Addiction (2000) 95 (Supplement 1), S29± S34

Addressing regulatory barriers to licensingnicotine products for smoking reduction

ROBERT WEST

Department of Psychology, St George’s Hospital Medical School, London, UK

Abstract

This paper examines the current regulatory obstacles to extending the permitted use of NRT, and to includesmoking reduction ways of addressing these. There are major differences between different countries in

regulations concerning NRT. These differences appear to be due to different attitudes to cigarette smoking as

an issue and different preconceptions about nicotine as an addictive and potentially toxic drug. The paperconsiders how existing WHO and American Psychiatric Association de® nitions of mental disorders may be

used in submitting proposals for use of NRT as an aid to smoking reduction and how concerns over safety

and abuse and dependence liability can be addressed. It also examines what new evidence may be needed.Coordinating the efforts of the pharmaceutical industry, clinicians and researchers will probably be important

in moving regulatory authorities further in the direction of accepting NRT for widespread use in smoking

reduction.

Introduction

Cigarette smoking is the leading preventablecause of premature death in our society.Cigarette smoking substantially increasesthe risk of cardiovascular disease,1 and is themajor cause of lung cancer.1 There are currentlyan estimated 1 billion smokers world-wide,1

and it is imperative that increasing efforts aremade to reduce tobacco-related morbidityand mortality. The health bene® ts associatedwith smoking cessation are well established,2

so an important way of reducing overall tobacco-related harm is to increase smoking cessationrates.

Nicotine replacement therapy (NRT) plays animportant role in aiding smoking cessation3 andhas been estimated as more than 10 times ascost-effective as most other life-preserving medi-cal interventions.4 Evidence suggests that theef® cacy of NRT is similar whether or not its use

is supervised by physicians (who are not smokingcessation specialists).5 Existing forms of NRT donot appear to have signi® cant abuse liability ordependence potential [e.g.5] and have a verygood safety record.6 Therefore it can be arguedthat there is considerable public health bene® t tobe gained by encouraging as many smokers aspossible to use NRT during their cessation at-tempts.7

Even with the widespread availability of NRTthe large majority of quit attempts will fail. Bestestimates put success rates for cessation usingNRT (outside of clinical trials and with no coun-selling or support) at around 6± 8%5 and even ifsmokers make repeated attempts to stop, therewill still be a substantial proportion of smokerswho continue to smoke until they die, quitepossibly from a smoking-related disease. Forsuch individuals an alternative, and important,approach may be to reduce exposure to tobacco

This paper is based on a presentation at the SRNT Satellite Symposium `Smoking reduction: from theory topractice’ , Copenhagen, 24 August 1998.

Correspondence to: Professor Robert West, Department of Psychology, St George’ s Hospital Medical School,Cranmer Terrace, London SW17 0TR, UK.

Submitted 17th March 1999; initial review completed 27th April 1999; ® nal version accepted 25th May 1999.

ISSN 0965± 2140 print/ISSN 1360-0443 online/00/01S029± 06 Ó Society for the Study of Addiction to Alcohol and Other Drugs

Carfax Publishing, Taylor & Francis Limited

S30 Robert West

smoke and it has been suggested that NRT canbe used to help with this [e.g.8].

A case can be made for bringing all nicotineproducts, including cigarettes, under the aegis ofa single regulatory authority so that regulationsconcerning access to them can take account oftheir relative toxicity. In the meantime, however,it will be necessary to convince existing authori-ties that access to NRT products should bewidened. When it comes to extending the use ofNRT for smoking reduction, still further obsta-cles present themselves and it may be that newevidence will need to be gathered.

This paper examines existing regulatory obsta-cles to extending use of NRT to include smokingreduction. It considers how these obstacles canbe overcome, bearing in mind that they appearto arise in part from preconceptions and misun-derstandings about nicotine and smoking.

The current situation

There are three key elements to the regulation ofmedicines: access, appropriate use (`indications’ )and labelling (which includes duration of use,contra-indications, precautions, side effects anduse of concurrent medication). This sectionbrie¯ y outlines the ® rst two of these.

Access to NRTThere are three main categories of licence formedications, not all of which are available in allcountries:

· prescription only Ð requiring involvement of amedical practitioner;

· over-the-counter from a pharmacistÐ held be-hind the counter; and

· over-the-counter/general sales Ð on open-ac-cess shelves in pharmacists, supermarkets orany other store.

From a public health perspective the last of theseis probably the most appropriate for NRT for thereasons given earlier, but in most countries ac-cess to NRT is far more restricted. In the UK,nicotine patches, nicotine 2 mg and 4 mg gumand the nicotine inhalator (inhaler) are availablefrom pharmacists without prescription. At thetime of writing, the Medicines Control Agencyhas approved an application for nicotine gum tobe available on general sale and this is expectedto be implemented later in 1999. By the time this

paper appears, it is highly likely that nicotinegum will be available on general sale and widelystocked in supermarkets and possibly even to-bacconists. The nicotine nasal spray is availableon prescription only. Having most forms of NRTavailable without prescription in the UnitedKingdom has almost certainly widened the userbase and currently about 25% of cessation at-tempts involve NRT.9 Unlike the United States,the United Kingdom has not required extensivemonitoring of abuse and dependence. In someother European countries NRT is only availableon prescription.

Accepted uses for NRTUnfortunately there is a lack of uniformity fromcountry to country, even within the EuropeanUnion, with regard to what is an approved usefor NRT. The UK Medicines Control Agencyhas not historically accepted that smoking is amedical condition. Thus, `aiding smoking cess-ation’ has not been the approved indication forNRT in the UK; rather it has been `control ofwithdrawal symptoms during a cessation at-tempt’ . This is different from the US situationwhere speci® c smoking cessation criteria areused (4 weeks of smoking abstinence starting2 weeks after the quit date) to establish ef® cacy.In other countries `treatment of nicotine depen-dence’ is the indication. To date, Denmark is theonly country that has accepted aid to smokingreduction as a legitimate use, and even thereonly short-term use as a prelude to cessation isallowed.

De® ning smoking reduction

This section examines what is meant by smokingreduction and how this would translate into abroadening of indications for NRT. It is import-ant to understand that there may be differentways in which smoking reduction can beachieved (Table 1). It may or may not involveperiods of abstinence and may or may not in-volve a reduction in number of cigarettes con-sumed. The ultimate objective is simply toreduce exposure to tobacco smoke. Thus NRTcan be used during voluntary or enforced short-term periods of abstinence, which may range induration from minutes on an underground trainto hours on a transatlantic ¯ ight. Some airlinesalready offer nicotine replacement products for

What can be achieved? S31

Table 1. Possible forms of smoking reduction

Category of smoking reduction Example

Short periods of voluntary abstinence A smoker may wish to reduce risk by not smoking during the dayand using NRT to help with this

Short periods of enforced abstinence A smoker may be unable to smoke in the of® ce and use NRT tocope with withdrawal during this time reducing the need to goout for cigarette breaks

Reductions in cigarette consumption A smoker may intersperse NRT and cigarettes to reduce cigaretteconsumption

Reductions in smoke intake from cigarettes A smoker may use a patch to reduce the need for nicotine so thatcigarettes are smoked less intensively

the purpose of preventing tobacco-withdrawalsymptoms experienced during periods ofshort-term abstinence. Also, a smoker concur-rently using NRT might smoke fewer cigarettesor might inhale smoke from each cigaretteto a lesser degree. It is also worth noting thatNRT may also be used as a prelude to cessation,which should be distinguished from inde® niteuse.

When one considers the existing approveduses of NRT and the possible harm reductionuses, the full range of possible uses for NRT areas follows:

1. Control of withdrawal symptoms during acessation attempt (symptom relief).

2. Aiding smoking cessation (primary or second-ary prevention).

3. Control of withdrawal symptoms during en-forced abstinence (symptom relief).

4. Aiding smoking reduction (primary or sec-ondary prevention).

However, `uses’ are not the same as `indications’ .An indication, from a regulatory point of view,generally involves a speci® c medical conditionthat a medicine can be used to treat. This raisesthe issue of what is the de® nition of a medicalcondition for this purpose. This issue is dis-cussed below.

Obstacles to acceptance of NRT for smoking

reduction

There are many obstacles to extending the indi-cations for NRT to include smoking reduction.Some of these are also relevant to wideningaccess to NRT and both of these issues will beaddressed in this section.

Finding a suitable indication

In disallowing smoking as a medical condition,the UK’s MCA could be argued as acting incontravention of the World Health Organiza-tion’ s international classi® cation of diseases,ICD-10. ICD-10 recognizes `mental and be-havioural disorders due to use of tobacco’ as aclass of diseases and includes `harmful use’ , `de-pendence syndrome’ and `withdrawal state’ asindividual diseases.10 It is interesting to note that`harmful use’ is included. No speci® c de® nitionof this term is adopted for tobacco, only a gen-eric one relating to substance use, but cigarettesmoking per se would fall within its purview giventhat any amount of cigarette smoking is clearlylinked with a variety of fatal diseases. Thus ICD-10 could provide a rational and widely acceptedbasis for both cessation and smoking reductionindications.

Whether or not it is necessary to work withinthe framework of disease classi® cation systems isa moot point. It is an interesting irony that theUS Food and Drug Administration acceptssmoking cessation as an indication although theAmerican Psychiatric Association’ s Diagnosticand Statistical Manual (DSM-IV) does not ex-plicitly recognize `cigarette smoking’ or even `to-bacco use’ as a disease.11 DSM-IV recognizestwo tobacco-related mental disorders: `nicotinedependence’ and `nicotine withdrawal’ . Both ofthese require more than that the person be aregular cigarette smoker. Although most smokerscould be presumed to be dependent on nicotine,arguably one would have to glean more infor-mation than simply smoking habits to make adiagnosis. Smokers would require three or moreof: tolerance; withdrawal syndrome; use of thesubstance for longer or in higher quantities thanintended; persistent or unsuccessful efforts to cut

S32 Robert West

down; a great deal of time spent obtainingcigarettes, using cigarettes or recovering fromtheir effects; giving up activities because ofcigarettes; using cigarettes despite knowledge ofharmful effects. A smoker who has not gonewithout cigarettes for a single day sincestarting smoking would not have an opportunityto score on two of these and two others are, asde® ned, dif® cult to apply to cigarette use. Forthe remainder, there is a question about whetherthey could be presumed or whether speci® cquestions or tests would need to be administeredto check.

The other DSM-IV disease, `nicotine with-drawal’ , offers some promise as a basis for aharm reduction indication. There is a well-recog-nized withdrawal syndrome11 associated withcigarette smoking which has a relatively rapidonset and appears whether or not an individual istrying to stop smoking. A temporary period ofabstinence, whether enforced or voluntary, couldbe expected to be accompanied by this syn-drome. Thus, for example, the current UK indi-cation of `withdrawal relief associated withsmoking cessation’ could move some way to-wards a goal of harm reduction simply by omit-ting the phrase `associated with smokingcessation’. However, more data may be needed,such as how quickly do withdrawal symptomsbegin to appear? Do we know to what extentthese acute withdrawal symptoms can be treatedwith particular NRT products? It may be thatthe regulatory authorities would request moreevidence regarding the effect of, for example,nicotine gum versus the patch with respect to theacute relief of withdrawal symptoms over shortperiods.

Acceptance of ef® cacy evidence

There is extensive evidence that NRT approxi-mately doubles successful smoking cessationrates compared to willpower alone.3 In addition,there is some evidence to suggest that NRT canhelp smokers to achieve signi® cant reductions incigarette smoking.12 However, the importantpublic health goal is long-term, sustained smok-ing reduction and, to date, there are insuf® cientdata on which to base conclusions about long-term reductions.13 There is also a question aboutthe extent to which current data on smoke ex-posure will translate into health bene® ts, particu-larly if the dose± response curve for any

nicotine-related health risks is not linear. Forexample, small amounts of nicotine have similareffects on heart rate to larger amounts.14 It is notknown if this has implications for cardiovasculardisease risk but it may need to be considered.Long-term clinical trials may therefore be re-quired by regulatory authorities in order to pro-vide scienti® c evidence of the clinical bene® tsresulting from smoking reduction. Equally im-portant, there is a real issue as to the extent towhich reductions achieved are attributable tonicotine in the NRT products. At the time ofwriting we do not yet have the weight of evidencefrom placebo-controlled studies to bring to bearon that issue.

Safety

In discussions with regulatory authorities, con-cerns regarding the safety of NRT are raisedrepeatedly. While it is true that nicotine is aneurotoxin, NRT products are much safer thanthe most widely used source of nicotine, i.e.cigarettes. In this respect, it is important to citethe huge amount of data now available from theUnited States.5 The point that needs to be em-phasized is that there is now so much experiencewith NRT use in large populations that specu-lation and surmise about adverse health effects ofNRT must give way to hard evidenceÐ and theevidence clearly indicates that the products aresafe.

Abuse liability and dependence potential

Nicotine per se has been labelled by some asaddictive without any quali® cation in terms ofpharmacokinetics and the rate of delivery fromdifferent products. It is therefore necessary topresent to regulatory authorities evidence thatthe rate of absorption from any given nicotine-containing product is an important factor, andthat those products that slowly deliver relativelylow doses of nicotine are much less addictivethan cigarettes. Indeed, extensive monitoring ofthe nicotine gum and patch has been carried outin the United States, and there is no evidence ofsigni® cant abuse.5

Paradoxically, under the current regulatorysystem nicotine replacement products that mayturn out to be more effective in aiding cessationand smoking reduction are probably less likelyto satisfy safety requirements. It may assist

What can be achieved? S33

regulatory authorities if evidence for each NRTproduct is presented separately. For example,concern has been expressed that the inhalatormight have a higher abuse liability than otherNRT products because nicotine is inhaled andthe action of smoking is being mimicked. In fact,nicotine is not delivered to the lungs and evi-dence indicates abuse and dependence liabilitysimilar to that of the gum, which is consistentwith its nicotine delivery pro® le.15

Comparability of labellingRegulatory authorities are apparently concernedabout the issue of comparability across labellingand statements that are made about the differentNRT products. Thus, if one brand of patch hasdraconian wording with regard to safety andprecautions, there is a tendency not to allownewer applications to `get away with’ ones thatmore lax. Similarly, if one brand of NRT hasspeci® c wording regarding accepted uses there isa tendency not to allow new products a wider setof uses even though there may be evidence tosupport this. The problem with this approach isthat when applications for modi® cations to thelabelling or indications are received one at atime, there is a strong tendency for inertia. Thiscould be addressed by preparing the ground forapplications by challenging the principle ofoverly draconian labelling requirements and re-strictive uses. This is something that can be donethrough a concerted approach of the pharmaceu-tical industry together with support from inde-pendent experts.

Professional interests

In the context of wider use and supply of NRT,professional and commercial interests also needto be addressed. Permitting NRT is to be usedby smokers in the long term as a way of cuttingdown on cigarettes further strengthens the argu-ment for widening access to it beyond pharma-cies. Many pharmacists may be concernedbecause they would see themselves losing busi-ness. While this concern is understandable, thepharmacists’ case must be based on a demon-stration that any increase in the usage of NRTthat would occur from broadening access wouldbe offset by a reduction in the effectiveness ofNRT used. At present that information is notavailable. Indeed, such evidence that exists with

regard to smoking cessation suggests that NRTis broadly as effective when used without super-vision as when used with it.3, 5

There may also be an issue of other healthprofessionals wishing to retain control of treat-ment for smoking and in that case there may beresistance to increasing access to NRT. How-ever, the onus should clearly be on these healthprofessionals to demonstrate added value beforeusing this argument to restrict access to NRT.

Concerns over reduction in cessation attemptsIncreasing access to NRT, and the advertisingand publicity surrounding the products, wouldbe expected to increase the number of cessationattempts made each year. However, it is plaus-ible that approving NRT for smoking reductionmay lead to a reduction in quit attempts. Thus ifsmokers believe that they can bring their riskswithin acceptable limits by reducing their smok-ing, perhaps they would be less motivated to stopaltogether. This is a valid concern in principlebut may not be a problem in practice. Perhapssurprisingly, smokers who have been involved insmoking reduction studies have shown an in-crease rather than a decrease in motivation tostop [e.g.12]. If this trend is borne out in furtherstudies, it suggests that far from militatingagainst cessation attempts, smoking reductionmight actually give them a boost. One possibleexplanation for this is that smokers who areinitially reluctant to make a quit attempt may begiven con® dence that this is a real prospect by apositive experience of use of NRT in helpingthem reduce their smoking. On the other hand,presentation of the idea of reduction in the me-dia and advertising may well be important indetermining whether quit attempts are fore-stalled by promotion of products aimed to helpwith reduction. The use of terms such as `lowtar’ or `light’ for cigarettes with reduced taryields when smoked using of® cial smoking ma-chines may have reduced quitting in smokerswho mistakenly believe that these are safe.

Conclusions

Many of the regulatory obstacles that exist in theimmediate term are country-speci® c. Differentcountries have approved different indications forNRT use and are applying different criteria to

S34 Robert West

judgements of safety and ef® cacy. In most cases,these are not based on different assessments ofthe evidence base, but rather on differences inregulatory structures, attitudes to and precon-ceptions about nicotine.

It should be possible to move countries withmore restrictive licensing regulations towardsones that allow greater ¯ exibility and availability,but it will be important to anticipate concerns,present clear evidence to address those concernsand enter a dialogue to ensure that preconcep-tions are corrected. The preconceptions sur-rounding nicotine as a toxic and addictive drugneed to be understood and dealt with globally.

Moreover, there is a need to anticipate anyconcerns that may be raised when submittingapplications for NRT products to regulatory au-thorities so that issues can be dealt with beforethey arise. If scienti® c evidence is not yet avail-able in order to address speci® c concerns, then itneeds to be collected.

Finally, a concerted approach to the regulatoryauthorities is required from the pharmaceuticalindustry, scientists and clinicians. Use of NRT isapproximately one-tenth of what it could beworld-wide. From a public health point of view,most probably smoking cessation attemptsshould involve NRT because of its provenef® cacy and in future NRT may well be a valu-able tool to aid smoking reduction. There is noquestion that, in so far as NRT replaces tobacco,the public health bene® ts could be immense. Torealize the full potential of NRT it will be necess-ary to work with regulatory authorities to achievea consensus on the bene® cial, safe and appropri-ate use of NRT.

Declaration of interest

Dr West has undertaken research and consul-tancy for, and received travel funds from, phar-maceutical companies that supply nicotinereplacement products and other products forsmoking cessation.

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