NAlmefene Versus Placebo in Addition to Treatment As Usual on Craving in Behavioural Addictions

Pre-inclusion Criteria:

• Males and females ≥ 18 years old

• Patient already in care or newly initiating care in Addictology departments for abeharioural addiction, diagnosed with current:

• Gambling disorder [NORC DSM Screen for Gambling Problems (NODS), revised forDSM-5]

• Food addiction [Yale Food Addiction Scale (YFAS), revised for DSM-5]

• Or Sexual addiction [interview adapted from the NODS to explore the diagnosticcriteria proposed by Carnes et al. (2012): NODS-SA]

• Able to regularly assess and report their craving episodes on a weekly diary

• Who provide their written informed consent

• Affiliated with French social security system or beneficiary from such system

Inclusion Criteria:

• Having presented at least one episode of craving with an intensity ≥ 4/10 at the NRSduring the week prior to inclusion

Women must meet one of the following criteria at the time of inclusion:

• use adequate contraceptive measures as recommended by the CTFG (Recommendationsrelated to contraception and pregnancy testing in clinical trials v1.1), and have anegative pregnancy test (urine test) prior to receiving the first dose of studydrug;

• or be post-menopausal (over 50 years of age with amenorrhea for at least 12 monthsafter discontinuation of all exogenous hormonal therapy)

• or (if under 50 years of age) have been amenorrheic for at least 12 months afterdiscontinuation of exogenous hormonal therapy and with luteinizing hormone (LH) andfollicle stimulating hormone (FSH) levels corresponding to post-menopausal levels

• or have undergone irreversible surgical sterilization by hysterectomy, bilateraloophorectomy or bilateral salpingectomy (this operation must be documented).

Exclusion Criteria:

• Being currently treated by another anti-craving drug that have been already testedfor craving reduction in BAs (naltrexone, acamprosate, baclofène, topiramate,bupropion, N-acetyl-cystéine, disulfiram, etc.);

• Presenting a contraindication for the use of nalmefene (listed in the SmPC):

• Known hypersensitivity to the active substance or to any of the excipients. Inparticular, intolerance to galactose or deficiency in Lapp lactase orglucose-galactose malabsorption (rare hereditary diseases);

• Treatment by opioid agonists (full or partial) (opioid pain relievers, opioidsubstitution drugs);

• Recent history of opioid dependence or current opioid dependence;

• Current symptoms of the acute opioid withdrawal syndrome;

• Suspected recent consumption of opioid (necessity to consider the half-life);

• Severe hepatic impairment (Child-Pugh stage B or C);

• Severe renal impairment (estimated glomerular filtration rate [TFGe] <30mL/min/1.73 m2);

• History of recent acute alcohol withdrawal syndrome (including hallucinations,convulsions and delirium tremens).

• Predictable opioid treatment during the study period;

• Unstable psychiatric disorders (meaning disorders for which the treatment wasmodified since less than a month (corresponding to the instauration of a newtreatment, or the increase in dosage of a treatment already being taken)), includingsevere risk of suicide (i.e. necessity to engage specific medication orhospitalization; psychotropic medication engaged since less than 1 month; absence ofimprovement after one month of medication) (because nalmefene has not been studiedin patients with unstable psychiatric disorders). Patients with a food addictiondiagnosed with eating disorders marked by the presence of binge eating can beincluded;

• Anorexia nervosa-restricting type (because food addiction concept is poorlyestablished among patients with AN-R, who do not have binge eating episodes inducedby craving);

• Extreme leanness (body mass index < 16.5) (because loss of appetite and/or weightloss are frequent adverse effects of nalmefene);

• Current treatment with potent inhibitor drugs of the UGT2B7 (UDP-Glucuronosyltransferase-2B7); for example: diclofenac, fluconazole,medroxyprogesterone acetate, meclofenamic acid;

• Current treatment with UGT inducing drugs; for example: dexamethasone,phenobarbital, rifampicin, omeprazole;

• Inability to indicate the time of day of the most intense craving episode (becausethis information will determine the time of day the treatment should be taken);

• Pregnancy (attested by a pregnancy urinary test for women of childbearing age) orbreastfeeding woman;

• Trusteeship;

• Major cognitive impairment;

• Not fluent in French;

• Participation to another interventional study during the last month or expectedparticipation to another interventional study during participation to the NABABstudy.