Abstract
Methadone is a synthetic opioid used as maintenance treatment for patients addicted to heroin. Skin irritation is one of the adverse events caused by opioid use. 344 methadone maintenance treatment (MMT) patients were recruited with records and measurements on methadone dose, plasma methadone concentrations, and treatment emergent symptom scales (TESS). 15 patients reported with skin irritation. Five SNPs located within the NECTIN4 genetic region were genotyped. The NECTIN4 gene within the adherens junction interaction pathway was associated with methadone dose in pathway-based genome wide association analyses (P = 0.0008). Three highly-linked SNPs, rs11265549, rs3820097, and rs4656978, were significantly associated with methadone dose (P = 0.0003), plasma concentrations of R,S-methadone (P = 0.0004) and TNF-α (P = 0.010) in all 344 MMT patients, and with self-report skin irritation symptom scores (P = 0.010) in the 15 MMT patients who reported with skin irritation. To identify the possible roles of plasma level of Nectin-4 in the responses to MMT and opioid use, additional age- and gender-matched 51 controls and 83 methadone-free abstinent former heroin users were recruited. Plasma level of Nectin-4 was the highest in MMT patients among the three groups. The results suggest involvement of genetic variants on NECTIN4 in methadone dose. Plasma Nectin-4 level is likely an indicator for continued use of opioids.
Highlights
Methadone is a synthetic opioid commonly prescribed for heroin dependent patients as a maintenance therapy [1]
Skin irritation is one of the adverse events caused by opioid use. 344 methadone maintenance treatment (MMT) patients were recruited with records and measurements on methadone dose, plasma methadone concentrations, and treatment emergent symptom scales (TESS). 15 patients reported with skin irritation
We identified that the NECTIN4 gene, one of such genes in the human expression nectin family, showed the most significant association with methadone dose among the adherens junction interactions in the pathwaybased association analyses (P = 0.0008) (S1 Table), it did not pass the pathway threshold
Summary
Methadone is a synthetic opioid commonly prescribed for heroin dependent patients as a maintenance therapy [1]. The mechanism of action has been well documented through its binding to the mu-opioid receptor as a full agonist [2]. NECTIN4 is associated with continued opioid use Medicine (NSC 100-3112-B-400-015); National Science Council (NSC 100-2314-B-400- 002-MY3); Ministry of Science and Technology (MOST 1062320-B-400-012) and the National Health Research Institutes, Taiwan (NP-107-PP-06, NP-108-PP-06, NP-109-PP- 07, NP-107-SP-04, NP-108-SP-04 , and NP-109-SP-04). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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