Evaluation of Nicotine Products

strength.฀ To฀ date,฀ the฀ prescribing฀ information฀ invariably฀ recommends฀ that฀ the฀ nicotine฀ replacement฀product฀should฀be฀administered฀singly.฀However,฀some฀studies฀ [30] ฀indicate฀ that฀combined฀administration,฀for฀example,฀of฀a฀nicotine฀patch฀+฀chewing฀gum฀or฀a฀patch฀ +฀nasal฀spray฀in฀the฀more฀severe฀forms฀of฀dependence฀is฀more฀likely฀to฀achieve฀success฀ than฀administration฀of฀a฀single฀formulation฀OR฀=฀1.55;฀CI:฀1.17–2.05฀ [24] . Additional฀individual฀counselling฀of฀patients฀helps฀to฀increase฀the฀success฀rate.฀One฀ study฀has฀shown฀that฀an฀8-week฀course฀of฀treatment฀with฀nicotine฀patches฀was฀just฀as฀ effective฀as฀longer฀courses฀of฀treatment฀ [31] .฀Stopping฀smoking฀abruptly฀was฀just฀as฀effec- tive฀as฀gradual฀smoking฀reduction.฀Furthermore,฀success฀rates฀do฀not฀differ฀depending฀on฀ whether฀the฀patch฀remains฀on฀the฀skin฀for฀16฀or฀24฀h฀a฀day฀ [23,฀32,฀33] .

11.1.2 Nicotine Chewing Gum

Chewing฀gum฀was฀the฀irst฀type฀of฀NRT฀to฀become฀widely฀available.฀Nicotine฀is฀absorbed฀ directly฀through฀the฀buccal฀mucosa,฀resulting฀in฀plasma฀concentrations฀which฀are฀approx- imately฀ half฀ those฀ produced฀ by฀ smoking฀ a฀ cigarette฀ [34] ฀ cf.฀ Figs.฀ 4.5 ฀ in฀ Chap.฀ 4 ,฀ Fig.฀ 11.3 .฀Both฀2-฀and฀4-mg฀preparations฀are฀available฀in฀many฀countries฀and฀these฀are฀ sold฀over-the-counter฀OTC฀2฀mg฀more฀than฀4฀mg.฀Several฀factors,฀including฀oral฀and฀ gastric฀side฀effects,฀and฀dental฀prostheses฀etc.,฀limit฀the฀usefulness฀of฀nicotine฀gum฀in฀ some฀smokers฀ [35] .฀It฀has฀been฀reported฀that฀some฀smokers฀may฀be฀at฀risk฀of฀switching฀ their฀ former฀ cigarette฀ addiction฀ across฀ to฀ the฀ nicotine฀ gum฀ [36] ;฀ however,฀ we฀ have฀ observed฀this฀addiction฀transfer฀extremely฀rarely.฀According฀to฀the฀Cochrane฀Group,฀51฀ trials฀have฀been฀carried฀out฀with฀nicotine฀gum฀cf.฀Table฀ 11.1 ,฀and฀two฀trials฀have฀com- pared฀the฀gum฀with฀combination฀of฀patch฀plus฀gum฀ [37,฀38] .฀Apart฀from฀eight฀of฀the฀indi- vidual฀trials฀ [5] ,฀the฀use฀of฀nicotine฀chewing฀gum฀4฀mg฀more฀than฀2฀mg฀has฀been฀reported฀ to฀ be฀ more฀ effective฀ than฀ placebo฀ in฀ promoting฀ smoking฀ cessation.฀ The฀ advantage฀ of฀ Chewing gum 2 mg Chewing gum 4 mg Cigarettes Patch Time of day 9:00 5 10 15 20 25 15:00 21:00 3:00 9:00 Nicotine Plasma Level [ngml] Fig. 11.3 ฀฀฀Plasma฀nicotine฀ concentrations฀measured฀ after฀different฀nicotine฀ formulations฀ [21] .฀The฀ curves฀illustrate฀that฀none฀฀ of฀the฀nicotine฀products฀ attains฀the฀plasma฀ concentrations฀or฀the฀rapid฀ delivery฀achieved฀by฀ cigarette฀smoking ฀nicotine฀chewing฀gum฀over฀the฀patch฀is฀that฀its฀dosage฀can฀be฀adjusted฀individually฀over฀ the฀course฀of฀a฀day฀in฀response฀to฀any฀cravings฀that฀may฀be฀experienced.

11.1.3 Nicotine Patch

Nicotine฀ patches฀ were฀ developed฀ as฀ transdermal฀ delivery฀ systems฀ to฀ ensure฀ constant฀ release฀of฀the฀active฀ingredient฀over฀a฀period฀of฀16–24฀h.฀These฀systems฀should฀be฀applied฀ to฀a฀dry฀area฀of฀hairless฀skin,฀and฀the฀application฀site฀should฀be฀varied฀daily.฀Nicorette ® ฀ patches฀are฀available฀in฀strengths฀of฀15,฀10฀and฀5฀mg.฀The฀15-mg฀patch฀contains฀25฀mg฀ nicotine.฀The฀Nicorette฀patch฀is฀intended฀to฀be฀worn฀for฀only฀16฀h,฀i.e.฀not฀during฀the฀night฀ Figs.฀ 11.2 ฀and฀ 11.3 . By฀contrast,฀NiQuitin ® ฀and฀Nicotinell ® ฀aim฀to฀administer฀nicotine฀over฀a฀24฀h฀period.฀ The฀three฀patch฀strengths฀of฀NiQuitin ® ฀and฀Nicotinell ® ฀deliver฀7,฀14฀and฀21฀mg฀nicotine฀to฀ the฀body฀every฀24฀h.฀Thanks฀to฀the฀special฀pharmaceutical฀formulation฀of฀NiQuitin ® ฀incor- porating฀a฀membrane฀type฀that฀releases฀nicotine฀for฀transcutaneous฀delivery,฀they฀contain฀ 36,฀78฀and฀114฀mg฀nicotine฀on฀patch฀areas฀of฀7,฀15฀and฀22฀cm 2 ฀respectively.฀Nicotinell ® ฀ contains฀52.5฀mg฀nicotine฀on฀an฀area฀of฀30฀cm 2 .฀During฀the฀irst฀2฀h฀after฀patch฀application,฀ differences฀have฀been฀detected฀in฀terms฀of฀body฀area฀selected฀chest฀฀leg฀฀back฀฀gluteal฀ region.฀One฀other฀study฀comparing฀absorbtion฀from฀hip฀and฀arm฀did฀not฀ind฀any฀differ- ence.฀The฀observed฀differences฀between฀application฀sites฀are฀without฀clinical฀relevance. Nicotine฀attains฀maximum฀concentrations฀between฀4฀and฀10฀h฀following฀single฀applica- tion,฀and฀levels฀then฀plateau฀over฀16–24฀h.฀Signiicant฀differences฀exist฀between฀the฀area฀ under฀the฀curve฀AUC฀values฀and฀the฀mean฀plasma฀concentration฀curve฀between฀single฀ dose฀and฀steady฀state฀for฀the฀24-h฀patches.฀The฀16-h฀patch฀has฀similar฀plasma฀concentra- tions฀during฀steady฀state฀as฀after฀a฀single฀dose,฀as฀the฀plasma฀level฀decline฀over฀night.฀ Separate฀investigations฀have฀established฀that฀nicotine฀is฀not฀inactivated฀metabolised฀dur- ing฀ transdermal฀ passage,฀ whereas฀ minimal฀ metabolism฀ to฀ the฀ analogous฀ N-oxide฀ or฀ N-methyl฀compounds฀has฀been฀demonstrated฀under฀in฀vitro฀conditions฀following฀6฀day฀incu- bation฀ [39,฀40] .฀Overall,฀the฀metabolism฀of฀nicotine฀to฀cotinine฀during฀transdermal฀passage฀ is฀estimated฀to฀be฀minimal. Nicotine฀release฀from฀patches฀has฀also฀been฀studied฀in฀terms฀of฀differences฀due฀to฀gen- der,฀age฀and฀obesity.฀While฀gender฀and฀age฀differences฀have฀been฀excluded,฀a฀correlation฀ with฀body฀weight฀has฀been฀conirmed,฀with฀AUC฀declining฀as฀body฀weight฀increases฀ [41] .฀ However,฀it฀was฀immaterial฀whether฀the฀patches฀were฀applied฀to฀the฀upper฀arm฀or฀upper฀ body.฀These฀investigations฀did฀not฀reveal฀any฀consequences฀for฀therapy. Plasma฀nicotine฀concentrations฀rise฀if฀cigarettes฀are฀smoked฀in฀addition฀to฀patch฀appli- cation฀see฀Fig.฀ 11.4 .฀Naturally,฀nicotine฀absorption฀from฀cigarettes฀is฀subject฀to฀numerous฀ inluences฀already฀discussed,฀even฀where฀the฀smoker฀is฀required฀to฀smoke฀one฀cigarette฀at฀ 30฀min฀intervals฀over฀a฀15฀h฀experimental฀period฀ [42,฀43] .฀Mean฀nicotine฀concentrations฀at฀ all฀time฀points฀are฀almost฀doubled.฀Mean฀concentrations฀of฀approximately฀40฀ngml฀day฀3฀ and฀50฀ngml฀day฀7฀are฀achieved฀with฀the฀patch฀+฀smoking฀combination,฀whereas฀very฀ much฀lower฀concentrations฀30฀ngml฀are฀found฀with฀an฀ad฀libitum฀smoking฀option.฀In฀ practice,฀however,฀the฀differences฀in฀measured฀plasma฀nicotine฀concentrations฀are฀of฀minor฀