The rare Arg181Cys mutation in the μ opioid receptor can abolish opioid responses.
BACKGROUND
Genetic variability contributes to variable clinical response to opioids. This study emerged from the observation of three Norwegian patients who showed no or extraordinary poor response to very high doses of opioids. We suspected a genetic defect and applied a 'most likely candidate gene' approach to investigate this possibility.


METHODS
DNA sequencing was used to search for mutations in coding regions of the OPRM1 gene, encoding the μ opioid receptor (hMOR), in one patient. The remaining two patients, and two cohorts comprising 2158 European cancer pain patients and 600 Norwegian healthy volunteers, respectively, were genotyped using a custom-made TaqMan SNP allelic discrimination assay.


RESULTS
DNA sequencing disclosed a homozygous, inactivating Arg181Cys mutation in hMOR in the patient who showed no effects from opioids. The two patients with poor effect from very high doses of opioids were both heterozygous for the mutation. Six heterozygous patients identified among the European cancer patients all used high doses of opioids and/or reported inferior effect on their pain. About one in every 100 Norwegians is heterozygous for the mutation.


CONCLUSIONS
The Arg181Cys mutation occurs at clinically relevant frequencies and produces a signaling dead hMOR which may abolish or significantly reduce opioid effects in affected individuals. Anesthesiologists and practitioners in pain medicine should be aware of this mutation as a possible explanation for inefficiency of opioids and consider genotyping in relevant cases. Individuals homozygous for the mutation may need a highly personalized approach to pain therapy.
Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.|European Palliative Care Research Center, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
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Skorpen
Regional Centre of Excellence for Palliative Care, Western Norway, Haukeland University Hospital, Bergen, Norway.|Sunniva Centre for Palliative Care, Haraldsplass Deaconess Hospital, Bergen, Norway.
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von Hofacker
Department of Anaesthesiology and Intensive Care Medicine, Volda Hospital, Volda, Norway.
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Bjørngaard
Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
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Skogholt
Department of Research and Innovation, St. Olav's University Hospital, Trondheim, Norway.|Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
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O
Dale
European Palliative Care Research Center, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.|Department of Oncology, St Olav's University Hospital, Trondheim, Norway.
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Kaasa
Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.|Department of Anaesthesiology and Intensive Care Medicine, St Olav's University Hospital, Trondheim, Norway.
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Klepstad
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017450:Receptors, Opioid, mu / Q000235:genetics*
D000701:Analgesics, Opioid; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu