Triple combination therapy for medically ill smokers

Today sees the publication of a new study by Dr Michael Steinberg and colleagues at the University of Medicine and Dentistry of New Jersey, examining the effect of more intensive smoking cessation treatment in smokers with pre-existing medical conditions. This randomized trial compared those treated with 9 brief face-to-face sessions (from assessment to 6 month follow-up) and either standard 10-week nicotine patch treatment, or a combination of nicotine patch, plus nicotine inhaler plus bupropion, for up to 6 months.

Participants in the triple combination condition were advised to keep using the full dose of each medicine until they had gone 14 consecutive days with no withdrawal symptoms, cravings or near lapses. Once they reached that point, they were advised to gradually reduce the patch dose (over 4 weeks) then bupropion (over 2 weeks), then inhaler, so long as they felt comfortable.

The study found that of patients treated with standard patch, 19% were not smoking at 6 months, compared with 35% of those treated with the extended duration triple combination pharmacotherapy. There were more reports of insomnia and anxiety among those treated with the triple combination, but a similar small proportion (6%) of both groups dropped out of the trial due to perceived adverse effects of the medications.

This is the first trial of this triple combination therapy, and the results are broadly consistent with other studies comparing standard nicotine patch mono-therapy with a combination of medicines including the patch. It is now clear that extended combination pharmacotherapy helps more smokers quit, and remain quit, and that serious adverse events are rare.

This link will take you to the abstract at Annals of Internal Medicine, where the study was published.
http://www.annals.org/cgi/content/abstract/150/7/447

Labels: bupropion, combination, jonathan foulds, Michael Steinberg, Nicotine Replacement, NRT, smoking cessation

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Combining varenicline and bupropion

I recently received the following comment on my April/15/2007 post:
Chantix: how does this new stop smoking medicine work? 4/15/07
http://www.healthline.com/blogs/smoking_cessation/2007/04/chantix-how-does-this-new-quit-smoking.html

“I have been searching the web and have wondered if anyone knows if you can take both wellbutrin and Chantix at the same time. I have tried Chantix before and I had many of the crazy adverse side effects. It was the one way that I actually stopped for more than a week. I relapsed after 1 year of being smoke free. I have to quit this stuff it is killing me! I am hoping that I can take both of the medications to offset the moodiness I experienced last time. Thanks for your help!”

This is actually a very good question. Varenicline (Chantix) partly works by blocking certain nicotine receptors in the brain. That mechanism makes us doubt the rationale for combining varenicline with nicotine replacement therapy (NT), as varenicline should also block the effects of the NRT. But bupropion, while possibly affecting nicotine receptors, is believed to work via additional mechanisms (e.g. slowing the reuptake of dopamine). So it makes sense to consider whether there may be an added effect of combining those medicines.

Fortunately, the first study of this kind of treatment was very recently published. The study was published in the journal, Nicotine & Tobacco Research” by Dr John Ebbert and colleagues at the Mayo Clinic, in Rochester MN. The treated 38 smokers with the usual dose of varenicline, plus the usual dose of bupropion (SR: sustained release) for 12 weeks. The study was “open label” meaning that there was no comparison or “placbo” treatment and everyone knew what treatment was being provided. All the smokers were also provided with behavioral therapy. After around 12 weeks of treatment, 71% were not smoking (confrmed by a low exhaled carbon-monoxide measure), and at 6 months (i.e. 3 months without any medication) 58% were not smoking.

The most common side effects were those that have already been reported with these medicines. For example, 26% reported sleep disturbance (common with bupropion) and 24% reported nausea (common with varenicline). No increase in depressive symptoms was observed, and no suicidal thoughts were reported. The authors concluded that combination therapy with varenicline and bupropion SR may be effective for increasing smoking abstinence rates above that observed with a single medicine.

Although this study was small, and it is likely that the participants were very highly motivated and received more intensive treatment than is typically available, I agree that these results are quite promising. It is extremely unusual for any smoking cessation study to report a 6-month quit rate above 50%. So this appears to suggest that there may be some additive effects from combining these two medicines that are each effective on their own.

So what should readers who are interested in such a combined treatment do? It is important to note that this is just the first relatively small study, and so overall there is very little experience with this combination. Many doctors may quite reasonably prefer not to take any chances by prescribing a combined treatment before its efficacy and safety have been adequately studied. If you are able to see a doctor who is experienced in using these medicines, and willing to prescribe them together, I would suggest that you remain in regular contact with that prescriber throughout your quit attempt. I would also suggest that you should access some regular behavioral support or counseling (as was provided to the study participants). Hopefully within a year or two we will have more information on the combined use of these two smoking cessation medicines.

Reference
Varenicline and bupropion sustained-release combination therapy for smoking cessation. Ebbert JO, Croghan IT, Sood A, Schroeder DR, Hays JT, Hurt RD.Nicotine Tob Res. 2009 Feb 25.

Labels: bupropion, combination, John Ebbert, jonathan foulds, Nicotine Replacement, smoking cessation, varenicline

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Suicidal thinking while taking varenicline or bupropion

There has been considerable discussion, including on this blog, about the potential for the latest smoking cessation medicine, varenicline (Chantix) to cause severe depression and suicidal thinking. The Food and Drug Administration issued additional warnings on the labeling for Chantix, including advice to monitor for “neuropsychiatric symptoms”.

Some additional data on this issue was recently published in the FDA Drug Safety Newsletter and is worth reading (link below). The report summarizes cases reported to FDA describing suicidal thinking and behavior in connection with bupropion and varenicline use from the date of each compound’s approval (from approval of the smoking cessation indication for bupropion) to November 27, 2007.

FDA identified 153 reports of suicidal adverse events for varenicline (suicidal thinking-116, suicide-37) and 75 reports for bupropion (suicidal thinking-46, suicide-29). These cases likely represent a fraction of those that occurred during this time period due to underreporting to FDA’s Adverse Event Reporting System (AERS). The total yearly prescriptions for these medicines is in the millions, so these cases also represent a tiny fraction of total users.

It was reported that for both medicines, the median time to onset of suicidal thoughts was less than two weeks. Now for both these medicines the recommended treatment procedure involves taking the medicine for a week before trying to quit smoking (on day 8). Both of the medicines are recommended to be taken for over 6 weeks (12-24 in the case of varenicline). It is noteworthy that the timing of these cases of suicidal thinking is typically in the first week after trying to quit smoking…i.e. the precise time period when nicotine withdrawal symptoms (depression, irritability, anxiety, poor concentration, insomnia, restlessness etc) are usually at their worst.

Half of the varenicline cases had a prior psychiatric history and 42% were known to be taking other psychiatric medicines at the same time. These proportions may not be much higher than typically occurs in smokers seeking treatment for tobacco dependence.

The outcomes were serious, and included hospitalization and death. The report provides brief description of 4 cases (2 on varenicline and 2 on bupropion). Surprisingly, no mention is made in these case reports of the timing of smoking cessation (if it occurred). This may be because when the event was originally reported, this information was not provided.

It is also surprising that in the whole report there is no discussion of the potential role of smoking cessation and nicotine withdrawal symptoms in precipitating the reported suicidal thoughts and behaviors (rather than the medicines, per se). At the beginning of the report there is a mention that the FDA also examined the association between the use of the nicotine patch and suicidal thinking, but that no clear association was found. Unfortunately no details were provided.

Overall, this report is useful in that it provides more information on some of the characteristics of these events, including their timing relative to the treatment process. It is interesting that FDA is now expressing a concern about these events in relation to bupropion, but appears not to be considering smoking cessation itself as a potential trigger in a very small minority of smokers.
The data in this report was not of the kind that can really clarify whether or not the medicines themselves may have caused these events. So healthcare providers (and consumers) are reminded to closely monitor for neuropsychiatric symptoms (e.g., changes in behavior, agitation, depressed mood, and suicidal thoughts and behavior) while they are using varenicline and bupropion as smoking cessation aids. Healthcare providers (and consumers or their families) should report any cases of suicidal ideation and/or behavior or any other serious adverse events in patients taking these drugs to FDA's MedWatch program at http://www.fda.gov/medwatch.

Id go further and suggest that providers and consumers should monitor for these symptoms during any attempt to quit tobacco use, regardless of whether or not a medicine is being used.

The report itself can be found at:
http://www.fda.gov/CDER/dsn/2009_v2_no1/postmarketing.htm#varenicline_bupropion

Other blog posts on related topics can be found at:
http://www.healthline.com/blogs/smoking_cessation/2007/11/chantix-varenicline-safety-being.html

and: http://www.healthline.com/blogs/smoking_cessation/2009/02/walmart-sells-smoking-cessation.html

Labels: bupropion, Chantix, FDA, jonathan foulds, smoking cessation, suicidal thinking, suicide, varenicline

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Walmart sells smoking cessation medicine for $9.

Last month Walmart announced that it has started selling the prescription-only smoking cessation medicine, bupropion (same drug as brand version, Zyban) at a lower price than any other effective smoking cessation medicine.

The starter pack, consisting of 17 bupropion 150mg extended-release tablets (a 10-day supply), sells for $9, and subsequent 30-day supplies (60 tablets) will cost $27 (less than $7 per week). Bupropion is typically taken as a single 150mg tablet per day for the first 3 days, then two tablets a day for the next 4 days. The smoker is advised to quit smoking completely on day 8, and continue on two tablets a day for approximately 8 weeks thereafter .

Currently smokers who don’t have health insurance coverage that includes smoking cessation medicines have to pay prices ranging from around $20 for a small box of generic nicotine gum intended to last a few days, up to around $55 for a 2-week supply of nicotine patches or around $130 for a month supply of varenicline (Chantix).

So the chance to get started on bupropion for an initial outlay of only $9, is much less expensive than other options, as is the continuing cost of around $27 per month. Not everyone can tolerate bupropion’s slightly stimulant initial side effect (including agitation and insomnia), but the initial 10-day supply is designed to take people to 3-days after their target quit date. So the smoker can find out if bupropion is helpful to them without a large initial financial outlay.
Bupropion also has the advantage that it can be combined with nicotine replacement therapy (e.g. nicotine gum) to obtain better results, as discussed in a prior blog posting: http://www.healthline.com/blogs/smoking_cessation/2007/09/does-it-help-to-add-nicotine-gum-to.html

You can find full details of the outcomes of smoking cessation treatment with bupropionas described in the New England Journal of Medicine at: http://content.nejm.org/cgi/content/abstract/340/9/685

You can find details of the Walmart announcement at: http://walmartstores.com/FactsNews/NewsRoom/8904.aspx

Labels: bupropion, Chantix, cigarette, jonathan foulds, nicotine gum, NRT, smoking cessation, varenicline

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Immediate and delayed quitting

Last week I attended the 4th annual meeting of the Society for Research on Nicotine and Tobacco (Europe) in Madrid. This is a conference where the top researchers present their latest research findings. As you can imagine a lot of fascinating stuff was presented. One that I particularly liked was presented by David Gonzales of the Health and Sciences University in Portland. He presented data on immediate quitting (i.e. those who succeeded in quitting on their target quit date with no lapses) and delayed quitting (i.e. those who had some lapses after the initial target quit date but then managed to get quit and stay quit) among patients treated with either varenicline (Chantix), bupropion (Zyban), or placebo.

For me the interesting thing was that Chantix and Zyban each improved the proportion who initially quit (over placebo), but Chantix also increased the proportion who managed to achieve abstinence after their initial target quit date. Dr Gonzalez presented a nice diagram showing that the number of patients achieving abstinence continued to increase across the first 12 weeks among those on Chantix or Zyban (although it increased faster among those on Chantix).

Colleagues have remarked that patients taking Chantix are less focused on the target quit day (typically day 8 of taking Chantix) than we are used to. We think that’s because almost all of the patients we treated before Chantix were also using nicotine replacement therapy (sometimes combined with Zyban/bupropion). The NRT (patch, gum etc) is typically started on the target quit day and so patients are very aware of the importance of that day. We don’t typically combine Chantix with NRT (as the Chantix is supposed to block the nicotine receptors in the brain) and so on Chantix its easier to see the target quit date as less distinct from any other day and just continue reducing cigarette consumption rather than quitting completely.

The take-home message for patients is that it still makes sense to select a target quit-date (day 8) and to try to quit smoking completely on that day. However, if you don’t immediately get quit, don’t give up on yourself or on the medicines. The evidence suggests that if you keep trying you will likely achieve abstinence, and that Chantix improves your chances, so long as you keep trying and keep taking the medicine. On the other hand, its important to be clear that the aim of the game is to quit completely, and its better in the long run to throw away the cigarettes and get on with it.

Labels: bupropion, Chantix, cigarette smoking, quit, varenicline, Zyban

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Does it help to add nicotine gum to bupropion?

Bupropion (marketed as Zyban for smoking cessation and Wellbutrin for depression) is approved by the US Food and Drug Administration as safe and effective for smoking cessation. It is taken in tablet form. There are also a number of nicotine replacement therapies (nicotine gum, patch, lozenge, inhaler and nasal spray) that are also approved treatments. Some previous studies have suggested that combining medications may improve smoking cessation success rates, and this has become normal practice at the tobacco treatment clinic here at UMDNJ.

Our experience in clinical practice has been that highly addicted smokers have better outcomes if they combine bupropion with NRTs. However, the only way to properly evaluate this is via a randomized placebo-controlled clinical trial. Such as study was just published in the journal, Nicotine & Tobacco Research, by Piper and colleagues at University of Wisconsin. They randomized 608 smokers to receive either (a) bupropion SR tablets plus 4mg nicotine gum, (b) buropion SR tablets plus placebo gum, or (c) placebo tablets and placebo gum, for 8 weeks, along with 6 brief counseling sessions. No more treatment was provided after the 8th week, but the participants were followed up at 6 and 12 months after the initial target quit date.

One week after the quit date, significantly more people had quit smoking while using active bupropion plus 4mg gum (47%), as compared with active bupropion plus placebo gum (38%) or placebo tablets and placebo gum (22%). At the end of treatment (8 weeks), the double medication group still had more successes (38%), as compared with active bupropion (31%) or double placebo (17%). However, at longer term follow-up (i.e. after the participants had stopped taking the medicines) the differences were relatively small. For example, at one year the quit rate was 21% for the double active group, 19% for active bupropion and 14% for double placebo.

So what does all of this mean? Firstly, it suggests that the advantage of adding nicotine gum to bupropion is real and statistically significant, but is quite small, even early in treatment. Secondly, it looks as though much of the advantage of early combination pharmacotherapy disappears at long term follow-up (off all medications). The other thing to note in this study is that the participants only used 4 pieces of gum per day. This is perhaps part of the reason for the smallish effects – the participants were only using smallish amounts of gum. Some may interpret these results as failing to demonstrate that adding nicotine gum to bupropion improves quit rates. Personally, I see a 38% quit rate at end of treatment as being meaningfully better than 31%. The drop-off after the medications are withdrawn is no surprise, and simply challenges us to consider why we continue to treat this chronic condition (tobacco dependence) with acute medications treatments. If a relative of mine was an addicted smoker seeking advice on which medicines to use, I’d probably still encourage something like bupropion plus the 21mg nicotine patch plus 4mg nicotine gum. I’d also encourage them to keep taking the full dose of all these medicines until they had experienced 14 consecutive days with no cravings, withdrawal symptoms or near lapses, and would be surprised if that day came within the first 6 months. Although each individual piece of this treatment may only add a few percent to their chances, this could be a life-saving treatment and every extra chance is worth the effort.

Labels: bupropion, Grand Rounds Nicotine Replacement, smoking cessation

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Can quitting smoking trigger depression?

Adolescent smokers are more likely than non-smokers to subsequently develop depression, and adult smokers are more likely to have either current depression or a history of depression than adult non-smokers. So although some have suggested that tobacco may have some component that “medicates” depression, the evidence for this is not at all clear. But for the smoker who has previously suffered a major depressive episode it is reasonable to wonder whether stopping smoking might increase the risk of suffering another episode of depression.

Depression is one of the most common and most unpleasant of all illnesses. It is characterized by feeling consistently sad, hopeless and pessimistic for more than 2 weeks (usually much longer), and often involves sleep disturbance, fatigue and changes in appetite. Perhaps most importantly, major depression is a risk factor for both attempted and completed suicide. So anyone who has ever suffered from major depression may understandably be very reluctant to do anything that may increase the risk of feeling that bad again. Remembering that low/depressed mood (which is not the same as full blown depression) is one of the symptoms of nicotine withdrawal, one can understand why someone with a history of depression would become concerned when they experience the onset of depressive symptoms after quitting smoking. Some studies find that people with a history of depression have a lower quit rate when they try to quit smoking, compared to those without such a history. One reason for this may be that onset of depressive symptoms raises the concern that a major depressive episode may return and triggers a return to smoking. However, a critical question is whether such fears are justified. Can quitting smoking increase the risks of onset of major depression?

Professor John Hughes, of the University of Vermont recently reviewed all the published studies providing evidence relevant to this question. The rate of major depression in the year after successfully quitting varied considerably across studies, from as low as 1% to as high as 31%. There was fairly consistent evidence that people with a history of major depression were more likely to have another episode after quitting, but this is not surprising as people with a prior history of depression are more likely to have another episode regardless of whether they quit smoking or not. Two studies by Professor Stan Glassman at Columbia University found that depression occurred more frequently in people with a history of depression who succeeded in quitting smoking compared with those who continued to smoke. In his review, Professor Hughes commented that none of the studies provided conclusive evidence and that there was a high risk of “publication bias”. This refers to the tendency for studies that don’t find a difference/effect to be less likely to be published. So what can we conclude from all this?

It looks likely that having a history of major depression is associated with slightly greater difficulty quitting smoking, and an increased risk of recurrence of depression in the months/years after quitting smoking. It remains uncertain whether quitting smoking can actually trigger an occurrence of depression, although it is clear that the majority (69-99%) of people who quit (even those with a history of depression) do NOT experience major depression within a year of quitting.
But how might this affect the choice of treatment, particularly for those with a history of depression? If I had a close relative who wanted to quit smoking but had a history of major depression, my advice would be as follows:
1. To ensure that you get the best advice and support, attend a treatment center with staff who have been trained to provide tobacco treatment, including access to medical staff with experience providing the range of tobacco treatment medications.
2. To increase the chances of successfully quitting AND preventing unpleasant withdrawal symptoms make sure you use an adequate dose of medication approved for smoking cessation. For the heavy smoker that should involve discussing with the doctor the potential advantages of combination therapy, such as Zyban (bupropion), plus the nicotine patch, plus one of the acute dosing nicotine replacement therapies (nicotine gum, lozenge, inhaler or nasal spray).
3. Make use of all the counseling support services available – ideally combining attendance at regular group or individual appointments, plus registering with a smoking cessation website (e.g. www.quitnet.com ), plus use of a telephone quitline.
4. Don’t start reducing the prescribed medication until you are feeling very confident about maintaining abstinence from tobacco and have discussed it with your prescriber. As a rule of thumb, don’t consider reducing your prescribed smoking cessation medications until you have had fourteen consecutive days with no cravings, withdrawal symptoms or near lapses.
5. Stay engaged in counseling for at least a few months (and ideally longer) after you have come off your smoking cessation medications. This could be as simple as scheduled monthly appointments or telephone calls, but even this relatively infrequent contact during months 4-12 after quitting smoking will help maintain focus on abstinence and will enable the counselors to monitor symptoms and treat as required.

Now all of this may sound like a great deal more work than people typically plan on when they try to quit smoking. It is. But I would remind my relative that this is a difficult but life-saving behavior change they are about to embark on. One likely to add ten healthy years to their life. Its well worth the effort both to successfully quit and to look after ones mental health in the process.

Labels: bupropion, cessation, depression, nicotine addiction cigarette smoking tobacco

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