Nicotine Inhaler Adverse Events Associated with NRT

11.1.9.5 Nicotine Sublingual Tablet

The฀nicotine฀sublingual฀tablet฀may฀cause฀irritation฀or฀soreness฀in฀the฀mouth฀or฀throat,฀hic- cups,฀ nausea,฀ gastrointestinal฀ discomfort,฀ dry฀ mouth฀ or฀ cough฀ [66,฀ 67] .฀ Most฀ AEs฀ are฀ generally฀mild฀and฀occur฀soon฀after฀commencing฀treatment,฀and฀the฀incidence฀diminishes฀ as฀treatment฀continues.฀Use฀of฀nicotine฀sublingual฀tablets฀for฀6฀months฀has฀no฀adverse฀ effect฀on฀the฀oral฀mucosa฀or฀the฀loor฀of฀the฀mouth฀ [67] .

11.1.9.6 Nicotine Lozenge

The฀nicotine฀lozenge฀was฀tested฀in฀one฀study฀with฀1,818฀smokers฀ [11] .฀61.8฀of฀partici- pants฀reported฀one฀or฀more฀adverse฀effects฀during฀6฀months.฀Severe฀adverse฀effects฀were฀ experienced฀by฀17฀of฀the฀participants฀headache,฀diarrhoea,฀latulence,฀heartburn,฀hiccup,฀ nausea,฀coughing.฀However,฀detailed฀information฀about฀the฀frequency฀of฀adverse฀effects฀ will฀be฀available,฀if฀larger฀treatment฀numbers฀are฀reached.

11.1.10 Withdrawal Symptoms

Withdrawal฀symptoms฀vary฀in฀severity฀from฀person฀to฀person฀and฀may฀last฀for฀several฀ weeks฀to฀months.฀Like฀alcoholics,฀many฀ex-smokers฀are฀severely฀at฀risk฀because฀the฀least฀ cause฀going฀to฀a฀restaurant฀and฀having฀an฀alcoholic฀drink,฀meeting฀up฀with฀smokers,฀stress฀ situations฀may฀trigger฀a฀return฀to฀smoking.฀Many฀smokers,฀however,฀“merely”฀miss฀the฀ manual฀cues฀associated฀with฀the฀activity฀of฀smoking.฀Withdrawal฀symptoms฀are฀commonly฀ misinterpreted฀as฀AEs฀of฀nicotine฀products฀Table฀ 11.4 ,฀especially฀where฀the฀symptoms฀ are฀of฀a฀psychological฀nature. Very฀rarely฀a฀drug-induced฀dependence฀reaction฀may฀also฀develop฀during฀the฀course฀of฀ smoking฀cessation฀therapy฀with฀nicotine฀preparations.฀In฀these฀circumstances,฀ex-smokers฀ become฀dependent฀on฀the฀nicotine฀preparations฀themselves฀nasal฀spray฀฀chewing฀gum฀ and฀then฀frequently฀continue฀to฀use฀these฀products฀over฀a฀period฀of฀months.

11.1.11 Drug Interactions During Smoking Cessation

No฀systematic฀studies฀have฀been฀conducted฀on฀interactions฀between฀nicotine฀and฀other฀ concurrently฀administered฀medication.฀The฀metabolic฀processes฀in฀the฀liver฀are฀stimulated฀ principally฀by฀the฀combustion฀products฀of฀tobacco฀and฀not฀by฀nicotine.฀Tobacco฀smoke฀ induces฀the฀cytochrome฀P450฀enzymes฀CYP1A1,฀CYP1A2฀and฀possibly฀CYP2E1฀ [68] .฀ Smokers฀therefore฀metabolise฀various฀drugs฀more฀rapidly,฀and฀the฀converse฀of฀this฀situa- tion฀is฀that฀during฀smoking฀cessation฀the฀activity฀of฀the฀drugs฀in฀question฀may฀be฀increased฀ because฀they฀are฀now฀metabolised฀more฀slowly฀ [69] .฀“Overdoses”฀resulting฀from฀this฀phe- nomenon฀have฀been฀described฀for฀theophylline,฀imipramine,฀haloperidol,฀tacrine,฀caffeine,฀ phenacetin,฀phenylbutazone,฀oestradiol฀and฀pentazocine฀ [68] .฀The฀absorption฀of฀insulin฀ given฀by฀subcutaneous฀injection฀is฀also฀reduced฀by฀smoking,฀with฀the฀result฀that฀higher฀ doses฀are฀required฀in฀smokers.฀After฀smoking฀cessation,฀this฀process฀is฀reversed฀reduction฀ of฀the฀insulin฀dose.฀Similarly,฀because฀smoking฀is฀known฀to฀increase฀catecholamine฀secre- tion,฀the฀higher฀doses฀of฀b-receptor฀blockers฀required฀in฀smokers฀may฀need฀to฀be฀reduced฀ after฀smoking฀cessation.฀Clozapine,฀a฀neuroleptic฀drug฀used฀in฀psychiatric฀medicine,฀slows฀ the฀metabolism฀of฀nicotine,฀as฀has฀been฀demonstrated฀on฀the฀basis฀of฀raised฀plasma฀coti- nine฀concentrations฀ [70] .

11.1.12 Contraindications for the Use of Nicotine Products

Sometimes,฀on฀the฀basis฀of฀misconceptions฀concerning฀the฀effects฀of฀nicotine฀on฀the฀cardio- vascular฀system,฀the฀prescribing฀information฀for฀nicotine฀products฀lists฀numerous฀contraindi- cations฀and฀warnings฀that฀require฀revision.฀The฀vasoconstrictor฀effects฀in฀the฀nicotine-dependent฀ smoker฀are฀attributable฀more฀to฀the฀inhaled฀combustion฀products,฀including฀CO,฀than฀to฀nico- tine฀itself฀ [71] .฀The฀same฀thinking฀also฀possibly฀applies฀for฀the฀administration฀of฀nicotine฀ products฀ during฀ pregnancy฀ [72] .฀ The฀ contraindications฀ listed฀ include:฀ recent฀ myocardial฀ infarction,฀cardiac฀arrhythmias,฀recent฀stroke฀and฀unstable฀angina.฀The฀following฀are฀cur- rently฀regarded฀as฀relative฀contraindications:฀stable฀angina,฀severe฀hypertension,฀cerebrovas- cular฀disease,฀vasospasms,฀severe฀heart฀failure,฀hyperthyroidism,฀insulin-dependent฀diabetes฀ mellitus,฀acute฀gastrointestinal฀ulceration฀and฀severe฀renal฀and฀hepatic฀impairment.฀Additional฀ relative฀ contraindications฀ listed฀ for฀ nicotine฀ chewing฀ gum฀ include฀ inlammation฀ of฀ the฀ mouththroatoesophagus.฀For฀the฀nicotine฀patch,฀the฀list฀includes฀chronic฀generalised฀derma- tological฀disorders฀psoriasis,฀chronic฀dermatitis฀and฀urticaria฀and฀for฀the฀nicotine฀nasal฀ spray฀nose฀bleed฀and฀chronic฀diseases฀of฀the฀nose. Nicotine฀products฀are฀not฀currently฀recommended฀for฀use฀during฀pregnancy฀and฀lacta- tion,฀unless฀the฀woman฀is฀unable฀to฀stop฀without฀nicotine฀products,฀and฀only฀after฀consult- ing฀a฀physician฀however,฀see฀ [73] .฀It฀was฀stated฀in฀many฀expert฀reviews฀that฀NRT฀is฀the฀ agent฀of฀choice฀for฀smoking฀cessation฀in฀pregnancy฀as฀the฀safety฀of฀other฀therapies฀in฀preg- nancy฀have฀not฀yet฀been฀proved฀ [74] .฀However,฀it฀also฀needs฀to฀be฀mentioned฀that฀while฀ NRT฀avoids฀exposure฀to฀the฀myriad฀compounds฀present฀in฀tobacco฀smoke,฀nicotine฀itself฀ causes฀damage฀to฀the฀developing฀nervous฀system฀ [75] .

11.1.13 Nicotine Formulations as OTC Products

Various฀nicotine฀formulations฀are฀sold฀as฀OTC฀products฀in฀several฀European฀countries฀e.g.฀ patch฀and฀gum฀in฀Germany.฀The฀rationale฀is฀that฀smokers฀absorb฀nicotine฀from฀cigarettes฀ in฀ higher฀ doses,฀ developing฀ higher฀ blood฀ levels฀ than฀ following฀ administration฀ of฀ NRT฀ products฀see฀Sects.฀ 11.1.2 – 11.1.6 ;฀Figs.฀ 11.2 ฀and฀ 11.3 .฀The฀current฀regulatory฀framework฀