Combination NRT gets higher quit rates: new study

A new study published this month in the journal “Archives of General Psychiatry” aimed to compare the effectiveness of some of the main medicines for stopping smoking and their combinations. The study, by Dr Megan Piper and colleagues at University of Wisconsin, recruited just over 1500 smokers seeking help to quit, and randomly allocated them to use either, placebo nicotine replacement, the nicotine patch, nicotine lozenge, bupropion tablets, buproion plus nicotine lozenges ,or the patch plus nicotine lozenges.

This was one of the biggest and most ambitious placebo-controlled trials of smoking cessation medicines ever published. Each participant was provided with medication to last a normal course of treatment, as indicated on the product label, plus 6 brief face-to-face counseling sessions. The key questions were:
1. Do each of the individual medicines (patch, lozenge, bupropion) produce higher quit rates than placebo?
2. Do combination medicines produced higher quit rates then individual medicines?


This was a “double-blind” study, meaning that both the participants and the researchers didn’t know who had active medicine and who had placebo, until the study was completed. Most of the medicines were provided for 8 weeks, but the lozenge could be used for 12 weeks after the planned quit date (as is normal according the labeling).

The researchers looked at the proportions of smokers who were quit (no smoking in previous week) at 2 and 6 months after the target quit rate. The quit rates at the 2 month follow-up were as follows:

Placebo : 30%
Patch: 45%
Lozenge: 40%
Bupropion : 40%
Bupropion plus lozenge: 50%
Patch plus lozenge: 54%

At 6 month follow-up the quit rates were:
Placebo : 22%
Patch: 34%
Lozenge: 34%
Bupropion : 32%
Buoropion plus lozenge: 33%
Patch plus lozenge: 40%

Each of the individual medicines achieved higher quit rates than placebo, but the patch plus lozenge combination had higher quit rate again. So these results add to the growing evidence suggesting that combining the nicotine patch plus another NRT is significantly better than either medicine alone.

This study was embedded in a larger 3-year study of factors influencing health, and this may explain the unusually high quit rate in the placebo group. To get into this study all the participants had to be willing to attend numerous appointments over a 3 year period, implying that they were (a) very highly motivated to improve their health and (b) relatively confident in the stability of their life over the coming 3 years.

One other noteworthy aspect of these results was that they appear to confirm the recent trend of results finding bupropion to be equivalent to but no better than NRT for smoking cessation. In the early bupropion trials it looked like bupropion may get slightly higher quit rates than the patch, but more recent studies (including this one) have found bupropion to give very similar outcomes to NRT. Perhaps the most disappointing result in this study was that of bupropion plus lozenge (no better than lozenge alone at 6 months). However, I suspect that this was a fluke poor outcome, caused by a few more participants relapsing after coming off their meds. Although the trial overall is relatively large, each “arm” has only around 250 participants, and so the quit rate is substantially influenced by just a few more people quitting or relapsing.

So this study confirms that the nicotine patch remains a pretty good basic smoking cessation aid, but that adding on another NRT on top of the patch helps more smokers to quit. Other studies suggest that quit rates could be boosted even further by (a) allowing participants to use the patch for a few weeks prior to their target quit date and (b) encouraging those doing well at two months to continue using their NRT for up to 6 months (or as log as needed). This trial did not provide a direct comparison with varenicline (Chantix/Champix) but other studies suggest that varenicline produces quit rates in the same ball park as patch plus another NRT.

We have now been consistently seeing research studies showing that combination NRT is more effective than single NRT for over a decade, and yet the labeling on all of these NRT products continues to warn patients not to combine them. Maybe its time the labeling on these medicines was changed so as not to warn smokers away from using them in the most effective way?

Reference:
Piper ME, Smith SS, Schlam TR, Fiore MC, Jorenby DE, Fraser D, Baker TB. A randomized placebo-controlled clinical trial of 5 smoking cessation pharmacotherapies.Arch Gen Psychiatry. 2009 Nov;66(11):1253-62.

This link should take you to the full report on the study:
http://archpsyc.ama-assn.org/cgi/content/full/66/11/1253

Labels: bupropion, combination, jonathan foulds, lozenge, Megan Piper, nicotine patch, nicotine replacement therapy, NRT, Smoking, smoking cessation, trial

Permalink | 1 Comments| Email Post

Post your comment

Varenicline ( Chantix ) does not produce depression or suicide: new study

The smoking cessation medicine, varenicline, has proven safe and effective in numerous placebo-controlled trials, but in the post-marketing phase there were numerous reports of patients experiencing “neuropsychiatric effects” ranging from poor concentration all the way to suicide. In July 2009, the US Food and Drug Administration (FDA) required the manufacturers of both varenicline and bupropion to add new “boxed warnings” to the product labeling based on continued review of postmarketing adverse event reports. These issues have been discussed on this blog before and many readers have provided very useful comments based on their own experience (you can find these by typing “varenicline “ in the box on the right and clicking on “search health experts”).

Today a major new study of this issue was published in the British Medical Journal (BMJ) by Professor Gunnell and colleagues of the University of Bristol in England. One of the main strengths of this study was its size. The study used the UK General Practice Research Database (GPRD) which collects all the clinical data and prescribing information from 500 family doctors (GPs) throughout the UK (covering 3.6 million patients). They identified all adult patients who were prescribed a smoking cessation medication between September 2006 and May 2008 and then searched their records for occurrence of suicide, self-harm (non-fatal self injury), and being prescribed an antidepressant medication in the following 6 months. Overall 80,660 patients were included in the study (63,265 on NRT, 6422 on bupropion and 10,973 on varenicline). So this is by far the largest and most thorough study examining this issue.

The researchers recognized that smokers are at increased risk of suicide and that smoking cessation itself can cause mood disturbance, and so they decided to compare the rates of adverse events in patients using varenicline with patients using nicotine replacement therapy (NRT) or bupropion. This is an excellent way to assess the risks of varenicline as compared with comparable patients trying to quit smoking, particularly as there is no concern about NRT causing depression or suicide. Another strength of this study was that the researchers had access to the patients’ prior medical history and so were able to control for potential differences in the characteristics of the patients using the different treatments.
Overall there were 166 episodes of self harm, 37 episodes of suicidal thinking and 2 suicides during the follow-up period. Both the suicides were in patients who had used NRT (no suicides in the 10,973 patients using varenicline) and there was no statistically significant increased risk of suicide, self-harm, suicidal thoughts, or subsequent use of antidepressants in patients using varenicline or bupropion as compared with NRT. In fact patients prescribed varenicline appear to have a significantly REDUCED risk of needing a prescription for antidepressants during the subsequent months. 208 people died during the follow-up period and patients on varenicline were significantly LESS likely to have died than patients taking NRT (although this analysis only controlled for age and sex and the effect may diminish when a wider array or risk factors are controlled for).
Overall, this large study found only 18 episodes of self harm out of 10,973 smokers prescribed varenicline, a proportion not significantly different from NRT or bupropion. In addition it found that significantly fewer varenicline-treated patients had a subsequent need for antidepressants.

The well controlled placebo-controlled trials found no evidence of varenicline causing more suicidal thoughts than placebo, but patients with serious mental health or medical problems were largely excluded from those studies. This sample, however, was a real world patient sample,. 10% had a history of alcohol misuse, 5% were using antipsychotic medication, 13% anti-anxiety medication and 24% antidepressants. 11% had experienced a previous suicide related event. So when such a large, well-designed study like this finds really no evidence to support the claim that varenicline causes depression or suicide I am inclined to believe the evidence.
I should disclose here that I have done consulting work for manufacturers of all of these products, but none of the authors of this report receive any funding from any of these companies.

This paper provides considerable reassurance over concerns that varenicline causes suicide. The data shows that it does not.

The reference and link for the paper are:

Gunnell D, Irvine D, Wise L, Davies C, Martin RM. Varenicline and suicidal behavior: a cohort study based on data from the General Practice Research database. BMJ 209: 339 (in press)

http://www.bmj.com/cgi/content/short/339/oct01_1/b3805?rss=1

Labels: bupropion, champix, Chantix, depression, Gunnell, jonathan foulds, NRT, self-harm, suicide, varenicline

Permalink | 2 Comments| Email Post

Post your comment

Comment on FDA Advisory on varenicline and bupropion

In my previous post I summarized the new information from FDA on varenicline and bupropion for smoking cessation. Before giving my opinion on this, there are a couple of things Id like to point out. The first is that I have done paid consulting work for the manufacturers of varenicline (Pfizer) and some brands of bupropion (GSK) as well as other companies marketing competing medicines (e.g. Novartis and Celtic Pharma). The second is that I take very seriously the major adverse events that some people have experienced while taking these medicines (and while attempting to quit smoking without these medicines). A number of family members of people who have committed suicide while taking these medicines have commented online on earlier posts on this blog, as have others who experienced marked mood changes. So one cannot help but be affected by hearing these stories and seek to understand what might be going on. In particular I think it is important to examine all the evidence, both from individual case histories and from analyses of larger clinical trials and population datasets, in order to try to form an opinion as to what may have caused the adverse events.

I also understand that those working for FDA who have to examine all the reports they have received, cannot help being affected by these also. A New York Times article published on July 1 stated that FDA had reports of 98 completed suicides in connection with varenicline (Chantix). Suicide is always an enormous tragedy and it is understandable that those reading the reports would be left feeling that they have to do something.

I have written previously on this issue, and you can find my previous posts by writing the appropriate search term (e.g. Chantix, varenicline, depression, bupropion or nicotine withdrawal) in the box on the right where it says, “search health experts”.

The first thing that has to be borne in mind is that mood disturbance is a normal part of nicotine withdrawal. Like most things, individuals vary in how severe that mood disturbance is, and for a small percentage it can be severe. Depression is just one of 8 recognized nicotine withdrawal symptoms. Here are some comments that readers of this blog made in response to my post on June 17, 2007 on, “Can quitting smoking trigger depression?”:

“I truly believe quitting can trigger depression. In fact, I am now 39 and have spent most of my 30's trying to quit. Have quit 4 times in the last nine years - twice for 9 months, once for 18 months and have not smoked now since New Year's Eve - so about 5 months. Physically I feel much better, no coughing in the morning, but mentally, I feel terrible.. Each time I have gone back to smoking it has been due to the hideous depression I suffer whilst not smoking. I alienate my friends and family - I feel so low, I am unable to string a sentence together at times, let alone motivate myself to leave the house. Work is a struggle as I work in an office and have to interact with others - love the weekends when I can shut myself away from the world.”

“I quit smoking 8 weeks ago. After consulting with my GP, because I've suffered from depression before (I came off antidepressants about 6 months ago after being on them for over 2 years!) and because every time I've tried quitting smoking before have been hit really badly by a bad bout of temporary depression from nicotine withdrawal, I started using patches and an inhalator for when I needed an extra 'boost' of nicotine to try to alleviate the depressive symptoms gradually.

The first 6 weeks on the 15mg patches was surprisingly easy and, apart from a couple of grumpy periods which lasted no longer than an hour or two at most, I didn't have the usual massive slump in my mood . I even succumbed whilst drunk to 1 cigarette about 3 weeks into my quit, but it tasted absolutely foul and I stubbed it out before I'd finished it - "this time" I thought, "I've really managed to do it".

But then I moved down to the 10mg patch, which coincided with a family holiday to the seaside...a time that I thought would be ideal for stepping down to less nicotine, as I'd be away from the day-to-day stresses of life & work. But unfortunately I just found that I was hit by a MASSIVE bout of depression - as bad as anytime that I've tried quitting cold turkey. I'm very wary of the 'danger signs' of my depression now and so, after a week where our family holiday was, frankly, pretty hellish all round, I succumbed to the fags again purely as I knew it would (even temporarily) alleviate the depression. After 2 evenings and a day of being back on the fags, I decided that I really didn't want to carry on smoking, as the sore throat and very stuffy nose that I've always had whilst smoking had come back, and getting rid of that had been one of the really strong reasons for quitting in the first place! So now I'm trying the 10mg patches again, and whilst yesterday I was pretty grumpy and stressed, I'm trying to put a more positive thought on things today in the hope that things will improve. If not, I'm considering whether going back onto antidepressants for a while would help, but it does make me wonder which is the lesser of two evils - the dangers of smoking, or the dangers of mental illness by not smoking!”

“I am approaching 6 months smoke free the end of march, after smoking heavy for 26 yrs. i went through the horrible depression, the uncontrollable crying, the overwhelming sense of nothingness and wothlessness in my life. did not want to get out of bed most days.”

These are posts by people trying to quit smoking who were not using varenicline (Chantix) or bupropion. The point here is that some people get depressed when they stop smoking. 11 million people have used varenicline as part of their attempt to quit smoking, with more than half of them in the United States. So it should be no surprise that when such a vast number of people use a drug to try to quit smoking, that a large number (even if only a very small proportion) report their experiences as side effects of the drug.

However, we also need to look at the thorough studies that have examined this issue in a systematic manner, for signs that these medicines could be actually causing some cases.

Earlier this year Kasliwal and colleagues in the UK reported (in the journal, Drug Safety”) on a cohort of 2682 varenicline users they have been following. The majority of people who stopped using the drug due to a side effect did so due to nausea or vomiting (n=91). The most frequently reported psychiatric events (causality not implied) were sleep disorder (n=43, 1.6% of the cohort), anxiety (n=33, 1.2%), depression (n=29, 1,1%), abnormal dreams (n=26, 1.0%) and mood change (n=17, 0.6%). 2 cases of attempted suicide wee reported during treatment with varenicline. Both of these patients had a previous history of psychiatric illness and precipitating factors for the event.

John Stapleton, another researcher in the UK, published in the journal, “Addiction” an analysis attempting to answer the question, “Do the 10 UK suicides among those taking the smoking cessation drug varenicline suggest a causal link?”. Stapleton noted that these 10 suicides occurred over the 21-month period from December 2006 to August 2008. He also noted that there are about 5500 suicides each year in the UK among those aged 15 or older, and that around 2000 of these are in smokers (or 3500 over the 21 months of the period under study). During that time around 5% of UK smokers tried varenicline, (n=500,000). On average, one would therefore expect about 175 suicides in 21 months among the 500,000 people who used varenicline. But of course they did not take varenicline for the full 21 months. Stapleton assumed that the typical varenicline user took the drug for only 6 weeks, and calculated that 12 suicides would be expected by chance among people taking varenicline, (i.e. slightly more than were actually reported). He concluded that,
“the UK data do not appear to suggest even an association between varenicline and suicide, far less a causal link.”

At a recent conference, Professor Serena Tonstad presented an analysis of adverse events in all 9 placebo-controlled trials of varenicline that were published by the end of 2008. Some of these trials also included patients randomized to treatment with bupropion. This analysis found the rate of suicidal behavior to be 0/2783 (0%) for varenicline, 1/795 (0.001 %) for bupropion, and 2/1655 (0.001 %) for placebo. Clearly no evidence that either drug cause an increased rate of suicidal behavior. But people with a recent history of psychiatric problems were excluded from those trials.

In the May 2009 issue of Annals of Pharmacotherapy, Purvis and colleagues reported on the safety and effeciveness of varenicline in a Veteran population with a high prevalence of mental illness (almost 50%). They followed 50 veterans for 12 weeks through their quit attempt with varenicline. 30% quit smoking, but the quit rate was lower in those whose partner also smokes or who had a mental illness. All 5 patients who reported mood or behavioral changes that they attributed to varenicline had a pre-existing psychiatric problem (all had depression, 2 also bipolar, one of whom successfully quit). So this study suggests a higher rate of behavioral problems on varenicline among those with current psychiatric problems, but still doesn’t point clearly to a causal effect.

There have been other publications on varenicline over the past year, including some reports of psychiatric effects, and one case report of a woman who smoked 50 cigarettes per day who had suffered depression with suicidal tendencies on prior quit attempts without varenicline, but who was finally able to quit successfully with varenicline and inpatient treatment.

Overall, my take on this evidence is that mild to moderately severe nicotine withdrawal symptoms are the norm for regular smokers trying to quit without any medicine. A small percentage (probably less than 1% ) of those who stay quit for more than a couple of weeks develop more severe effects, that may include depression and suicidal thinking. While both varenicline and bupropion are known to cause some side effects (e.g. nausea or sleep disturbance) it remains unclear and I’d say unlikely that varenicline or bupropion actually cause or exacerbate any of these more severe psychiatric illnesses to any greater extent than quitting smoking itself. On the contrary, the evidence from placebo-controlled trials is very clear that both these medicines reduce the severity of nicotine withdrawal symptoms like low mood and irritability.

While I do agree with FDAs advice that patients using these medicines should be made aware of potential mood and behavior changes and monitored closely, I would extend that advice to anyone attempting to quit smoking, with or without medication.

Labels: bupropion, Chantix, Chantrix, jonathan foulds, nicotine withdrawal, smoking cessation, varenicline, Zyban

Permalink | 3 Comments| Email Post

Post your comment

FDA: Boxed Warning on Serious Mental Health Events to be Required for Chantix and Zyban

On the first of July, 2009 the U.S. Food and Drug Administration issued additional information for healthcare professionals and announced that additional warnings will be required on the boxes of smoking cessation aids varenicline (Chantix in U.S.) and bupropion (Zyban, and generics in U.S.) and for the use of bupropion as an antidepressant (Wellbutrin and generics in the U.S.). The advisory is copied in full below and the link is provided. It highlights the risk of serious neuropsychiatric symptoms in patients using these products. These symptoms include changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide.

I’ll give my comments on this in my next posting.

Link to FDA advisory (cut and paste into your browser if link not active):

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170100.htm


"Information for Healthcare Professionals: Varenicline (marketed as Chantix) and Bupropion (marketed as Zyban, Wellbutrin, and generics)

FDA ALERT [7/1/2009]: 
FDA has required the manufacturers of the smoking cessation aids varenicline (Chantix) and bupropion (Zyban and generics) to add new Boxed Warnings and develop patient Medication Guides highlighting the risk of serious neuropsychiatric symptoms in patients using these products. These symptoms include changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide. The same changes to the prescribing information and Medication Guide for patients will also be required for bupropion products (Wellbutrin and generics)that are indicated for the treatment of depression and seasonal affective disorder.

The added warnings are based on the continued review of postmarketing adverse event reports for varenicline and bupropion received by the FDA. These reports included those with a temporal relationship between the use of varenicline or bupropion and suicidal events and the occurrence of suicidal ideation and suicidal behavior in patients with no history of psychiatric disease. Some of these cases may have been confounded by symptoms typically seen in people who have stopped smoking and are experiencing withdrawal from nicotine.

Healthcare professionals should advise patients to stop taking varenicline or bupropion and contact a healthcare provider immediately if they experience agitation, depressed mood, and any changes in behavior that are not typical of nicotine withdrawal, or if they experience suicidal thoughts or behavior. If varenicline or bupropion is stopped due to neuropsychiatric symptoms, patients should be monitored until the symptoms resolve.

Family members and caregivers should also be alerted to the potential for changes in mood or behavior and contact the health care provider if they observe these changes in the person taking varenicline or buporpion. Varenicline and bupropion are effective smoking cessation aids. The possible risks of serious adverse events occurring while using varenicline or bupropion should always be weighed against the significant health benefits of quitting smoking. The health benefits of quitting smoking include a reduction in the chance of developing lung disease, heart disease, or cancer. 
 
This information reflects FDA’s current analysis of data available to FDA concerning these drugs. FDA is not advising practitioners to discontinue prescribing these products. FDA intends to update this sheet when additional information or analyses become available.
To report any unexpected adverse or serious events associated with the use of these drugs, please contact the FDA MedWatch program using the information at the bottom of the page.

FDA last informed healthcare professionals and patients of the addition of suicidal ideation, attempted and completed suicide, changes in behavior, agitation, and depressed mood in the WARNINGS and PRECAUTIONS sections of the varenicline prescribing information and patient Medication Guide on May 16, 2008. Varenicline (marketed as Chantix) Information FDA is now requiring the addition of this information to the BOXED WARNING and to the Medication Guides for patients who are prescribed varenicline and bupropion under the authorities provided in the Food and Drug Administration Amendments Act (FDAAA).

Recommendations and Considerations for Healthcare Professionals
It is important to discuss the possibility of serious neuropsychiatric symptoms in the context of the benefits of quitting smoking with patients before prescribing these medications. Varenicline and bupropion are both effective smoking cessation aids and the health benefits of smoking cessation are immediate and substantial.
Healthcare professional should monitor all patients taking varenicline and bupropion for serious neuropsychiatric symptoms. These symptoms include changes in behavior, hostility, agitation, depressed mood, suicidal ideation, suicidal behavior and attempted suicide. These symptoms have occurred in patients without pre-existing psychiatric illness and have worsened in some patients with pre-existing psychiatric illness. In most cases, neuropsychiatric symptoms developed during treatment with varenicline or bupropion but in others, symptoms developed after stopping drug treatment.
Patients should be informed that it is not unusual to have symptoms such as irritability, feeling anxious, depressed mood and trouble sleeping when they are withdrawing from nicotine, independent of whether they are taking varenicline or bupropion.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder, may experience worsening of their pre-existing psychiatric illness while taking varenicline or bupropion.
Patients who discontinue treatment because of neuropsychiatric events should continue to be monitored until symptoms resolve. Although symptoms resolved after treatment was stopped in many cases, there were also some cases where the symptoms persisted.

Information for healthcare professionals to discuss with patients, family members, and caregivers:
Quitting smoking can decrease the chances of lung and heart disease and getting cancer. These important health benefits should be weighed against the small, but real, risk of serious adverse events with use of varenicline or bupropion.
Worsening or recurrence of psychiatric illness. Patients should be told that some patients taking varenicline or bupropion have experienced worsening of their psychiatric illness, even when the illness was under control and some patients have experienced a recurrence of a previous psychiatric illness when taking these drugs for smoking cessation.
Unusual changes in mood and behavior. Patients should be instructed to contact their healthcare provider immediately if they observe or develop thoughts about suicide or attempting suicide, feel agitated, aggressive or violent and other unusual changes in mood or behavior.
Some symptoms are to be expected when quitting smoking. Patients should be told that it is not unusual to have symptoms such as irritability, feeling anxious, depressed mood and trouble sleeping when they are withdrawing from nicotine, independent of whether they are taking varenicline or bupropion and that vivid, unusual, or strange dreams may occur while taking Chantix and are not a cause for alarm.
Discuss other methods of quitting smoking if it is decided that varenicline or bupropion are not the best treatment option
Background Information and Data
FDA first informed the public about the possibility of serious neuropsychiatric symptoms with varenicline in the November 20, 2007 FDA Early Communication About an Ongoing Safety Review. A complete history of related communications on varenicline and bupropion can be found at: Varenicline (marketed as Chantix) Information Since that time, information about serious neuropsychiatric symptoms in patients taking varenicline has been added to the POST-MARKETING EXPERIENCE section of the prescribing information.
As FDA received additional information the suggestion of a possible association between both varenicline and bupropion (which was evaluated as a comparator to varenicline) and serious neuropsychiatric symptoms, in both patients with and those without previous history of psychiatric illness, became more evident as its review progressed. As a result, FDA has required the manufacturers of the smoking cessation products varenicline, and bupropion to add information regarding neuropsychiatric symptoms to the Boxed Warning, and Warnings sections of the varenicline and bupropion prescribing information and update the Medication Guides for patients so that healthcare professionals and patients can be more alert to these issues.

A summary of the data from FDA’s review of varenicline and bupropion were published in FDA Drug Safety Newsletter, Volume 2, Number 1, 2009. This analysis was for all reports received by FDA from the time of marketing approval to November 2007. Access to the article is provided in the link below. FDA has continued to receive reports of neuropsychiatric events in association with use of varenicline and bupropion since the data cut off date for the analysis presented in the Drug Safety Newsletter analysis.
 FDA Drug Safety Newsletter Volume 2, Number 1, 2009 - PDF."

Labels: bupropion, champix, Chantix, Chantrix, jonathan foulds, smoking cessation, varenicline, Zyban

Permalink | 0 Comments| Email Post

Post your comment

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

Permalink | 1 Comments| Email Post

Post your comment

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

Permalink | 0 Comments| Email Post

Post your comment

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

Permalink | 0 Comments| Email Post

Post your comment

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

Permalink | 0 Comments| Email Post

Post your comment

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

Permalink | 13 Comments| Email Post

Post your comment

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

Permalink | 3 Comments| Email Post

Post your comment

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

Permalink | 71 Comments| Email Post

Post your comment