The impact of MC1R variants on anaesthesia and pain: myth or clinical reality?

The "red-haired patient" often raises questions in oral surgery or implantology, particularly due to conflicting literature on a potential resistance to local anaesthetics and a specific sensitivity to pain. This systematic review, published by Mary Clark Allen in 2026, analyses 20 scientific articles to synthesise current evidence regarding the role of MC1R (melanocortin-1 receptor) gene variants in altering physiological responses. The central objective is to determine whether the genetic mutations associated with red hair genuinely modulate nociceptive perception, opioid efficacy, or anaesthetic requirements, in order to validate or refute the need to adjust our treatment protocols. The study tests the hypothesis that these genetic specificities could induce a distinct clinical response, while seeking to identify whether current recommendations should evolve towards differentiated management according to the melanic phenotype.

Review methodology

This systematic literature review aimed to synthesise the clinical evidence regarding the influence of MC1R gene variants — responsible for the "red hair and fair skin" phenotype — on physiological responses to pain and anaesthetic agents. The search was conducted via the University of Arkansas OneSearch platform, specifically querying the CINAHL, MEDLINE and PubMed databases. From all the identified results, the authors selected 20 peer-reviewed articles after applying rigorous inclusion and exclusion criteria.

The qualitative analysis of these 20 publications focused on four distinct physiological domains:

• Quantitative requirements for anaesthesia.
• The efficacy of opioid analgesia (sensitivity to k-opioids).
• Overall perception and pain sensitivity thresholds.
• Anxiety and fear related to pain (pain-related fear).

The methodology consisted of comparing the results of initial small-scale studies with those of larger cohorts to assess the reproducibility of the measurements and the clinical relevance of the variations observed in carriers of the MC1R variant.

Results of the synthesis of 20 studies on the MC1R variant

This systematic review analysed the data from 20 peer-reviewed articles to determine the impact of MC1R gene variants on the physiological response. The authors report heterogeneous results, varying depending on the clinical field studied.

• Anaesthesia: Compiled data show that evidence of an increased need for anaesthetics in red-haired patients, although present in early studies, is not confirmed by larger-scale studies.
• Opioid pharmacology: The review highlights an increased response to k-opioids. This pharmacological sensitivity appears particularly pronounced in female subjects carrying MC1R variants.
• Psychological factors: Unlike physiological measures of pain, which remain contradictory, the psychological dimension is stable across studies: individuals carrying MC1R variants consistently exhibit higher apprehension and fear of pain.

Clinical interpretation and limitations of the synthesis

This systematic review of 20 studies challenges certain misconceptions in implantology and oral surgery regarding the "red-haired" patient. Although the idea of increased resistance to anaesthesia is common, the data synthesised here show that the results remain inconsistent: large-scale studies do not confirm a significant clinical difference. However, increased sensitivity to opioids (particularly k-opioids in women) and a systematically higher fear of pain in carriers of the MC1R variant constitute robust clinical realities. The practitioner must therefore distinguish the pharmacological response, which is still debated, from the psychological and anxiety component, which is clearly documented here.

The limitations of this work lie in the contradictory nature of the data on raw pain perception and the lack of standardisation in the assessment methods across the included studies. The author highlights that hair colour is an occasionally imprecise phenotypic marker compared to the actual genetic analysis of the MC1R gene, which may explain the discrepancies in results between the cohorts.

Towards a personalised approach in the practice

For the surgeon, these results do not dictate a systematic modification of local anaesthesia protocols based solely on phenotype. They do, however, suggest proactive management of preoperative anxiety, which is particularly pronounced in these patients. The implication is direct: assessment must remain individualised. While the red hair phenotype should alert to a possible alteration in the physiological response, it must not replace careful titration and attentive listening to the patient's pain history.

In practical terms, for the practitioner:

• Maintain your standard protocols: Hair colour alone is not a reliable predictor of anaesthetic resistance; do not preemptively overdose, as large cohort studies demonstrate no significant difference.
• Anticipate anxiety: Fear of treatment and pain is statistically higher in patients carrying MC1R variants; plan for enhanced psychological management or sedative premedication.
• Individualise analgesia: Be mindful of a potentially heightened response to opioids post-operatively, while remaining vigilant regarding pain perception, which may prove unpredictable depending on the individual.

Technical glossary

MC1R (Melanocortin 1 Receptor): Membrane receptor whose polymorphisms regulate pigmentation and appear to influence nociceptive pathways and the response to anaesthetic agents.

k-opioids (Kappa opioids): Subclass of opioid receptors involved in analgesia; red-haired patients, particularly women, appear to exhibit increased sensitivity to their agonists.

Anaesthetic requirements: Minimum dose required to achieve a loss of sensation or consciousness; a parameter often suspected to be higher in red-haired patients without a definitive consensus.

Pain-related fear: Anticipatory emotional response to a painful stimulus, identified as a common comorbidity factor in carriers of MC1R gene variants.

Systematic review: Critical synthesis of existing scientific literature, using a rigorous methodology to answer a specific clinical question.

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