Rimonabant

• cannabinoid CB1 receptors have been shown to play an important role in food intake control
  
  
• on October 23rd 2008 the European Medicines Agency (EMEA) recommended the suspension of the marketing authorisation for rimonabant (Acomplia). The EMEA's Committee for Medicinal Products for Human Use (CHMP) has concluded that the benefits of rimonabant no longer outweigh its risks and the marketing authorisation should be suspended across the EU
  
  
• rimonabant
  • a potent, specific CB1 receptor antagonist - this agent selectively reduces the consumption of certain types of food, e.g. sweet food, and reduces body weight
  • ameliorates the pathologically heightened salience of food (1)
  • is being found to be an effective adjunct to behavior modification in smoking cessation (2)
    • CB1 antagonists have been shown to inhibit the dopamine-releasing effects of nicotine in the shell of the nucleus accumbens - animal studies have shown they can also decrease nicotine self-administration. Thus, rimonabant may block the reinforcing properties of nicotine
  • has been shown to effectively reduce weight, reduce abdominal circumference, improve blood glucose, increase highdensity lipoprotein cholesterol and reduce triglycerides
    • rimonabant used for up to 2 years, in addition to a calorie restricted diet, produced greater weight loss (around 4 to 6kg) compared with placebo in clinical trials (3)
      • the majority of weight loss occurred in the first year and was only maintained if treatment was continued. Participants involved in trials received a high level of support throughout treatment
      • a Cochrane Review of the one-year data from the four main obesity RCTs of rimonabant in addition to diet and exercise (including RIO-diabetes) has also been published (4) The authors of the review concluded that rimonabant produces modest weight loss of approximately 5%, but they were concerned about the quality of studies; for example, the high drop-out rates (40% at one year when the trials were pooled)
      • patient and safety aspects (3)
        • in studies almost twice as many people discontinued rimonabant compared with placebo because of adverse events (13.8% vs. 7.2%)
          • adverse effects consistently involved psychiatric disorders (8.5% vs. 3.2%), including depression and anxiety
          • other common side effects included insomnia, nausea, vomiting, diarrhoea and fatigue
          • it was noted that patients will need to maintain motivation and commitment to ongoing exercise and diet, and monitoring and support
          • all trials excluded people with a history of psychiatric disorders or with severe depression (4). Therefore, rimonabant is not recommended for patients with uncontrolled psychiatric disease, including major depression, or those on antidepressant medication (5)

• in clinical trials, depressive disorders or mood alterations with depressive symptoms have been reported in up to 10%, and suicidal ideation in up to 1% of patients receiving rimonabant (6)

Notes:

• the involvement of the endocannabinoid system in drug addiction (8)
  • the endocannabinoid system is directly involved in the primary rewarding effects of cannabinoids, nicotine, alcohol and opioids by acting on common cellular mechanisms and/or by permitting the effects of these drugs on mesolimbic transmission
  • the endocannabinoid system is involved in the motivation to seek the drug by a dopamine-independent mechanism - has been demonstrated for psychostimulants and opioids and might also be the case for other drugs of abuse
  • the endocannabinoid system is implicated in relapse to drug-seeking behaviour participating in the motivational effects of drug-related environmental stimuli and drug re-exposure, probably by acting on the synaptic plasticity underlying memory processes
• rimonabant for smoking cessation (9):
  • rimonabant 20 mg may increase the odds of quitting approximately 1(1/2)-fold
    • evidence for rimonabant in maintaining abstinence is inconclusive

The summary of product characteristics must be consulted before prescribing this drug

Reference:

• (1) Black, S.C. Cannabinoid receptor antagonists and obesity. Curr. Opin. Investig. Drugs 2004;5:389-394.
• (2) Fernandez, J.R. and Allison, D.B. Rimonabant Sanofi-Synthelabo. Curr. Opin. Investig. Drugs 2004;5:430-435
• (3) National Prescribing Committee (July 2006). New medicine alert - rimonabant.
• (4) Curioni C, André C. Rimonabant for overweight or obesity. Cochrane database of systematic reviews 2006, Issue 4. Art No.: CD006162. DOI: 10.1002/14651858.CD006162.
• (5) MeReC Extra (January 2007). Rimonabant for obesity.
• (6) MHRA (letter 20/7/07).Risk of depression and suicidal behaviour with Acomplia (rimonabant).
• (7) MeReC Extra (2008); 32.
• (8) Maldonado R et al. Involvement of the endocannabinoid system in drug addiction. Trends Neurosci. 2006 Apr;29(4):225-3
• (9) Cahill k, Ussher M. Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation.Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005353.