NAQC Issue Paper INTRODUCTION

Transcription

1 NAQC Issue Paper NAQC s Issue Papers aim to provide critical knowledge on important quitline topics and guidance for decision making. Integration of Tobacco Cessation Medications in State and Provincial Quitlines: A Review of the Evidence and the Practice with Recommendations (2014 Update) INTRODUCTION Tobacco quitlines are currently available in all 50 U.S. states and three territories, and have consistently proven effective in helping tobacco users quit (USPHS 2008). The range of services offered by state and territorial tobacco quitlines varies, often depending on limited funding and priority populations identified by quitlines. Tobacco quitlines began providing over-the-counter cessation medications in the mid- to late-1990 s as they recognized improved quit outcomes from integrating pharmacological treatment with behavioral counseling (Guideline 2008), and became comfortable providing pharmacological assistance and support for those quitting tobacco. The percent of U.S. quitlines that provide quit medications has increased since the first edition of Integration of Tobacco Cessation Medications in State and Provincial Quitlines: A Review of the Evidence and the Practice with Recommendations, from 70% in 2008 to 87% in The median state medication budget was $310,024 (n=28) in 2008 while in 2012, it was $212,251 (n=53). According to the 2012 NAQC Annual Survey of Quitlines, 46 states offered free medications, three states provided access to discounted medications and three states provided medication vouchers. With seven of 11 Canadian provinces responding to the survey, none reported providing free or discounted quit medications. Among those states providing free medications, the nicotine patch is most likely to be covered (n=46 states), followed by gum (n=34) and lozenge (n=26). Free prescription quit medications include bupropion SR (n=3), varenicline (n=3), the nicotine inhaler (n=2) and nicotine nasal spray (n=2). Only three states offer some form of discounted medication, with the same number of states providing vouchers to those interested in using cessation medications. The purpose of this NAQC Quality Improvement Initiative Issue Paper is to provide an update on the comprehensive review of th e literature and practice related to the integration of tobacco cessation medications and quitline services that reflects additions to the evidence base and improv ements in practice since the first publication (2009). This paper is intended to provide an update on the provision and distribution of Food and Drug Administration (FDA)-approved cessation medications, with special emphasis on: 1. Trends in medication coverage and budgeting, and how quitlines have evolved in the integration of cessation medications with counseling and other support services; 2. FDA revision of nicotine replacement therapy (NRT) labeling and the impact this may have on the application and utilization of cessation medications in quitline settings, including the use of combination NRT, extended use of NRT, and pre-quit use of NRT; 3. The increase in the promotion of, and use of, electronic cigarettes and the challenges these present with regard to cessation medications; 4. The increasing numbers of callers who are using two or more tobacco products, including electronic cigarettes; 5. Providing an update on published studies on the use of medications by quitlines and the effect medications have on quitline utilization and

2 abstinence rates; 6. Updating readers on cost-effectiveness analysis, choice of medication, determination of quantity of medication to provide and the method of distribution of medications that will be used; 7. Identifying areas that need to be explored further through research and rapid-cycle testing to optimize the effectiveness of cessation medications in quitline settings; and 8. Providing recommendations on issues related to use of cessation medications in quitline settings. The paper relies on a number of references, including the U.S. Department of Health and Human Services Clinical Practice Guideline, Treating Tobacco Use and Dependence, 2008 Update ( Cochrane Review and other peer-reviewed scientific articles to identify and document evidence-based recommendations regarding use of medications in the treatment of tobacco use and dependence. While we are fortunate that there is a great deal of scientific evidence on the use of cessation medications in quitline settings, in some cases the evidence is not specific to quitline settings. Since quitlines were first launched in 1992, evidence generated in settings other than tobacco quitlines has had to be considered and evaluated to determine if it can be effectively and safely implemented in the quitline environment. Finally, there is also a great body of clinical and operational experience that is relevant to this subject area, and it is used to supplement the empirical evidence gathered from research. Current Models of Tobacco Cessation Medication Integration and the Factors that Influence Them All state and provincial quitlines provide some form of behavioral support / counseling to callers interested in quitting tobacco. As of 2012, all U.S. state quitlines provide some form of free or discounted cessation medications. Most Canadian quitlines do not provide medications to quitline callers. However, there are some partnerships that link medication provision by a provider with quitline counseling. For example, free or reduced-cost medication may be available through a clinical or community program and the quitline is promoted as a source of assistance for the client to access and/or the provider may obtain client consent to make a referral to the quitline and the quitline vendor calls the client directly. While more U.S. states are providing access to cessation medications today than in 2008, the types of medications and the durations of therapy have changed countless times. Perhaps more than any time in their history, quitlines are purposely striving to effectively serve more callers with less money. This has put enormous pressure on treatment services --- counseling and medication alike. The issues since 2009 have not so much been whether to provide medication, but what types of medications, how much and to which callers. Over the years, quitlines have routinely shifted in how they integrate medications, with factors like funding and priority populations playing increasingly important roles. Funding pressures have limited quitlines in their ability to provide full regimens of NRT. These pressures have coincided with efforts to increase reach, which has put further pressure on limited budgets affecting the ability to provide full regimens of medication to callers and / or to restrict medication access to all callers ready to quit. For example, some quitlines have limited NRT to starter kits, which are typically 2-week or 4-week regimens, while others have limited free NRT to those who are uninsured or to other priority populations. Starter Kits

3 The evidence for starter kits can be traced to trials conducted by New York (J Public Health Manag Pract Jan-Feb;12(1): Reach, efficacy, and cost-effectiveness of free nicotine medication giveaway programs. Cummings KM) and Oregan (Nicotine Patches and Uninsured Quitline Callers; McAfee/Bush 2008). New York experimented with different durations and delivery modalities. Some callers were mailed NRT while others received a voucher. Durations of therapy ranged between 1-week, 2-weeks and 6 weeks. Quit rates varied by the amount of NRT sent, with those sent 6-weeks of NRT reporting the highest rates (35%) while those sent 1-week reporting the lowest rates (21%). However, the quit rates were not reliably different between the durations of therapy. In the Oregon study, callers were randomized to 2-week starter kits or to a full 8-week regimen. While 8 weeks of NRT resulted in higher quit outcomes (19.6%) compared to 2-weeks (14.3%), the length of use of NRT was longer with 8-weeks and call completion was higher (6.3 weeks and 2.0 calls respectively) than use and call completion with 2-weeks (4.3 weeks and 1.6 calls). Of those provided starter kits, 39.3% reported that they accessed additional NRT on their own. Among NRT starter kits, you will also find short regimens of combination NRT, most commonly combining the nicotine patch with the nicotine gum. Priority Populations Tobacco quitlines have served specific priority populations since they first launched. One of these models was that of the public / private partnership. In this model, those who self-identified as uninsured received NRT free of charge, while those who had health insurance were provided varying levels of counseling intensity, but were referred back to their health plan to access NRT. The intent was to dedicate quitline treatment services to those who had fewer resources at their disposal. The model recognized that many of the insured had no coverage for NRT or tobacco cessation-related counseling, and was intended to put pressure on health plans and self-insured employers to step up to the plate and provide coverage consistent with the 2000 USPHS Guideline. One could argue whether or not the model was successful, but eventually more and more quitlines offered some duration of NRT to all callers who were not pregnant, under the age of 18 and had no medical exclusionary criteria. Cost-Sharing As the Affordable Care Act (ACA) is implemented there may be increased opportunity for sharing the costs associated with the provision of cessation medications. For example, quitlines might create partnerships with health plans that serve callers from their state whereby the quitline would provide medications and the health plans reimburse the quitline. This approach would avoid creating duplicative services and would leverage the infrastructure created by the quitline. Models for this have been explored in Michigan. Alere Health has used a coordination of services model to triage those who call the quitline to the most robust services available to them. Under this model, callers are asked about their employment and / or health plan coverage. If information about coverage offered by the employer or health plan is available, the Registration Agent enrolls the caller to the program that offers the most comprehensive services. However, the ACA may also present some unique challenges that are beyond the immediate scope of this paper. Coverage for smoking cessation is illdefined by the ACA. Many are concerned that short-sighted plans will take a check the box approach whereby they offer inadequate services leaving their consumers technically covered but underserved when it comes to evidence-based treatment for tobacco cessation. Quitlines will need to position themselves through advocacy and funding to be able to cover any potential gap of this sort. Medication Models

4 1. Medication information only. While all U.S. quitlines reported providing some form of medication in 2012, state quitlines may temporarily discontinue providing medication, and offer counseling-only due to inadequate or inconsistent funding. Washington State is a quitlines that has been poorly funded by the legislature over the past several years. In some cases, all services have been halted, only to be started again for priority populations. As of April of 2014, five of 28 state quitlines operated by Alere Health offered no NRT coverage. How the ACA will impact medication coverage is unclear. There may or may not be opportunities for cost-sharing between quitlines and health insurance coverage. 2. Limited medication distribution. U n d e r t h i s m o d e l, quitlines distribute tobacco cessation medications to selected populations such as the uninsured, underinsured, or specific priority populations. Some may provide NRT starter kits for 2-weeks to 4-weeks to all callers, or as a temporary promotional tool to encourage calls to the quitline. Limited budgets and efforts to increase quitline reach make starter kits more appealing than trying to provide longer regimens to fewer callers. Most quitlines require the caller to actively participate in telephonic coaching in order to receive medications, but not all. Even if counseling is not provided the individual s experience with tobacco cessation medication may increase the awareness of the benefits of these medications and prompt a quit attempt. Those receiving NRT, but who are unsuccessful in quitting, may contact the quitline at some point in the future to make another quit attempt (6). 3. Full medication distribution. Some quitlines view medications as an integral part of their mission to provide comprehensive tobacco intervention services consistent with strength-of-evidence A recommendations in the 2008 Guideline Update (USPHS 2008). While behavioral counseling alone and medication use alone are effective in increasing tobacco abstinence rates, there is a greater likelihood of tobacco abstinence when they are used in combination (8). Linking free tobacco cessation medications for all callers with counseling ensures more tobacco users will receive both types of interventions (9). While most provinces in Canada do not provide medication through their quitlines, in British Columbia 12-weeks of free nicotine gum and patch are available to all callers from that province by phoning The operators at can make a warm transfer to the QuitNow phone service, but it is not mandatory. There is also subsidized Champix or Zyban through the BC Fair Pharmacare program. It is a means-tested program for a subsidy based on income level ( Provision of Medication Has a Positive Impact on Many Quitline Activities: A Literature Review (key words for PubMed search: tobacco quitline medication NRT cost-effectiveness promotion utilization) Published studies continue to demonstrate that free medication positively impacts quit outcomes and reach of tobacco quitlines, with some approaches more successful than others. (Am J Prev Med Oct;35(4): doi: /j.amepre Epub 2008 Aug 3. Tobacco quitline use: enhancing benefit and increasing abstinence. Campbell SL; Tob Control Dec;16 Suppl 1:i42-6. Offering free NRT through a tobacco quitline: impact on utilization and quit rates. Tinkelman D 1 ) The provision of combination NRT (the nicotine patch plus either the gum or lozenge) to quitline callers has further enhanced this treatment effect (Smith et al 2013). Quit outcomes for those randomized to either 2-weeks or 6-weeks of combined patch/gum were significantly higher for the both combined NRT cells than 2-week or 6-week patch only. Furthermore, experience shows that callers receiving NRT delivered via mail in a split shipment are more likely to complete more counseling calls those receiving their NRT in a single shipment. (16).

5 Earlier published studies demonstrated that the provision of free NRT increased call volume. Over the years callers may have come to view the provision of free NRT as an expectation in the range of services offered by state tobacco quitlines. To some degree smokers in states where NRT has been part of the QL landscape for some years may have become somewhat de-sensitized to the offer of free NRT. However, given the low overall utilization of tobacco quitlines it is quite likely that discontinuing free NRT would result in a decline in call volumes and decreased caller satisfaction, as well as harming quit outcomes. Callers to quitlines who use cessation medications are more likely to be abstinent from tobacco than those callers who do not use medications. This continues to be true despite the self-selection bias where those less dependent and more confident use no medications in their quit attempts and those who are more nicotine dependent and less confident in their ability to quit opt to use quit medications. )Tob Control Oct;14(5): Characteristics of selectors of nicotine replacement therapy. Shiffman S 1 ) Brief clinic-based interventions are effective but not reliably offered. Health care systems can effectively link patients with population-based treatment, such as quitlines. Access to evidence-based services that includes counseling and access to free NRT provides a feasible, cost-effective way to increase the reach of treatment. (Am J Prev Med Nov;41(5): doi: /j.amepre Offering population-based tobacco treatment in a healthcare setting: a randomized controlled trial. Rigotti NA) However another trial in a hospital setting resulted in lower use of medications and quitline services. Interest in quitting was high among smoking patients and hospital counselors fax-referred 56% to quitlines. At 6-months post-discharge 34% had used a quit smoking medication, but only 5% of those referred to the quitline reported using it. One recent study looked at whether personalized letters from primary care doctors advising their smoking patients to quit, along with a voucher for one month of nicotine gum would result in them making quit attempts. While calls to the quitline did not increase, about 9% of those receiving the letter did redeem their NRT voucher. The study showed that it was feasible for primary care doctors to encourage a quit attempt by sending a personalized letter and voucher for NRT, but doing so did not increase calls to the quitline. (J Prim Health Care Mar;2(1):4-10.Impact on quit attempts of mailed general practitioner 'brief advice' letters plus nicotine replacement therapy vouchers. Watson D 1 ) Showing how the offer of different types of medication might influence use of the quitline, the Montana State Quitline offered callers the choice between varenicline and NRT. Those who selected varenicline had a different demographic than those selecting NRT, with improved quit outcomes at 6 months (17% versus 11%). Those selecting varenicline completed more counseling calls than those selecting NRT. (Nicotine Tob Res Jun;12(6): doi: /ntr/ntq045. Epub 2010 Apr 8. Characteristics and abstinence outcomes among tobacco quitline enrollees using varenicline or nicotine replacement therapy. Biazzo LL) Vermont smokers (n=884) were called by random digit dialing to determine past and future use of treatment. Among those who had recently attempted to quit, 61% had ever used a treatment, 21% had ever used a psychosocial treatment, and 57% had used a medication. Among those who planned to quit in the next month, 68% stated they would use a treatment, 35% would use a psychosocial treatment, and 62% would use a medication. The major predictors of past or future use of treatment were greater cigarettes per day, older age, being a woman, and seeing a health professional. This survey suggested that many smokers have used or plan to use a smoking cessation treatment, however less than 10% of VT smokers who try to quit use the state quitline, counseling, or free medication provision. (J Subst Abuse Treat Jan;36(1): doi: /j.jsat Epub 2008 Jun 11.Interest in

6 treatments to stop smoking. Hughes JR.) The authors suggest that just because a service exists does not mean it will be used. On the other hand, the fact that 10% of Vermont smokers intend to use these services exceed the current 1%+ reach rate of tobacco quitlines in the U.S. tenfold. Appendix D is a list of publications and peer-reviewed articles that address use of pharmacotherapy for smoking cessation. It should be noted that many of these we not conducted in QL settings. Each article will need to be assessed for its relevance to the reader s needs. Integration of Tobacco Cessation Medications into Quitline Services is Cost Effective Pharmacologic interventions are proven to be additive to quitline counseling abstinence rates as documented above. Absolute costs of providing services do rise with the addition of medications. Quitlines need to determine if the value they bring across the entire spectrum of quitline services is worth the additional costs. Different medication types and durations of therapy will result in different quit outcomes. Quit outcomes will vary based on the population they are promoted within. Just because free medication are made available does not mean that quit rates will increase. Promoting free medications may attract more dependent callers than promotions where no medications were offered. The odds ratios for these different medications and durations are readily available (USPHS 2008) and from the Cochrane Review of pharmacological treatments (2013). Cost per quit are easily calculated taking the cost of treatment (counseling, medications, printed materials, etc.) and factoring it by the quit outcomes for various formulations. See the example below. Offering free OTC NRT via earned media may be a very cost-effective means of promoting a quitline compared to traditional unearned media. Free NRT serves two roles. First, it provides tobacco users considering a quit a free product that they would otherwise have to pay for. Secondly, the costs of the NRT are a treatment component and increase the percent of successful quit outcomes. The Guide to Preventative Community Services: The Community Guide: What Works to Promote Health ( provides an economic assessment of: Cost-effectiveness of providing quitline counseling and cessation information; Cost-effectiveness of adding cessation medications to existing quitline services; Cost-effectiveness of providing a combination of quitline counseling, nicotine replacement therapy (NRT), and media promotion More cost-effectiveness information can be found at the URL cited above or in Appendix C. Example: Fellows and colleagues prepared a cost-effectiveness analysis of the Oregon quitline program providing a free 2-week supply of nicotine patches (15). They compared the costs of promotion and intervention services before a free patch program to the costs for promotion and intervention services resulting from the free patch program. Cost per call and cost per quit could then be determined. Promotional costs prior to the free patch program were primarily television and radio advertisements, although the Centers for Disease Control (CDC) paid for the production costs, the quitline program costs included those for air time, talent fees paid to the actors, tagging of the ads with logos and phone numbers and duplication costs, and were an estimated total of $1,385,537 annually. The free patch program used no paid advertising. Instead, media kits were distributed to the counties that included fact sheets, news releases and a costs of smoking chart. They also made contact with various other state and

7 local agencies providing information about the program. Cost for this promotion was estimated to be $48,600. Intervention costs included a one 30- minute telephone counseling session at $91 and two weeks of the nicotine patch at $42.82 (price includes shipping). Guidelines for Determining Cost-Effectiveness There is an additional cost for providing medications to tobacco intervention programs however, it may prove to be cost- effective so long as the quit rates are increased sufficiently to justify the added expense. The Cochrane Review table (Table 1) provides odds ratios for each medication and combination of medication (compared to placebo) that can be used to determine cost-effectiveness. For heavily addicted smokers, medication is highly recommended to achieve a reasonable quit rate. For less addicted smokers, the use of medication may not be as critical. Most quitlines tend to attract highly-dependent smokers so the addition of medication to the treatment program is probably worthwhile. However a decision to add medications is often not easy to make since it adds expense to the overall program and may limit the number of smokers who can be served overall. Before making a final decision on medication integration, create a checklist and consider the following: 1. Determine the existing cost to market the quitline and deliver the existing services to the population being targeted. Estimate the potential increased number of calls that will occur from promotion of medications based on other quitlines experiences. Will the addition of medications increase reach enough to allow you to reduce current marketing costs and by what amount? Subtract added costs from the current costs to determine the incremental cost of adding medication (see #2 below). Will the additional costs bring sufficient value to the quitline to make it a good business decision? 2. Define the costs of administrative processes involved with setting up and maintaining the provision of medications to participants. This includes the obvious cost of the medication and mailing of the medication or voucher and any software and personnel time to directly manage the distribution. 3. Look carefully at all of the options available, many of which are discussed in this paper. For example: Direct mailing of medication or providing a voucher? Or provision of coupons for a discounted price on the medication? Offer medications only to populations with the greatest need rather than to everyone? 4. It can be helpful in the discussions of funding of medications to also include the savings from reduced healthcare costs that may be gained in the first year and subsequent years of tobacco abstinence to the governmental and health care organizations that may be funding the quitline. The USPHS Guideline provides a succinct review of cost-effectiveness and other economic outcomes of treating tobacco dependence (22). CONSIDERATIONS IN THE INTEGRATION OF TOBACCO CESSATION MEDICATIONS INTO QUITLINE SERVICES Does provision of medication fit within our quitline s strategic objectives?

8 There are two primary considerations that quitlines should consider in deciding whether or not to provide cessation medications, as well as some secondary considerations. The first is one of cost. While cessation medications will increase quit outcomes, utilization of the quitline and satisfaction with the services provided by the quitline, they will also add cost. Each quitline will need to decide whether their strategic vision is one of providing somewhat fewer callers with more comprehensive treatment, that is, both medications and counseling, or a potentially larger number of callers with less comprehensive treatment (counseling only) (USPHS Guideline 2008). For some, the increase in successful quit outcomes and higher satisfaction may offset the fact that they are able to serve fewer callers. In practice, most quitlines have tried to strike a balance between the number of callers they serve and the effectiveness of the treatment they provide. Providing 2-week or 4-week starter kits of OTC NRT may drive callers to the service, whereas providing no NRT may cause the service to be under-used. Quitlines who find themselves prematurely running short of funds during the fiscal year may decide to turn off the medication benefit in order to continue to provide more basic services throughout the remainder of the fiscal year. Doing this can cause some disruption and confusion among callers, as well as frontline staff, but if it is communicated well internally it can be an effective means of using a finite budget. Another consideration is somewhat philosophical - whether the quitline has adopted a public-private partnership model and has concerns that covering medications will undermine health plans and self-insured employers from doing so, putting further stress on limited quitline dollars. While the concern is valid, experience has not born this out, especially with the trend towards shorter regimens of NRT (starter kits). The return-on-investment (ROI) for tobacco cessation is well established. (PLoS One. 2012;7(1):e doi: /journal.pone Epub 2012 Jan 6.The return on investment of a Medicaid tobacco cessation program in Massachusetts.Richard P 1 ) There is a meaningful dose-response effect for durations of NRT longer than 2-weeks or 4-weeks that provide self-insured employers strong incentive to provide additional coverage for cessation medications. Health plans are also invested in the wellness of their consumers and have many have provided meaningful benefits for cessation medications. It is still unclear how the implementation of the ACA will impact quitlines. While the ACA does require that plans cover cessation services, what is covered is unclear and will very likely vary from plan to plan ( There may be an opportunity to synergize NRT starter kit coverage by quitlines, and coverage for the remaining regimen through the health plan. Leveraging bi-directional communication between health plans and quitlines using electronic health records may create opportunities to share the costs associated with tobacco cessation. State tobacco quitlines may serve as the portal to these services, or quitlines can provide the services and be reimbursed by the health plans. Some quitlines use a coordination of services model to triage inbound callers to services that provide the best coverage. These quitline vendors provide cessation services to self-insured employers and health plans as well. Using this model the vendor assesses whether the caller has health coverage through their employer or a health plan, and if they do, can enroll the caller in the program that provides the best coverage for counseling and cessation medications. Other considerations may include: 1. Role of Quitline: Some quitlines may see their role as limited to providing counseling, not medications. While fulfillment of medications is common in the U.S., it is much less common in other parts of the world. 2. Risk: Does the quitline want to assume the risk associated with sending out cessation medications? While the risk is minimal it is still there. It is one thing to provide information and facilitate access to cessation medications, but another to actually

9 mail them out. To do the latter, a quitline needs to provide good training and supportive infrastructure for their counselors. To be sure, fulfillment of OTC medications can be safely done, but it requires good systems support to be done well. 3. Resources: Does the quitline want to train counselors to provide medications? Training counselors and providing intervention support systems to safely and effectively provide medication decision support is not a small undertaking. On the other hand, the ability to address and dose cessation medication is considered a core competency by the Tobacco Treatment Specialist Standards of Practice (ATTUD). 4. Shipping: Does the quitline want to create fulfillment systems? Those quitlines who provide NRT typically do so using a fulfillment vendor. Inhouse fulfillment can be labor intensive, requiring space to safely and securely store costly medications and systematic shipping processes. Depending on the scale, in-house fulfillment can be costly which is why most use an qualified vendor. What determines which tobacco cessation medications our quitline should offer? Cost Nicotine patches, nicotine lozenges and nicotine gum are available in generic form and are among the least expensive medications available. Bupropion SR is also available as a generic at a very low cost but does require a prescription. With implementation of the ACA more and more quitline callers will have a medical coverage. However, seeing a doctor for an prescription medication will still be a cost factor due to deductibles and co-pays. Varenicline, nicotine nasal spray and nicotine inhaler are only available by prescription and no generics are available, making them the most expensive medications. For a detailed description of each FDA approved medication, including average cost, please refer to the USPHS Guideline (23) and individual medication package inserts. Cost of each medication varies widely depending on brand, geography, volume discounts, etc. Local pharmacies and national pharmacy benefit managers can provide more specific information. The cost of cessation medications are also affected by the regimen provided. Using 2-week or 4-week starter kits of OTC NRT, costs can be minimized. Using the Wisconsin quitline, Stevens Smith demonstrated that 2-weeks of combination NRT (2 weeks patch and 1 box of gum) produced higher ITT 7-day quit rates (48.2%) than either 2 weeks (38.4%) or 6 weeks of patch only (46.2%), and had a lower cost per quit ($442) than all other regimens (2 weeks patch $464; 6 weeks patch $505; and 6 weeks patch + 1 week gum $675). Effectiveness in Achieving Tobacco Abstinence The use of effective medications is obviously important. All of the FDA-approved medications have been shown to be effective in increasing smoking abstinence rates when used with some counseling compared to placebo. Meta-analysis tells us that some can be more effective than others. There are a few studies that have compared various medications to each other in terms of effectiveness in a given population. In two head-to-head trials varenicline demonstrated significantly higher abstinence rates than bupropion SR. (Harm Reduct J Sep 18;6:25. doi: / Efficacy of pharmacotherapies for short-term smoking abstinence: a systematic review and meta-analysis.mills EJ) Varenicline and combination NRT, such as patch plus gum, have similar effectiveness. There appears to be no added effect of adding bupropion SR to NRT. Different NRT products seem to be equally effective, while combination NRT is more effective than any single form of NRT. Cytisine may prove to be a low-cost medication, but is not FDAapproved in the U.S. (Cochrane Review. Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 2013 Cahill K. Issue 5) The Cochrane Review published a meta-analysis of multiple studies in T h i s i s t h e m o s t r e c e n t m e t a - a n a l y s i s o f m e d i c a t i o n e f f e c t i v e n e s s t h e a u t h o r i s a w a r e o f. The odds ratios (OR) of all medication were compared again placebo. Meta-

10 analysis are useful when looking at a group of studies, but the results need to be carefully evaluated for application in quitline settings when being considered. 1. Although meta-analysis attempts to adjust for such factors the studies compared used different populations of study participants varying by such factors as amount smoked, age, geography, counseling intervention used, duration of treatment and year performed. 2. All of the reported findings are from clinical research studies involving multiple face-to-face contacts, usually including behavioral counseling, with the participants. The number of these contacts sometimes greatly exceed those offered by most quitlines. 3. Integration of Rx medications into a quitline setting can be more challenging than OTC medication. Because there is always a medical prescriber in the loop the quitline counselor will need to use caution to avoid contradicting the advice given by the health care provider and thereby undermining the physician-patient relationship. Prescription medications usually have more potential side effects and drug interactions. Each quitline will have to determine to what degree it is comfortable with regard to the scope of medication support provided by counselors. Table 1: Network meta-analysis of first-line pharmacotherapies versus placebo and versus each other, with NRT split by type

11 Adapted from Pharmacological interventions for smoking cessation: an overview and network meta-analysis (Review) 2013 Cahill K. Issue 5 Implications for practice 1. Both NRT and bupropion perform similarly compared with placebo in helping people to quit (odds ratios (ORs) of 1.84 (95% CredI 1.71 to 1.99) and 1.82 (95% CredI 1.60 to 2.06) respectively).

12 2. Different types of NRT are generally equally effective. 3. Combinations of NRT outperform single formulations (versus patch: OR 1.43 (95% CredI 1.08 to 1.91); versus gum: OR 1.63 (95% CredI1.21 to 2.20); versus other : OR 1.34 (95% CredI 1.00 to 1.80)). 4. Varenicline is more effective than NRT or bupropion, when each is compared with placebo (varenicline vs placebo OR 2.88 (95% CredI 2.40 to 3.47)). 5. Varenicline is superior to any single type of NRT, and is as effective as combinations of NRT (OR 1.06 (95% CredI 0.75 to 1.48)). 6. Varenicline outperforms bupropion in head-to-head comparisons (OR 1.59 (95% CredI 1.29 to 1.96)). 7. NRT combined with nortriptyline or with bupropion is not shown to be more effective than NRT alone. 8. Cytisine increases the chances of quitting compared with placebo, without significant adverse or serious adverse events (RR 3.98 (95% CI 2.01 to 7.87)) 9. Nortriptyline approximately doubles the chances of quitting (RR 2.03 (95% CI 1.48 to 2.78)). 10. Bupropion demonstrates no excess of neuropsychiatric events (RR 0.88 (95% CI 0.31 to 2.50)) or of cardiovascular events (RR 0.77 (95% CI 0.37 to 1.59)). 11. Varenicline demonstrates no excess of neuropsychiatric events (RR 0.53 (95% CI 0.17 to 1.67)), and a marginal but non-significant increase in cardiovascular events (RR 1.26 (95% CI 0.62 to 2.56)). Combination NRT is arguably the standard of care when considering the nicotine patch, gum, or lozenge. Combinations of a long-acting form of NRT (nicotine patch) along with a short-acting form of NRT (gum or lozenge) consistently out-perform single forms of NRT in reducing nicotine withdrawal symptoms and producing higher quit outcomes. With the removal of the do not use more than one form of nicotine replacement product at a time warning from OTC NRT packaging, quitlines are free to provide combination without concerns of off-label use. Ease of Use Effectiveness of any medication is dependent on the medication being used correctly, including at the recommended frequency and duration. (This is referred to as adherence). Medications that are administered once or twice a day are more likely to be taken as directed than medications that need to be taken multiple times each day. Complexity of administration can also affect adherence. For example, to maximize the effectiveness of the nicotine gum it must be chewed several times after which the gum is to be parked against the side of the mouth to allow absorption of the nicotine. After a few minutes the user is to chew again and repeat the cycle several times for minutes, at which time the gum is discarded. This is much more complex than applying one nicotine patch to the skin once a day. If it is more difficult to adhere to a more complicated regimen reduced effectiveness of the medication is likely to result in poorer quit outcomes among some users. When providing any cessation medication quitlines should have protocols to advise on correct use to optimize medication adherence. Callers to the quitline may say they know how to use the medications, but when asked to describe how they are to be used, they often respond incorrectly. Even a nicotine patch that is applied once a day needs to be applied correctly above the waist and below the neck, and rotated daily avoiding the same location for at least seven days. While it is important to provide detailed use instructions at the time of dosing it is even more important to ask the caller during ongoing calls to describe how they are using the medication, reinforcing proper use and offering corrective advice to those who are using their medication incorrectly. When callers say a medication is not working, further examination shows more often than not that they are either using it

13 incorrectly or at the wrong frequency. Ease of Distribution Legal and procedural issues related to over-the-counter and prescription medications are usual key factors in determining how complex distribution of medication to callers will be. A process for distributing over-the-counter medications will be much simpler as there is no need to add the steps necessary to engage a licensed provider to write a prescription. With prescription medications multiple steps with clear communication to the tobacco user and his or her physician are required. Safety and Frequency of Side-Effects Closely tied to adherence is the potential of the medication to cause adverse effects (unwanted side-effects). Prescription medications typically have more side effects than OTC NRT. The type of side-effect, their frequency and their severity can influence use of medication by the caller. Quitlines will want to consider these characteristics in choosing medication for distribution to minimize liability concerns over adverse events and maximize effectiveness of the medication through improved adherence. It should be noted that callers will frequently assign many symptoms to their use of a medication that may have nothing to do with the medication itself, and may simply be coincidental or an idiosyncratic symptom associated with quitting tobacco. Quitline counselors should be knowledgeable and have available support resources to guide them in discussing the side effect profiles of medications as well as common symptoms of nicotine withdrawal in order to know when to refer the caller to see their health care provider and when to normalize the symptom as common among those quitting tobacco. Most minor symptoms reported by those using NRT resolve themselves quickly, and may be addressed by suggesting changes to the dosage or helping the caller to use the medication correctly. Nicotine Replacement Therapy (NRT) Most quitlines providing medications are distributing the over-the-counter NRT medications that include the nicotine patch, nicotine gum and nicotine lozenge, individually or in some combination. Almost all of the reported studies of medications and quitlines concern nicotine patches and/or nicotine gum. Proven effectiveness, generic medications at lowest cost, low side-effect profiles, ease of use and no requirement for a prescription make these medications most appealing in the quitline setting. Most callers, when given the choice, will choose to use the nicotine patch. The most common side effects from the nicotine patch is local skin irritation, which is easily managed by daily rotating the patch to a different site, avoiding putting the patch in the same location for at least seven days. Side effects associated with the nicotine gum and lozenge are most commonly associated with incorrect chewing or swallowing of nicotine by aggressive sucking on the lozenge. These are minor and include upset stomach and hiccups. The greatest concern are not the side effects but the fact that nicotine is poorly absorbed when the gum or lozenge are incorrectly used, and can result in higher levels of cravings to use tobacco. Bupropion SR (Zyban, Wellbutrin SR ) According to the 2012 NAQC Annual Survey of Quitlines, three state quitlines provides bupropion SR as a medication option to its callers. There is one published study of tobacco abstinence outcomes with the use of bupropion SR and quitline counseling conducted within a health plan setting (20). Physicians affiliated with the quitline were the prescribing physicians of record and an office visit with their primary care physician was not required if the caller passed an extensive phone interview that excluded certain medical conditions. Use of either 150 mg/day or 300 mg/day doses of bupropion SR resulted in substantial abstinence rates, with moderate to intensive telephone counseling enhancing the outcomes of both doses. The most common side effect is insomnia (trouble sleeping) which has been reported to occur in about one third of people who take the medication. Less common adverse effects include dry mouth, anxiety and hypertension. There is a slight risk of seizures (approximately 1/1000) which can be minimized further with careful

14 screening of participants for contraindications to its use, although meta-analysis has shown seizure occurrence of less than 1:1500 (Cochrane Review 2013). This includes a history of: seizures, closed head trauma, brain surgery or strokes and the eating disorders of anorexia nervosa and bulimia. Recently the FDA has required a boxed warning regarding bupropion SR and its association with psychiatric symptoms with its use (see further discussion below) (28). Varenicline (Chantix ) NAQC 2012 data also showed that three quitlines currently report offering varenicline as a medication option. Varenicline was approved by the FDA for use in 2006 and is available only by prescription with no generic equivalent available until the patent expires in Clinical trials have demonstrated increased efficacy for smoking cessation compared to placebo and bupropion (29, 30). There appear to be no drug interactions with varenicline and except for a dosage adjustment in the setting of renal failure, there do not appear to be any medical contraindications to its use. Nausea and sleep disturbances such as vivid dreams and insomnia are the most frequently reported side-effects. The FDA recently issued a boxed warning regarding use of varenicline and the risk of developing serious psychiatric problems (see further discussion below). In a recently published preliminary analysis of the use of varenicline in a quitline study 17% discontinued medication prematurely, about one-half due to side effects and other symptoms. However, those who received telephone counseling (compared to web-based support) were less likely to have discontinued their medication (31). Thus, there are more risk management issues with use of varenicline in a quitline setting than with other, more established medications. As noted earlier, the Montana State Quitline offered callers varenicline. Those who selected varenicline had a different demographic than those selecting NRT, with improved quit outcomes at 6 months (17% versus 11%). Those selecting varenicline completed more counseling calls than those selecting NRT. (Nicotine Tob Res Jun;12(6): doi: /ntr/ntq045. Epub 2010 Apr 8.Characteristics and abstinence outcomes among tobacco quitline enrollees using varenicline or nicotine replacement therapy. Biazzo LL) Alere Health (formerly Free & Clear) has provided decision support for bupropion and varenicline to callers from self-insured employers and health plans since 1999 and 2006, respectively. While Alere does not mail out prescription medications, the phone counselors do conduct a behavioral assessment of relevant medical conditions and medications with those interested in using these medications following a tightly scripted computerized set of questions. Each caller is provided a written summary of information about the medication for themselves and one for their health care provider who will make the decision whether the medication is medically suitable for their patient. Communication is made with pharmacy benefit managers, as needed, to provide coverage should the health care provider approve the medication. Boxed Warnings for Bupropion SR and Varenicline (28) The FDA can require Boxed Warnings be included in prescribing information when there is post marketing surveillance evidence that use of the medication has been associated with serious adverse effects. This mechanism is meant to heighten the awareness that these effects could occur. It does not mean the medication should not be used for its intended purpose. They are usually based on adverse reactions reported by physicians, pharmacists and people who have used the medications. In July 2009, the FDA issued this warning because of increased reports of neuropsychiatric symptoms in people using these medications to stop smoking (28). The symptoms included changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, attempted suicide and completed suicides. These could occur in people with or without a history of mental illness, and whether they had stopped smoking or not. With the boxed warning, healthcare providers are to advise patients, family members and caregivers of the potential

15 for these symptoms and if they develop to stop the medication immediately and contact their health care provider. Patients are also to be advised to use caution when driving, operating machinery or involved in other hazardous activities until they know how the medications affect them. As consideration is given regarding provision of these medications by quitlines, two important points should also be entertained: 1. The 2013 Cochrane Review of pharmacological treatments states that: Bupropion demonstrated no excess of neuropsychiatric events (RR 0.88 (95% CI 0.31 to 2.50)) or of cardiovascular events (RR 0.77 (95% CI 0.37 to 1.59)). Similarly, Varenicline demonstrated no excess of neuropsychiatric events (RR 0.53 (95% CI 0.17 to 1.67)), and a marginal but non-significant increase in cardiovascular events (RR 1.26 (95% CI 0.62 to 2.56)). 2. Many of the symptoms described are symptoms typically seen in people who are trying to stop smoking and are experiencing nicotine withdrawal. This confounds the interpretation of the reports. These reports are further confused by the fact that anyone can make the report, and the same incident can be reported by several different persons. Recently published studies have shown no significant differences between use of bupropion SR and varenicline, or placebo. Cochrane Database Syst Rev Feb 28;2:CD doi: / CD pub3.Interventions for smoking cessation and reduction in individuals with schizophrenia.tsoi DT JAMA Jan 8;311(2): doi: /jama Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial.evins AE 3. The possible risks of serious adverse events that might occur using either of these medications should also be weighed against the significant health benefits of quitting smoking and known risks of continued smoking. Simultaneous Use of More Than One Tobacco Cessation Medication Certain combinations of medications have been shown to be more effective than use of one medication alone; e.g. nicotine patch and nicotine gum or nicotine patch and bupropion SR (33) The first published trial comparing combination patch & gum with patch only in a quitline setting showed combination NRT significantly more effective than patch- only.(stevens Smith 2012). While the Clinical Practice Guideline 2008 gave combined NRT a strong recommendation, OTC NRT labeling was not updated until October of Among other changes the revised labeling eliminated the do not use more than one form of NRT simultaneously, implicitly endorsing combining two forms of NRT. Based on extensive scientific evidence demonstrating improved quit outcomes and no significant increase in serious adverse reactions combinations of patch and gum or patch and lozenge are commonly encouraged by some quitline vendors. Some clinicians have been combining NRT with varenicline, and while both medications are FDA approved for smoking cessation, and the two drugs appear to be well tolerated when taken together, to-date there is no empirical evidence to demonstrate improved efficacy.(nicotine Tob Res May;11(5): doi: /ntr/ntp042. Epub 2009 Apr 7.Combination treatment with varenicline and nicotine replacement therapy. Ebbert JO) Use of multiple patches (high dose patch exceeding 21mg) (Nicotine Tob Res Jan;9(1):43-52.Effect of high-dose nicotine patch therapy on tobacco withdrawal symptoms among smokeless tobacco users. Ebbert JO) and use of three or more cessation medications have been used in clinical care but such