מידע לרופאים ואנשי מקצוע

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μ Opioid Receptor

קבוצה:       גנים פרמקודינמיים

תפקיד פזיולוגי:    קולטני אופיואיד

גנוטיפים:   אלל G – תגובה מופחתת לאופיואידים משויך לתגובה לנלטרקסון לטיפול בתלות באלכוהול

תרופות:     אופיואידים, נלטרקסון

קליניקה:    מעקב זהיר של נטילת אופיואידים עדיפות למשככי כאבים שאינם אופיואידים.

דירוג רמת הראיות  LOE:   2B


OPRM1 Opioid Receptor Mu 1 הוא גן שמקודד קולטנים ל-μ Opioid. קולטנים אלו ממוקמים בכל מעגלי המוח המעורבים בעיבוד תגמולים, שיכוך כאבים ותגובת מתח. OPRM1 הוא היעד העיקרי לתרכובות טבעיות וסינתטיות רבות, כולל תרופות אופיאטיות. שינויים בגן זה קשורים להתמכרות לאופיואידים ולאלכוהול. בנוסף, יש לו תפקיד משמעותי בקביעת הרגישות לכאב.

אלל G שינוי זה נקשר לביטוי מופחת של OPRM1. מבחינה קלינית, שינוי זה נקשר לעוצמת כאב גבוהה יותר ולהחלמה איטית יותר מפציעות מסוימות כמו פריצת דיסק. 186, 187 מחקרים מצאו גם כי חולים עם אלל G עשויים להזדקק למינונים גבוהים יותר של אופיואידים להשגת שיכוך כאבים, בהשוואה לבקרות A / A. 188-192 משככי כאבים שאינם אופיואידים עשויים להיות אפשרות טיפולית עבור חולים אלה אם ישנה לכך התוויה קלינית.


נתונים קליניים מצביעים גם על כך שנושאי אלל G עשויים להיות בעלי סיכוי נמוך יותר להישנות עם  Naltrexone לטיפול בתלות באלכוהול. 193-197

ג'נומיינד (Genomind) היא הבדיקה הפרמקוגנטית (PGx) המתקדמת ביותר בפסיכיאטריה. היא בודקת 24 גנים, הקשורים לפירוק תרופות. קבלת תשובת הבדיקה בתוך 10 ימים מנטילת דגימת הרוק, בצורת דו"ח מעמיק ונוח לקריאה. הדו"ח מכיל מידע פרמקוגנטי על יותר מ-130 תכשירים פסיכיאטריים, והתאמתם הגנטית לנבדק. מחקרים שנערכו על הבדיקה הוכיחו את יתרונותיה בקיצור הזמן להשגת אפקט טיפולי ושיפור הההיענות לטיפול.


186. Hasvik, E., et al., Subjective health complaints in patients with lumbar radicular pain and disc herniation are associated with a sex – OPRM1 A118G polymorphism interaction: a prospective 1-year observational study. BMC Musculoskelet Disord, 2014. 15: p. 161.

187. Olsen, M.B., et al., Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor mu 1 gene: evidence of a sex and genotype interaction. J Neurosci, 2012. 32(29): p. 9831-4.

188. Crist, R.C. and W.H. Berrettini, Pharmacogenetics of OPRM1. Pharmacol Biochem Behav, 2014. 123: p. 25-33.

189. Ren, Z.Y., et al., The impact of genetic variation on sensitivity to opioid analgesics in patients with postoperative pain: a systematic review and meta-analysis. Pain Physician, 2015. 18(2): p. 131-52.

190. Hajj, A., et al., Genotyping test with clinical factors: better management of acute postoperative pain? Int J Mol Sci, 2015. 16(3): p. 6298-311.

191. Lee, M.G., et al., The Influence of Genotype Polymorphism on Morphine Analgesic Effect for Postoperative Pain in Children. Korean J Pain, 2016. 29(1): p. 34-9.

192. Baber, M., et al., The pharmacogenetics of opioid therapy in the management of postpartum pain: a systematic review. Pharmacogenomics, 2016. 17(1): p. 75-93. 

193. Chen, A.C., et al., Variation in Mu-Opioid Receptor Gene (OPRM1) as a Moderator of Naltrexone

Pharmacogenetics of OPRM1.

http://www.ncbi.nlm.nih.gov/pubmed/24201053/ [188]

“The OPRM1 gene has been a target of interest in a large number of pharmacogenetic studies due to its genetic and structural variation, as well as the role of opioid receptors in a variety of disorders. The muopioid receptor (MOR), encoded by OPRM1, naturally regulates the analgesic response to pain and also controls the rewarding effects of many drugs of abuse, including opioids, nicotine, and alcohol.

Genetic variants in OPRM1, particularly the non-synonymous polymorphism A118G, have beenrepeatedly associated with the efficacy of treatments for pain and various types of dependence. This review focuses on the current understanding of the pharmacogenetic impact of OPRM1, primarily with regard to the treatment of pain and addiction.” [188]

The impact of genetic variation on sensitivity to opioid analgesics in patients with postoperative pain: a systematic review and meta-analysis.

http://www.ncbi.nlm.nih.gov/pubmed/25794200 [189]

“This study sought to clarify the impact of distinct genetic variations on pain, opioid consumption, and opioid side effects in patients with postoperative pain…The results showed that human μ-opioid

receptor gene (OPRM1) 118G allele variant carriers consumed more opioids for analgesia (SMD = – 0.17, 95% CI = [-0.25, -0.10], P < 0.00001), but reported higher pain scores (MD = -0.11, 95% CI = [-

0.17, -0.04], P = 0.002) and less nausea and vomiting (odds ratio = 1.30, 95% CI = [1.08, 1.55], P = 0.005) than the homozygous 118AA patients during the first 24 hour but not the 48 hour postoperative

period… The A118G allele variant of OPRM1 has the most potent influence on pain management of postoperative patients. Opioid receptor gene information may provide valuable information for clinicians

to properly manage the analgesic use of opioids individually for better pain management.” [189]

Genotyping test with clinical factors: better management of acute postoperative pain?

http://www.ncbi.nlm.nih.gov/pubmed/25809606 [190]

“The aim of this study is to investigate the influence of genetic and non-genetic factors on the variability of response to morphine in acute postoperative pain…OPRM1 and ABCB1 polymorphisms were

significantly associated with administered dose of morphine (p = 0.038 and 0.012 respectively). Patients with at least one G allele for c.118A>G OPRM1 polymorphism (AG/GG) needed 4 times the dose of

morphine of AA patients…Our preliminary results support the evidence that OPRM1/ABCB1 genotypes along with age, weight and duration of operation have an impact on morphine consumption for acute

postoperative pain treatment.” [190]

The Influence of Genotype Polymorphism on Morphine Analgesic Effect for Postoperative Pain in Children.

http://www.ncbi.nlm.nih.gov/pubmed/26839669 [191]

“Children with at least one G allele for OPRM1 (AG/GG) had higher postoperative pain scores compared with those with the AA genotype at the time of discharge from the post-anesthesia care unit

(P = 0.025). Other recovery profiles were not significantly different between the two groups. There was no significant relationship between genotypes and postoperative pain scores in analysis of ABCB1 and

COMT polymorphisms…Genetic polymorphism at OPRM1 A118G, but not at ABCB1 C3435T and COMT Val158Met, influences the analgesic effect of morphine for immediate acute postoperative pain

in children.” [191]

The pharmacogenetics of opioid therapy in the management of postpartum pain: a systematic review.

http://www.ncbi.nlm.nih.gov/pubmed/26652709 [192]

“Among the 2082 papers retrieved from the search, 17 were included in the review. These 17 papers consisted of various study designs, opioids, polymorphisms and patient outcomes. This systematic

review reveals that CYP2D6, OPRM1 A118G, UGT2B7 C802T and ABCB1 G2677AT may contribute to postpartum analgesia or adverse events.” [192]

Variation in Mu-Opioid Receptor Gene (OPRM1) as a Moderator of Naltrexone Treatment to Reduce Heavy Drinking in a High Functioning Cohort.

https://www.ncbi.nlm.nih.gov/pubmed/24729984 [193]

“It is well known that naltrexone, an FDA-approved medication for treatment of alcohol dependence, is effective for only a subset of individuals. Recent studies have examined the utility of a functional A118G

single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1) as a predictor of naltrexone treatment response. Although the findings to date have generally been consistent with a

moderating effect of the SNP, further evaluation of this hypothesis is warranted…Naltrexone-treated subjects with one or two 118G alleles had a significantly greater percentage of non-hazardous drinking (NoH) (p < 0.01) than those treated with placebo or A118 homozygotes in either medication group. These results are consistent with a modest moderating effect of the OPRM1 118G allele on the reduction of heavy drinking by naltrexone treatment.” [193] 

Variation in OPRM1 moderates the effect of desire to drink on subsequent drinking and its attenuation by naltrexone treatment.

https://www.ncbi.nlm.nih.gov/pubmed/22784013 [194]

“To evaluate the role of the functional Asn40Asp polymorphism in the mu-opioid receptor gene on drinking behavior and naltrexone's ability to attenuate drinking, we used a daily diary method in a 12-

week, randomized clinical trial of naltrexone to reduce drinking. Participants (n = 158 problem drinkers) were assigned to receive either daily or targeted naltrexone 50 mg (n = 81) or matching placebo (n =

77)… In summary, when the evening level of desire to drink was relatively high, Asp40 allele carriers were at greater risk than Asn40 homozygotes to drink more, which was attenuated by naltrexone.

Although average measures across the study were not informative, daily reports helped to demonstrate the moderating effects of genetic variation on the relation between desire to drink and alcohol

consumption and the effects of naltrexone on that phenotype.” [194]

Association of μ-opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta-analysis.

https://www.ncbi.nlm.nih.gov/pubmed/22515274 [195]

“Previous studies have suggested that the effect of naltrexone in patients with alcohol dependence may be moderated by genetic factors. In particular, the possession of the G allele of the A118G polymorphism of the micro-opioid receptor gene (OPRM1) has been associated with a better response to naltrexone, although controversial results have been reported. The aim of this paper is to combine previous findings by means of a systematic review and a meta-analysis. We retrieved studies on the relationship between A118G polymorphism in OPRM1 gene and response to treatment with naltrexone in patients with alcohol dependence by means of electronic database search. A meta-analysis was conducted using a random-effects model. Calculations of odds ratio (OR) and their confidence intervals (CI) and tests for heterogeneity of the results have been performed. Six previous studies have analyzed the role of A118G polymorphism in response to naltrexone for alcohol dependence. After meta-analysis, we found that naltrexone-treated patients carrying the G allele had lower relapse rates than those who were homozygous for the A allele (OR: 2.02, 95% CI 1.26-3.22; P = 0.003). There were no differences in abstinence rates. Our results support the fact that the G allele of A118G polymorphism of OPRM1 moderates the effect of naltrexone in patients with alcohol dependence. This genetic marker may therefore identify a subgroup of individuals more likely to respond to this treatment.” [195]

A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans.

https://www.ncbi.nlm.nih.gov/pubmed/15608594 [196]

“Recent research has implicated the endogenous opioid system in the development of alcohol use disorders. The A118G polymorphism of the OPRM1 gene has been shown to confer functional differences to mu-opioid receptors, such that the G variant binds beta-endorphin three times more strongly than the A variant. The goal of this study was to test whether the A118G polymorphism is associated with sensitivity to the effects of alcohol…These findings may help to explain previous research suggesting that naltrexone is more effective among individuals with the G allele. A medication that reduces feelings of euphoria after alcohol consumption may be more successful among individuals with a genetic predisposition to greater feelings of euphoria after consuming alcohol.” [196]

An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study.

https://www.ncbi.nlm.nih.gov/pubmed/18250251 [197]

“Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict

naltrexone response. To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone…These results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 genotyping in alcoholic individuals might be useful to assist in selecting treatment options.” [197]

אין במידע ו/או בתכנים המופיעים במאמר משום מתן עצה רפואית, חוות דעת מקצועית, תחליף להתייעצות עם מומחה או מתן אבחנה בנוגע לטיפול במצב רפואי מסויים. לשם קבלת ייעוץ אישי יש לפנות להתייעצות עם רופא בתחום המומחיות המתאים. מבלי לגרוע מכלליות האמור, כל הסתמכות על התכנים המופיעים במאמר ופעולה על פיהם נעשים על אחריותך הבלעדית והמלאה ולא תהיה לך כל תביעה ו/או טענה ו/או דרישה כנגד כותבי ומפרסמי המאמר או מי מטעמם, בגין נזקים הנובעים משימוש במידע הכלול במאמר זה.