Nicotine pharmacokinetics and subjective responses after using nicotine pouches with different nicotine levels compared to combustible cigarettes and moist smokeless tobacco in adult tobacco users

Probably not a substantial claim: may not pass S3 (load-bearing).

The nicotine PK analysis and the subjective measures used in this study are well-established methods for evaluating the abuse potential of tobacco/nicotine products.

“the nicotine PK analysis and the subjective measures used in this study are well-established methods for evaluating the abuse potential of tobacco/nicotine products”

• cites Carter et al. 2009 sourceSupported
• cites Cobb et al. 2010 sourcePartly supported

  The Methods and Discussion (page unavailable) show that the paper used plasma nicotine and subjective measures to evaluate tobacco products, adapting clinical laboratory methods used for other products. It presents these as methods for assessing acute effects and harm-reduction potential, but does not establish them specifically as well-established measures of abuse potential. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites Cox et al. 2001 sourceNot checked — no full text of the source

May combine two claims.

The tmax of nicotine uptake from all five nicotine pouches (range: 32.5 to 33.9 min) was slower than own brand cigarettes (8.5 min) and was similar to own brand moist smokeless tobacco (34.4 min).

“The tmax of nicotine uptake from all five NPs (range: 32.5 to 33.9 min) was slower than OBCs (8.5 min) and was similar to OBMST (34.4 min; Supplementary Table 2).”

May combine two claims.

The mean nicotine Cmax for nicotine pouches increased with nicotine level, ranging from 3.5 ng/mL (1.5 mg NP) to 15.4 ng/mL (8 mg NP), compared with 12.2 ng/mL for own brand cigarettes and 9.8 ng/mL for own brand moist smokeless tobacco.

“The mean nicotine Cmax for NPs increased with nicotine level, ranging from 3.5 ng/mL (1.5 mg NP) to 15.4 ng/mL (8 mg NP), compared with 12.2 ng/mL for OBCs and 9.8 ng/mL for OBMST.”

May combine two claims.

The 1.5, 2, 3.5, and 4 mg nicotine pouches resulted in statistically significantly lower (p < 0.05) Cmax values, while the 8 mg nicotine pouch resulted in a statistically significantly (p < 0.05) higher Cmax relative to participants' own brand cigarettes.

“The 1.5, 2, 3.5, and 4 mg NPs resulted in statistically significantly lower (p < 0.05) Cmax values, while the 8 mg NP resulted in a statistically significantly (p < 0.05) higher Cmax relative to participants’ OBCs.”

May combine two claims.

No statistically significant differences were observed for AUC(0-180) for the 3.5 and 4 mg nicotine pouches relative to participants' own brand cigarettes, and the 8 mg nicotine pouch's AUC(0-180) was significantly higher (p < 0.0001) relative to participants' own brand cigarettes.

“No statistically significant differences were observed for AUC(0–180) for the 3.5 and 4 mg NPs, and the 8 mg NP’s AUC(0–180) was significantly higher (p < 0.0001) relative to participants’ OBC.”

May combine two claims.

Relative to participants' own brand moist smokeless tobacco, the Cmax for the 1.5, 2, and 3.5 mg nicotine pouches was significantly lower (p < 0.0001); the 4 mg nicotine pouch resulted in similar Cmax; and the 8 mg nicotine pouch resulted in significantly higher Cmax (p < 0.0001).

“Relative to participants’ OBMST, the Cmax for the 1.5, 2, and 3.5 mg NPs was significantly lower (p < 0.0001). The 4 mg NP resulted in similar Cmax, and the 8 mg NP resulted in significantly higher Cmax (p < 0.0001) relative to participants’ OBMST.”

May combine two claims.

The 1.5, 2, 3.5, and 4 mg nicotine pouches resulted in significantly lower (p < 0.05 for all comparisons) AUC(0-180), while the 8 mg nicotine pouch resulted in a significantly higher (p < 0.0001) AUC relative to participants' own brand moist smokeless tobacco.

“The 1.5, 2, 3.5, and 4 mg NPs resulted in significantly lower (p < 0.05 for all comparisons) AUC(0–180), while the 8 mg NP resulted in a significantly higher (p < 0.0001) AUC relative to participants’ OBMST.”

May combine two claims.

Mean QSU-Brief Factor 1 scores ranged from 5.9 to 6.5 before the ad libitum use period and decreased to 4.8 to 5.2 for nicotine pouches, 2.5 for own brand cigarettes, and 4.2 for own brand moist smokeless tobacco at the end of the ad libitum use period.

“The mean Factor 1 scores ranged from 5.9 to 6.5 before the ad libitum use period; scores decreased to a range of 4.8 to 5.2 for NPs, and 2.5 for OBCs, and 4.2 for OBMST at the end of the ad libitum use period.”

May combine two claims.

After study product randomization on day −1, 61 adverse events were reported by 20 participants (67%), with 59 mild and two moderate (headache in the OBC group and nausea in the 8 mg NP group).

“After study product randomization on day − 1, 61 AEs were reported by 20 participants (67%), with 59 of the events being mild in severity and two events (headache in the OBC group and nausea in the 8 mg NP group) being moderate in severity.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The percent coefficient of variation was relatively higher for OBC (75.4%) in this study compared to that reported for OBC (42.4%) by Rensch et al. (2021).

“For example, the percent coefficient of variation was relatively higher for OBC (75.4%) in this study (Supplementary Table 2) compared to that reported for OBC (42.4%) by Rensch et al. (2021).”

• cites Rensch et al. (2021) sourceNot checked — no full text of the source

May combine two claims.

The magnitude of reduction in craving a cigarette was statistically significantly lower (p < 0.05) for the 1.5, 2, 3.5, and 4 mg nicotine pouches and not statistically different for the 8 mg nicotine pouch compared to own brand cigarettes.

“The magnitude of reduction in craving a cigarette was statistically significantly lower (p < 0.05) for the 1.5, 2, 3.5, and 4 mg NPs and not statistically different for the 8 mg NP compared to OBCs.”

May combine two claims.

Among the NPs tested, the 8 mg NP engendered the lowest percentage of positive (46%) responses, the highest percentage of negative (36%) and neutral (18%) responses, relative to OBC and OBMST.

“Among the NPs tested, the 8 mg NP engendered the lowest percentage of positive (46%) responses, the highest percentage of negative (36%) and neutral (18%) responses, relative to OBC and OBMST.”

May combine two claims.

During ad libitum use, participants reported that the NPs were satisfying, pleasant, and reduced craving a cigarette and urges to smoke based on QSU-Brief scores.

“During the ad libitum use, participants reported that the NPs were satisfying, pleasant, and reduced craving a cigarette and urges to smoke (based on the QSU-Brief scores).”

May combine two claims.

The NPs delivered nicotine in a manner consistent with their nicotine level, with increased nicotine delivery with increasing nicotine level.

“Our findings demonstrate that the NPs delivered nicotine in a manner consistent with their nicotine level (increased nicotine delivery with increasing nicotine level).”

May combine two claims.

While there was a reduction in QSU-Brief factor scores after 4-hour ad libitum use of the nicotine pouches, the magnitude of reduction relative to baseline was much smaller than with participants' own brand cigarettes.

“While there was a reduction in the QSU-Brief factor scores (Factor 1 — desire and intention to smoke and Factor 2 — anticipation of relief from negative affect) after 4-h ad libitum use of the NPs, the magnitude of reduction relative to baseline was much smaller than with participants’ OBCs.”

May combine two claims.

The NPs, regardless of nicotine level, delivered nicotine far slower (higher tmax values) than participants' OBCs and similar to OBMST.

“The NPs, regardless of nicotine level, delivered nicotine far slower (higher tmax values) than participants’ OBCs and similar to OBMST.”

May combine two claims.

No serious adverse events were reported, and no participants were discontinued due to adverse events.

“No serious adverse events (AEs) were reported, and no participants were discontinued due to AEs.”

May combine two claims.

The maximum change in these subjective outcomes occurred later for 8 mg NP (15 min) than for OBC (5 min) and at a similar time to OBMST.

“The maximum change in these subjective outcomes occurred later for 8 mg NP (15 min) than for OBC (5 min) and at a similar time to OBMST.”

May combine two claims.

Headache was the most frequently reported event, experienced by eight participants (27%), followed by nausea, experienced by six participants (20%).

“Headache was the most frequently reported event, experienced by eight participants (27%), followed by nausea, experienced by six participants (20%).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Seven adverse events were considered likely related to study products and 13 possibly related.

“Seven events were considered to be likely related to study products and 13 events possibly related.”

May combine two claims.

Compared with own brand moist smokeless tobacco, responses to craving a cigarette on the Tobacco/Nicotine Withdrawal Questionnaire were significantly lower for the 1.5, 2, 3.5, and 4 mg nicotine pouches, and responses to urges to smoke were significantly lower for the 1.5 and 4 mg nicotine pouches (p < 0.05).

“Compared with OBMST, responses to craving a cigarette on the TNW Questionnaire were significantly lower for the 1.5, 2, 3.5, and 4 mg NPs and responses to urges to smoke were significantly lower for the 1.5 and 4 mg NPs (p < 0.05).”

May combine two claims.

Subjective ratings for the NPs on the DEP Questionnaire were either statistically significantly lower (p < 0.05) than or similar to participants' OBCs.

“Subjective ratings for the NPs on the DEP Questionnaire were either statistically significantly lower (p < 0.05) than or similar to participants’ OBCs (Table 3; Supplementary Table 3.”

May combine two claims.

The time-course of maximum reduction in nicotine withdrawal symptoms was similar among all NPs and OBMST and occurred 10 to 25 min later than with OBCs.

“The time-course of maximum reduction in nicotine withdrawal symptoms was similar among all NPs and OBMST and occurred 10 to 25 min later than with OBCs.”

May combine two claims.

The time-course of changes in "urges to smoke" suggests that the maximum reduction during use of the NPs occurred later than for OBCs (15 to 30 min vs. 5 min) and at a similar time to OBMST (30 min).

“The time-course of changes in “urges to smoke” suggests that the maximum reduction during use of the NPs occurred later than for OBCs (15 to 30 min vs. 5 min) and at a similar time to OBMST (30 min; Fig. 2).”

May combine two claims.

The mean mCEQ factor scores for satisfaction, psychological reward, enjoyment of sensation, and craving reduction after 4-hour ad libitum use were generally similar among all nicotine levels of nicotine pouches and were lower than mean scores for participants' own brand cigarettes and own brand moist smokeless tobacco.

“The mean factor scores for satisfaction, psychological reward, enjoyment of sensation, and craving reduction from the mCEQ after 4-h ad libitum use were generally similar with the use of NPs among all nicotine levels and were lower than mean scores for participants’ OBCs and OBMST (Supplementary Fig. 1).”

May combine two claims.

During each 4-hour ad libitum product use period, the mean cigarette consumption was about 10 cigarettes, and own brand moist smokeless tobacco use was about 3 quids/pinches.

“The mean cigarette consumption was ~ 10 cigarettes, and OBMST use was ~ 3 quids/pinches.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Out of 66 people screened, 36 failed screening procedures, and 30 participants were enrolled, completed the 5-day ambulatory product trial, and checked in to the clinic.

“Out of 66 people screened for this study, 36 people failed screening procedures. A total of 30 participants (29 males and 1 female) were enrolled, completed the 5-day ambulatory product trial, and checked in to the clinic on day − 1.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

One male participant withdrew on day 2 due to unrelated adverse events (body aches, chills, and fatigue), and one male participant withdrew on day 5 due to a family emergency.

“One male participant chose to withdraw from the study on day 2 due to unrelated AEs (body aches, chills, and fatigue), and one male participant withdrew on day 5 due to a family emergency.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The sample size of 30 participants was considered adequate for the current study design.

“The sample size of 30 participants was considered adequate for the current study design.”

• cites Carter et al. 2009 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Cobb et al. 2010 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Cox et al. 2001 sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

The randomized 7-way crossover design allowed each participant to use all five nicotine levels and their own brand cigarettes and own brand moist smokeless tobacco products in a within-subject design.

“The randomized, 7-way, crossover design allowed each participant to use all five nicotine levels and their OBCs and OBMST products in this within-subject design.”

Classified as probably not a substantial claim.

Rensch et al. (2021) concluded that based on pharmacokinetic profiles and subjective responses, on! nicotine pouches containing 4 mg nicotine were likely to be associated with lower abuse potential than cigarettes.

“The authors concluded that based on the PK profiles and subjective responses, the NPs were likely to be associated with lower abuse potential than cigarettes.”

• cites Rensch et al. 2021 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study population was predominantly white (90%) and male (97%) with an average age of 35 years.

“The study population was predominantly white (90%) and male (97%) with an average age of 35 years (Table 1).”

Classified as probably not a substantial claim.

The 15-hour overnight abstinence from use of any tobacco- or nicotine-containing products was monitored by clinic staff.

“The 15-h overnight abstinence from use of any tobacco- or nicotine-containing products was monitored by the clinic staff.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Lunell et al. (2020) observed no obvious correlation between nicotine levels and the maximum score for head buzz.

“The authors had also measured subjective effects (“head buzz”) and observed no obvious correlation between nicotine levels and the maximum score for “head buzz.””

• cites Lunell et al. 2020 sourceNot checked — no full text of the source

May combine two claims.

All participants were cigarette smokers and concurrent moist smokeless tobacco users at screening, had smoked an average of about 15 cigarettes per day for 14 years, and used about 3.5 cans of moist smokeless tobacco per week for 12 years.

“All participants were cigarette smokers and concurrent MST users at screening, had smoked an average of about 15 CPD for 14 years, and used ~ 3.5 cans of MST per week for 12 years.”

May combine two claims.

Nicotine pouches are tobacco-leaf free and contain far fewer harmful and potentially harmful constituents (HPHCs) than cigarette smoke.

“NPs are tobacco-leaf free and contain far fewer HPHCs than cigarette smoke (Wagner et al. 2020).”

• cites Wagner et al. 2020Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

The study used a randomized, in-clinic, partial single-blind, 7-way crossover design.

“We used a randomized, in-clinic, partial single-blind, 7-way crossover design to assess nicotine PK and subjective effects in dual users of cigarettes and MST.”

• Also stated in: § Study design · plain

  “This study used a randomized, partial single-blind, 7-way crossover design.”

May combine two claims.

The average length of time that the nicotine pouches were used in the mouth ranged from about 29 minutes (1.5 mg) to about 56 minutes (2 mg), and own brand moist smokeless tobacco quids were used for about 42 minutes per use during the 4-hour ad libitum product use period.

“The average length of time that the NPs were used in the mouth ranged from ~ 29 (1.5 mg) to ~ 56 (2 mg) min. OBMST quids were used for ~ 42 min per use during the 4-h ad libitum product use period.”

Classified as probably not a substantial claim. May combine two claims.

Participants were blinded to the nicotine level of the nicotine pouch but knew whether the product was a nicotine pouch, own brand cigarette, or own brand moist smokeless tobacco (partial single-blind).

“participants knew whether the study product was an NP, OBC, or OBMST, but were blinded to the nicotine level of the NP (partial single-blind).”

Classified as probably not a substantial claim.

Rensch et al. (2021) indicated that nicotine pouches may be potentially acceptable switching products for adult cigarette smokers and adult moist smokeless tobacco users.

“and the NPs may be potentially acceptable switching products for AS and adult MST users (Rensch et al. 2021).”

• cites Rensch et al. 2021 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

During the product trial period, participants reported using about five nicotine pouches per day.

“During the product trial period, participants reported using about five NPs per day.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

All 30 participants were randomized to one of seven study product sequences, and 28 participants completed the study.

“All 30 participants were randomized to one of seven study product sequences, and 28 participants completed the study.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Rensch et al. (2021) found that flavor does not appear to influence nicotine pharmacokinetics or subjective responses.

“The findings from the study also indicated that flavor does not appear to influence nicotine PK or subjective responses”

• cites Rensch et al. 2021 sourceNot checked — no full text of the source

May combine two claims.

The slower onset of nicotine delivery and lower peak concentration, along with lower ratings of positive subjective effects relative to participants' OBCs and/or OBMST, suggest likely lower reinforcing effects and therefore likely lower abuse potential for the NPs with nicotine levels of 1.5, 2, 3.5, and 4 mg.

“The slower onset of nicotine delivery and lower peak concentration, along with the lower ratings of positive subjective effects relative to participants’ OBCs and/or OBMST, suggests likely lower reinforcing effects (Carter et al. 2009; Henningfield and Keenan 1993), and therefore, likely lower abuse potential for the NPs with nicotine levels of 1.5, 2, 3.5, and 4 mg.”

• cites Carter et al. 2009 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Henningfield and Keenan 1993 sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

The study did not directly measure dependence potential of the NPs because validated methods do not exist for such products.

“First, we did not directly measure dependence potential of the NPs because validated methods do not exist for such products.”

May combine two claims.

Gender balance in this study reflects the population of ST product users, as it is well established that the vast majority of ST users are predominantly male.

“Additionally, gender balance in this study reflects the population of ST product users, as it is well established that the vast majority of ST users are predominantly male.”

• cites CDC 2021Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The relatively small sample size and lack of sufficient gender balance may be a potential limitation.

“Finally, the relatively small sample size and lack of sufficient gender balance may be a potential limitation as well.”

May combine two claims.

These observations suggest that, regardless of nicotine level, the NPs relieve nicotine withdrawal symptoms, but not to the same extent as smoking.

“These observations suggest that, regardless of nicotine level, the NPs relieve nicotine withdrawal symptoms, but not to the same extent as smoking.”

Classified as probably not a substantial claim.

For a tobacco/nicotine product to have the potential for reducing risk, the associated abuse potential should be sufficiently high enough, but not higher, than that of cigarettes.

“Therefore, for a tobacco/nicotine product to have the potential for reducing risk, the associated abuse potential should be sufficiently high enough, but not higher, than that of cigarettes (Institute of Medicine 2012).”

• cites Institute of Medicine 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Lower reinforcing efficacy can be expected from the NPs, regardless of nicotine level, because despite the positive subjective effects and some cigarette craving relief, the magnitude of change was lower than participants' OBCs or OBMST.

“Lower reinforcing efficacy can be expected from the NPs, regardless of nicotine level, because despite the positive subjective effects and some cigarette craving relief, the magnitude of change was lower than participants’ OBCs or OBMST.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

According to CDC, non-Hispanic whites have the highest prevalence of ST use, and the number of women who use ST products is so small that statistically reliable estimates could not even be calculated.

“According to Centers for Disease Control and Prevention, non-Hispanic whites have the highest prevalence of ST use, and the number of women who use ST products is so small that statistically reliable estimates could not even be calculated (CDC 2021).”

• cites CDC 2021Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

The in-clinic product use allowed for obtaining reliable observations since the product use took place in the presence of the clinic staff.

“Nonetheless, the in-clinic product use allowed for obtaining reliable observations since the product use took place in the presence of the clinic staff.”

May combine two claims.

Overall, results from this study demonstrated that the 1.5, 2, 3.5, and 4 mg NPs likely have a lower abuse potential relative to OBCs and OBMST and the 8 mg NP is not likely to exhibit higher abuse potential than OBCs and OBMST.

“Overall, results from this study demonstrated that the 1.5, 2, 3.5, and 4 mg NPs likely have a lower abuse potential relative to OBCs and OBMST and the 8 mg NP is not likely to exhibit higher abuse potential than OBCs and OBMST.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The likely/possibly related adverse events were as typically expected with use of oral nicotine products.

“and were as typically expected with use of oral nicotine products.”

May combine two claims.

The abuse potential for the NPs, assessed in this study, is not likely to be higher than cigarettes or MST products and the NPs may be potentially acceptable substitutes for cigarettes.

“The abuse potential for the NPs, assessed in this study, is not likely to be higher than cigarettes or MST products and the NPs may be potentially acceptable substitutes for cigarettes.”

• AssumptionRests on an assumption: Reduction in harm can only be achieved if adult tobacco users are willing to switch products.
• AssumptionRests on an assumption: The abuse liability or dependence potential of a tobacco product must be considered in the context of that product’s harm reduction potential.
• AssumptionRests on an assumption: Assessment of the abuse potential of the NPs informs the likelihood of switching from cigarettes and MST.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The sample size is reasonable and is typical of other studies examining PK and subjective effects across different tobacco/nicotine conditions.

“the sample size is reasonable and is typical of other studies examining PK and subjective effects across different tobacco/nicotine conditions”

• cites Carter et al. 2009 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Cobb et al. 2010 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Cox et al. 2001 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

The study design involved measurement of subjective responses after a relatively brief duration of a 4-h period of in-clinic ad libitum product use.

“Second, the study design involved measurement of subjective responses after a relatively brief duration of a 4-h period of in-clinic ad libitum product use.”