Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial

ABSTRACT

To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n=82) were significantly more likely than those homozygous for the Asn40 variant (n=238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. USPHS. A clinical practice guideline for treating tobacco use and dependence. JAMA 2000; 283: 3244–3254.

  2. Transdermal Nicotine Study Group. Transdermal nicotine for smoking cessation: six-month results from two multicenter controlled trials. JAMA 1991; 266: 3133–3138.

  3. Fiore M, Smith S, Jorenby D, Baker T . The effectiveness of the nicotine patch for smoking cessation. A meta-analysis. JAMA 1994; 271: 1940–1947.

    Article  CAS  Google Scholar 

  4. Zadina JE, Hackler L, Ge LJ, Kastin AJ . A potent and selective endogenous agonist for the mu-opiate receptor. Nature 1997; 386: 499–502.

    Article  CAS  Google Scholar 

  5. Boyadjieva NI, Sarkar DK . The secretory response of hypothalamic beta-endorphin neurons to acute and chronic nicotine treatments and following nicotine withdrawal. Life Sci 1997; 61: PL59–66.

    Article  CAS  Google Scholar 

  6. Davenport KE, Houdi AA, Van Loon GR . Nicotine protects against mu-opioid receptor antagonism by beta-funaltrexamine: evidence for nicotine-induced release of endogenous opioids in brain. Neurosci Lett 1990; 113: 40–46.

    Article  CAS  Google Scholar 

  7. Bond LaForge K et al. Single nucleotide polymorphism in the human mu opioid receptor gene alters Beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 1998; 95: 9608–9613.

    Article  Google Scholar 

  8. Gelernter J, Kranzler H, Cubells J . Genetics of two mu opioid receptor gene (OPRM1) exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjects. Mol Psychiatry 1999; 4: 476–483.

    Article  CAS  Google Scholar 

  9. Crowley JJ et al. A genetic association study of the mu opioid receptor and severe opioid dependence. Psychiatr Genet 2003; 13: 169–173.

    Article  Google Scholar 

  10. Henningfield J, Keenan R . Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol 1993; 61: 743–750.

    Article  CAS  Google Scholar 

  11. Henningfield J . Nicotine medications for smoking cessation. N Engl J Med 1995; 333: 1196–1203.

    Article  CAS  Google Scholar 

  12. Hughes J . Pharmacotherapy for smoking cessation: unvalidated assumptions, anomalies, and suggestions for future research. J Consult Clin Psychol 1993; 61: 751–760.

    Article  CAS  Google Scholar 

  13. Johansson CJ, Olsson P, Bende M, Carlsson T, Gunnarsson PO . Absolute bioavailability of nicotine applied to different nasal regions. Eur J Clin Pharmacol 1991; 41: 585–588.

    Article  CAS  Google Scholar 

  14. Benowitz N . Pharmacology of nicotine: addiction and therapeutics. Annu Rev Pharmacol Toxicol 1996; 36: 597–613.

    Article  CAS  Google Scholar 

  15. Oslin DW et al. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 2003; 28: 1546–1552.

    Article  CAS  Google Scholar 

  16. Silagy C, Mant D, Fowler G, Lodge M . Meta-analysis on efficacy of nicotine replacement therapies in smoking cessation. Lancet 1994; 343: 139–142.

    Article  CAS  Google Scholar 

  17. Tonnesen P, Norregaard J, Simonsen K, Sawe U . A double-blind trial of a 16-h transdermal nicotine patch in smoking cessation. N Engl J Med 1991; 325: 311–315.

    Article  CAS  Google Scholar 

  18. Hjalmarson A, Franzon M, Westin A, Wiklund O . Effect of nicotine nasal spray on smoking cessation. A randomized, placebo-controlled, double-blind study. Arch Intern Med 1994; 154: 2567–2572.

    Article  CAS  Google Scholar 

  19. Wetter D et al. Gender differences in smoking cessation. J Counsel Clin Psychol 1999; 67: 555–562.

    Article  CAS  Google Scholar 

  20. Lerman C et al. Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial. Health Psychol 2003.

  21. Cardon LR, Palmer LJ . Population stratification and spurious allelic association. Lancet 2003; 361: 598–604.

    Article  Google Scholar 

  22. Pritchard J, Rosenberg N . Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet 1999; 65: 220–228.

    Article  CAS  Google Scholar 

  23. Hurt RD et al. Nicotine patch therapy for smoking cessation combined with physician advice and nurse follow-up. One-year outcome and percentage of nicotine replacement. JAMA 1994; 271: 595–600.

    Article  CAS  Google Scholar 

  24. Sachs DP, Sawe U, Leischow SJ . Effectiveness of a 16-h transdermal nicotine patch in a medical practice setting, without intensive group counseling. Arch Intern Med 1993; 153: 1881–1890.

    Article  CAS  Google Scholar 

  25. Lerman C et al. Mediating mechanisms for the impact of bupropion in smoking cessation treatment. Drug Alcohol Depend 2002; 67: 219–223.

    Article  CAS  Google Scholar 

  26. Gu DF, Hinks LJ, Morton NE, Day IN . The use of long PCR to confirm three common alleles at the CYP2A6 locus and the relationship between genotype and smoking habit. Ann Hum Genet 2000; 64: 383–390.

    Article  CAS  Google Scholar 

  27. Lerman C et al. Pharmacogenetic investigation of smoking cessation treatment. Pharmacogenetics 2002; 12: 627–634.

    Article  CAS  Google Scholar 

  28. Lerman C et al. Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial. Health Psychol 2003; 22: 541–548.

    Article  Google Scholar 

  29. Houdi AA, Pierzchala K, Marson L, Palkovits M, Van Loon GR . Nicotine-induced alteration in Tyr–Gly–Gly and Met-enkephalin in discrete brain nuclei reflects altered enkephalin neuron activity. Peptides 1991; 12: 161–166.

    Article  CAS  Google Scholar 

  30. Pierzchala K, Houdi AA, Van Loon GR . Nicotine-induced alterations in brain regional concentrations of native and cryptic Met- and Leu-enkephalin. Peptides 1987; 8: 1035–1043.

    Article  CAS  Google Scholar 

  31. Wewers ME, Tejwani GA, Anderson J . Plasma nicotine, plasma beta-endorphin and mood states during periods of chronic smoking, abstinence and nicotine replacement. Psychopharmacology (Berl) 1994; 116: 98–102.

    Article  CAS  Google Scholar 

  32. Gilbert DG, Meliska CJ, Plath LC . Noise stress does not modulate effects of smoking/nicotine on beta-endorphin, cortisol, ACTH, glucose, and mood. Psychopharmacology (Berl) 1997; 130: 197–202.

    Article  CAS  Google Scholar 

  33. Pomerleau OF, Fertig JB, Seyler LE, Jaffe J . Neuroendocrine reactivity to nicotine in smokers. Psychopharmacology (Berl) 1983; 81: 61–67.

    Article  CAS  Google Scholar 

  34. Spanagel R, Herz A, Bals-Kubik R, Shippenberg TS . Beta-endorphin-induced locomotor stimulation and reinforcement are associated with an increase in dopamine release in the nucleus accumbens. Psychopharmacology (Berl) 1991; 104: 51–56.

    Article  CAS  Google Scholar 

  35. Low MJ, Hayward MD, Appleyard SM, Rubinstein M . State-dependent modulation of feeding behavior by proopiomelanocortin-derived beta-endorphin. Ann NY Acad Sci 2003; 4: 192–201.

    Article  Google Scholar 

  36. Appleyard SM et al. A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology 2003; 4: 1753–1760.

    Article  Google Scholar 

  37. Radcliffe RA, Erwin VG . Genetic relationship between central beta-endorphin and novelty-induced locomotor activity. Pharmacol Biochem Behav 1998; 60: 709–718.

    Article  CAS  Google Scholar 

  38. Jorenby D et al. Varying nicotine patch dose and type of smoking cessation counseling. JAMA 1995; 274: 1347–1352.

    Article  CAS  Google Scholar 

  39. Tonnesen P et al. Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Collaborative European Anti-Smoking Evaluation. European Respiratory Society. Eur Respir J 1999; 13: 238–246.

    Article  CAS  Google Scholar 

  40. Pomerleau OF et al. Prolonged nicotine patch use in quitters with past abstinence-induced depressed mood. J Subst Abuse Treat 2003; 24: 13–18.

    Article  Google Scholar 

  41. Magura S, Rosenblum A . Leaving methadone treatment: lessons learned, lessons forgotten, lessons ignored. Mt Sinai J Med 2001; 68: 62–74.

    CAS  PubMed  Google Scholar 

  42. Ahluwalia JS, McNagny SE, Clark WS . Smoking cessation among inner-city African Americans using the nicotine transdermal patch. J Gen Intern Med 1998; 13: 1–8.

    Article  CAS  Google Scholar 

  43. Perng RP, Hsieh WC, Chen YM, Lu CC, Chiang SJ . Randomized, double-blind, placebo-controlled study of transdermal nicotine patch for smoking cessation. J Formos Med Assoc 1998; 97: 547–551.

    CAS  PubMed  Google Scholar 

  44. Xu C, Goodz S, Sellers EM, Tyndale RF . CYP2A6 genetic variation and potential consequences. Adv Drug Deliv Rev 2002; 54: 1245–1256.

    Article  CAS  Google Scholar 

  45. Sutherland G et al. Randomised controlled trial of nasal nicotine spray in smoking cessation. Lancet 1992; 340: 324–329.

    Article  CAS  Google Scholar 

  46. Silagy C, Mant D, Fowler G, Lancaster T . Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2001; CD000146.

  47. Fiore MC et al. Two studies of the clinical effectiveness of the nicotine patch with different counseling treatments. Chest 1994; 105: 524–533.

    Article  CAS  Google Scholar 

  48. Brown R, Burgess E, Sales S, Whiteley J . Reliability and validity of a smoking timeline follow-back interview. Psychol Addictive Behav 1998; 12: 101–112.

    Article  Google Scholar 

  49. Hughes JR et al. Measure of abstinence in clinical trials: issues and recommendations. Nicotine Tobacco Res 2003; 5: 13–25.

    Article  Google Scholar 

  50. Ossip-Klein DJ et al. Classification and assessment of smoking behavior. Health Psychol 1986; 5(Suppl): 3–11.

    Article  Google Scholar 

  51. SRNT Subcommittee on Biochemical Verification. Biochemical verification of tobacco use and cessation. Soc Res Nicotine Tobacco 2001: 149–159.

  52. Hosmer DW, Lemeshow S . Applied Survival Analysis: Regression Modeling of Time to Event Data. John Wiley & Sons: New York, NY 1999.

    Google Scholar 

  53. Lawson GM et al. Application of serum nicotine and plasma cotinine concentrations to assessment of nicotine replacement in light, moderate, and heavy smokers undergoing transdermal therapy. J Clin Pharmacol 1998; 38: 502–509.

    Article  CAS  Google Scholar 

  54. Jacob III P, Wilson M, Benowitz NL . Improved gas chromatographic method for the determination of nicotine and cotinine in biologic fluids. J Chromatogr 1981; 222: 61–70.

    Article  CAS  Google Scholar 

  55. Watson D, Clark L, Tellegen A . Development and validation of brief measures of positive and negative affect: the PANAS scales. J Personality Social Psychol 1988; 54: 1063–1070.

    Article  CAS  Google Scholar 

  56. Long JC, Williams RC, Urbanek M . An E-M algorithm and testing strategy for multiple-locus haplotypes. Am J Hum Genet 1995; 56: 799–810.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Mander A . Haplotype analysis in population-based association studies. Stata J 2001; 1: 58–75.

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr Christopher Jepson, Susan Kucharski, and Angela Pinto for their assistance with database preparation. We also acknowledge Sandi Herman for conducting the behavioral counseling, and Maryanne Foster for assistance with manuscript preparation. We also thank Dr Debra Leonard for input on study design and implementation issues, Dr David Allison for input on statistical genetics issues, Shiva Krishnan for assistance with the processing of blood samples, and Lita Ramos who performed the plasma cotinine assays. This work was supported by a Transdisciplinary Tobacco Use Research Center Grant from the National Cancer Institute and the National Institute on Drug Abuse P5084718, and the Abramson Cancer Center and Annenberg Public Policy Center (CL) and PHS grants P60DA005186 (WB), DA02277, DA12393, CA078703, and the UCSF Comprehensive Cancer Center (NB), and a Public Health Services Research Grant M01-RR0040 from the National Institutes of Health. Nicotine nasal spray (Nicotrol®) was provided by Pharmacia, Helsingborg, Sweden.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C Lerman.

Additional information

DUALITY OF INTEREST

None declared

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lerman, C., Wileyto, E., Patterson, F. et al. The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial. Pharmacogenomics J 4, 184–192 (2004). https://doi.org/10.1038/sj.tpj.6500238

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500238

Keywords

This article is cited by

Search

Quick links