surgical procedures.30 While this study had limitations in terms of its small sample size, it revealed a significant increase in the requirement for desflurane among patients with red hair compared to those with different hair colours.
Myles et al, in their larger prospective matched cohort study, found no evidence that patient hair colour affects anaesthetic requirements or recovery characteristics in a broad range of surgical procedures.31
Another matched cohort study showed there were no demonstrable differences between red-haired patients and controls in response to anaesthetic and analgesic agents, or in recovery parameters.32
The evidence is conflicting, but the larger, stronger studies support the belief that peri-operative anaesthetic and analgesic management should not be altered based on self-reported red-hair phenotype.
Liem et al conducted an investigation into the differences in requirements for local anaesthetics between individuals with red hair and a control group comprising individuals with black or brown hair.33 It was observed that subcutaneous lidocaine (lignocaine) had reduced effectiveness in the red-haired group, who also displayed an increased sensitivity to pain caused by exposure to cold and heat in comparison to the control group. The authors suggested that the malfunction of the MC1R gene associated with red hair might trigger an elevated release of α-melanocyte-stimulating hormone, which activates specific cells. Importantly, this particular hormone also stimulates a brain receptor linked to pain sensitivity. However, this was a very small study.
Mutations of the MC1R appear to influence pain sensitivity. However, it remains uncertain whether this influence operates primarily at a central level, peripheral level, or both. It is important to note that a genetic association does not always guarantee a straightforward explanation for the observed phenotypic effect. So far, these distinctions in pain sensitivity appear to be most pronounced when individuals are exposed to drugs such as local anaesthetics or volatile anaesthetics, which dampen responses to painful stimuli.34
Anaesthetic efficacy of the inferior alveolar nerve block in red-versus dark-haired women was looked at by Droll et al.35 They concluded that there was no significant difference in anaesthetic success between any of the groups.
The available evidence is limited and once again conflicting. Available research shows that MC1R mutations do have an impact on pain perception, although what these impacts are is not fully explained.
A study by Mogil et al involving mice and humans with red hair, both characterized by non-functional MC1Rs, demonstrated reduced sensitivity to painful stimuli and an increased responsiveness to opiate-based pain relief.36
This was a small study, but provided some interesting findings. Further large-scale genetic association studies need to be carried out to support these claims.
Binkley et al37conducted a study to explore whether possessing red hair, an MC1R variant, or both factors could serve as predictors for patients experiencing anxiety related to dental care and avoiding dental treatment. The findings revealed that individuals with MC1R variants reported notably higher levels of anxiety related to dental care, and they were twice as likely to avoid seeking dental treatment.
The authors concluded that dentists should assess all patients, with particular attention to individuals with natural red hair, for signs of dental care-related anxiety and employ suitable approaches to address their anxiety.
Droll et al35 reported significantly higher levels of dental anxiety in the red-versus black-haired group.
The limited available evidence supports the link between the MC1R mutation and increased dental anxiety.
An article from 2013 documented a noteworthy observation: red-headed men exhibited a considerably lower likelihood of developing prostate cancer compared to their brown-haired counterparts. The risk for prostate cancer in redheads was approximately half that of brown-haired men. While the study did not establish a definitive mechanism for this phenomenon, it proposed that MC1R variants might potentially play a role in influencing prostate cancer development.38 Further research will be beneficial in this area.
Redheads may possess a greater ability to produce their own vitamin D compared to individuals with different hair colours. A small-scale study discovered that redheads had elevated levels of a vitamin D precursor in their bloodstream and proposed that this might represent an evolutionary adaptation allowing for the efficient synthesis of provitamin D, especially under conditions of lower-intensity sunlight, such as those prevalent in northern Europe.39 Vitamin D offers benefits for bone health, immunity and mood.
The available evidence contradicts the belief that redheads bleed excessively. The data regarding the connection between red hair and resistance to volatile anaesthetics is inconclusive. There are limited findings indicating that MC1R variants impact the pain perception and threshold, which carries implications for pain management in individuals with red hair. Research suggests that local anaesthetics may be less effective in individuals with red hair. There is evidence indicating a higher incidence of anxiety related to dental treatment in individuals with red hair.
A crucial reminder is stressed however, and that is to emphasize the importance of applying sunscreen, regularly examining the skin for any unusual changes, and promptly seeking evaluation for any atypical skin concerns for this group of patients.
