Can a laboratory test help smokers decide how to stop?

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3 February 2015

There is variation in the way that individuals respond to two of the most effective treatments to give up smoking: nicotine patches and the prescription drug varenicline. Nicotine patches are applied once a day to release nicotine through the skin and varenicline is a once a day tablet (Champix, Pfizer) that has an effect similar to that of nicotine on the central nervous system. In the UK both are available on NHS prescriptions while nicotine patches can also be purchased over the counter.

Nicotine is broken down in the liver to cotinine which is then metabolised to 3’-hydroxycotinine. The ratio of 3’-hydroxycotinine to cotinine (nicotine metabolite ratio; NMR) in plasma and urine has been shown to be related to the genetically determined activity of the liver enzyme CYP2A6 which is responsible for the differing breakdown rates of nicotine and other substances in individuals. Lower NMR values (slower nicotine clearances) are known to be associated with lighter smoking and higher rates of stopping.

Researchers from the US and Canada involved in nicotine dependence wondered whether the differing response to the two treatments in individuals might be related to the differing individual rates of nicotine metabolism as revealed by the NMR. Between November 2010 and September 2014 they undertook a randomised controlled trial at four centres with 1624 smokers who were seeking treatment. They excluded e-cigarette users, those on other smoking treatments and those with significant medical problems. Their study was reported online in The Lancet Respiratory Medicine on 11 January 2015.

On the basis of initial NMR tests the 1624 participants were divided into 662 slow metabolisers and 584 normal metabolisers of nicotine. Nearly equal numbers of normal and slow metabolisers were allocated randomly to each of three treatment groups:

  • Varenicline tablets together with patches that had no active ingredient (placebo)
  • Nicotine patches together with tablets that had no active ingredient (placebo)
  • Placebo tablets together with placebo patches

Treatment was double-blind, with neither researchers nor investigators knowing either the treatment allocation or the NMR result. All groups were given behavioural counselling during the 11 week stop smoking treatment period. The primary endpoint was biochemically verified 7-days of abstinence at the end of the 11 weeks. Side effects of treatment were recorded. Participants were followed up at six and twelve months, those lost to follow-up being recorded as failed abstainers.

Normal metabolisers gave up smoking more often with varenicline tablets than with nicotine patches. At the end of treatment 39% had given up with tablets and 23% with patches; at six months successes were 22% and 14%. The success rates for slow metabolisers did not differ significantly: 30% for tablets and 28% for patches at the end of treatment and 19% and 22% at six months.

The most common side effects of both treatments were nausea (feeling sick) and headache. Slow metabolisers experienced more severe nausea with varenicline than with patches and also had abnormal dreams.

Because the abstinence rate of slow metabolisers did not differ between treatments but they experienced more severe side effects with varenicline, the authors concluded that treating normal metabolisers with varenicline and slow metabolisers with nicotine patches could maximise the number quitting while minimising the side effects of treatment.

At present NMR is a research test. Because in untreated smokers it correlates with the number of cigarettes smoked, it remains to be seen whether cessation rates are better using measurements of NMR rather than simply using smoking rate to allocate treatment to varenicline or nicotine patch. There is some research evidence that e-cigarettes, which deliver nicotine but no harmful tars, can help people stop or cut down smoking, so they are likely to be included in future studies.

 

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