Nicotine Deprivation Produces Deficits in Pain Perception that are Moderately Attenuated by Caffeine Consumption

During withdrawal, nicotine users experience aversive withdrawal symptoms, such as increased nociceptive processing, which may be responsible for subsequent use. Smokers often consume more caffeine than non-smokers and the combined effects of these two psychoactive drugs result in an enhanced analgesic effect of nicotine. We examined the effects of caffeine (via coffee consumption) and nicotine withdrawal on pain perception in minimally deprived smokers and non-smokers. Pain threshold and pain tolerance were assessed using a radiant heat stimulus before and 30 minutes after caffeine consumption. Nicotine deprivation (2 hrs) produced increases in pain threshold and decreases in pain tolerance representative of hyperalgesia. When smokers are nicotine deprived, caffeine consumption diminished baseline elevations in pain threshold, but had no effect on pain tolerance. These data suggest that caffeine consumption can dampen deficits in sensory discrimination related to pain during nicotine deprivation by reducing pain threshold to levels representative of non-smoking controls.     

Decreased pain tolerance before surgery and increased postoperative narcotic requirements in abstinent tobacco smokers

IntroductionThe clinical influence of smoking cessation on pain tolerance before surgery and postoperative pain perception is not fully understood. This clinical study investigated the effect of smoking cessation on pain threshold during the perioperative period in patients undergoing hepatic resection.MethodsWe enrolled 148 male patients (68 non-smokers and 80 abstinent smokers) who underwent hepatic resection and received postoperative patient-controlled intravenous analgesia. Patients were tested for preoperative pain thresholds in response to electrical stimuli. We recorded the cumulative amount of extra morphine equivalent required during the first 48 h after surgery. Pain intensity was evaluated at 1 h, 6 h, 24 h and 48 h after surgery using the visual analogue scale (VAS). Additionally, button-pressing consumption was recorded by a patient-controlled analgesia (PCA) pump.ResultsThe groups did not differ with respect to baseline clinical characteristics. Compared with non-smokers, abstinent smokers exhibited lower pain thresholds before surgery and demanded a larger quantity of extra morphine equivalent during the first 48 h after surgery. Abstinent smokers also exhibited more severe postoperative pain than non-smokers. Postoperative complications, such as nausea, vomiting, dizziness, sedation, and respiratory depression, did not significantly differ between the two groups.ConclusionsIn this study, smokers deprived of cigarettes exhibited decreased pain tolerance before surgery and required a larger quantity of postoperative extra morphine equivalent than non-smokers. Health care providers must be aware of the potential for increased narcotic requirements in smokers.     

The effects of cigarette smoking on the response to stress in a driving simulator

1. Some behavioural and physiological responses of cigarette smokers and non-smokers exposed to varying degrees of stress in a driving simulator were compared.2. When the smokers were smoking a cigarette, some of their reaction times to light signals differed significantly from those of non-smokers, some being longer and some shorter. These differences disappeared when the smokers were not smoking.3. Of the physiological measurements, only heart rate differed significantly between smokers and non-smokers, being higher at all levels of stress in the smokers. There were no significant differences in blood pressure, calf blood flow and respiration rate between smokers and non-smokers.4. The results of the Cattell Sixteen Personality Factor Questionnaire showed that the smokers were significantly more extroverted and self-reliant than the non-smokers.5. The results are discussed in relation to the pharmacology of cigarette smoking. It is concluded that the differences in reaction times and heart rates between smokers and non-smokers were a consequence of cigarette smoking.     

Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians

Genetically variable CYP2A6 is the primary enzyme that inactivates nicotine to cotinine. Our objective was to investigate allele frequencies among five ethnic groups and to investigate the relationship between genetically slow nicotine metabolic inactivation and smoking status, cigarette consumption, age of first smoking and duration of smoking. Chinese, Japanese, Canadian Native Indian, African-North American and Caucasian DNA samples were assessed for CYP2A6 allelic frequencies (CYP2A6*1B-*12,*1x2). Adult Caucasian non-smokers (n = 224) (1-99 cigarettes/lifetime) and smokers (n = 375) (> or = 100 cigarettes/lifetime) were assessed for demographics, tobacco/drug use history and DSM-IV dependence and genotyped for CYP2A6 alleles associated with decreased nicotine metabolism (CYP2A6*2, CYP2A6*4, CYP2A6*9, CYP2A6*12). CYP2A6 allele frequencies varied substantially among the ethnic groups. The proportion of Caucasian slow nicotine inactivators was significantly lower in current, DSM-IV dependent smokers compared to non-smokers [7.0% and 12.5%, respectively, P = 0.03, odds ratio (OR) = 0.52; 95% confidence interval (CI) 0.29-0.95]; non-dependent smokers showed similar results. Daily cigarette consumption (cigarettes/day) was significantly (P = 0.003) lower for slow (21.3; 95% CI 17.4-25.2) compared to normal inactivators (28.2; 95% CI 26.4-29.9); this was observed only in DSM-IV dependent smokers. Slow inactivators had a significantly (P = 0.03) lower age of first smoking compared to normal inactivators (13.0 years of age; 95% CI 12.1-14.0 versus 14.2; 95% CI 13.8-14.6), and a trend towards smoking for a shorter duration. This study demonstrates that slow nicotine inactivators are less likely to be adult smokers (dependent or non-dependent). Slow inactivators also smoked fewer cigarettes per day and had an earlier age of first smoking (only dependent smokers).     

Effects of smoking on acoustic startle and prepulse inhibition in humans

RATIONALE: Prepulse inhibition of the acoustic startle response (PPI) is a paradigm in which a startle response to an auditory stimulus is reduced when that stimulus is preceded by a lower intensity, non-startling stimulus (prepulse). PPI is used as an operational measure of sensorimotor gating in both humans and other mammals. Acute administration of nicotine enhances PPI in rats, an effect that has been recently demonstrated in humans. OBJECTIVES: We compared PPI in 12 male smokers and 14 male non-smokers tested in four repeat startle sessions across 2 test days in order to examine further the effects of smoking and smoking withdrawal on acoustic startle and PPI. METHODS: In a crossover design, the smokers smoked ad lib or abstained from smoking overnight prior to 9 a.m. testing. These 2 test days were in randomized order. On both days, smokers were immediately retested after smoking three cigarettes. Non-smokers were tested twice on each of 2 separate days. RESULTS: Across sessions, the smokers had reduced startle to pulse alone stimuli in the first block of each session when compared to the non-smokers. The non-smokers had no change in gating across their four test sessions. For the smokers, the abstinence condition produced a non-significant reduction in PPI compared to that of the ad lib smoking day. During the smoking abstinence session, smokers had comparable gating to non-smokers. Smoking immediately after washout produced a significant improvement in PPI such that gating in the smokers exceeded that of the non-smokers. CONCLUSION: Smoking after overnight washout from cigarettes enhanced sensorimotor gating compared to pre-smoking values and compared to gating in non-smokers.     

A nicotine dependent and a nicotine independent component of smoking related pulse and activity variation

In a field study, heart rate and motor activity were continuously assessed during two days in smokers, abstinent smokers and non-smokers. Smoking abstinence reduced heart rates by about 10 bpm to the non-smoker level without affecting motor activity. Averaging heart rate and activity using lighting of the cigarettes as the triggering event revealed the characteristic profiles described previously. Both variables increased during the last five minutes before lighting the cigarettes and decreased immediately upon lighting to near or even below the prelighting levels. This lighting response was maintained in a similar fashion when the subjects marked the time points of the desire for smoking but omitted lighting the cigarettes and it remained highly similar for the first and last five cigarettes of the day. In non-smokers a similar pattern was also obtained using the first sip of coffee as triggering event. In smoking smokers, this lighting response was followed by an increase of heart rate without changes in activity. In contrast to the lighting response, this smoking related increase of heart rate disappeared for the last five as opposed to the first five cigarettes of the day, and it was also absent for ‘imaginary’ smoking without lighting.     

Improvements in performance without nicotine withdrawal

Two tests were made of the withdrawal-relief explanation of the improvements in performance obtained with smoking. Study 1 examined the extent to which abstinence from smoking produced poorer performance in smokers in comparison with non-smokers. No evidence was obtained of differences in performance in smokers who were deprived of cigarettes for 10 h and non-smokers. Study 2 tested smokers with a standard cigarette or sham smoking after one hour and 12 h of deprivation. There was no difference in performance for the two deprivation intervals either in the sham smoking condition, or after smoking the lit cigarette. This study gave no evidence for withdrawal-relief being an explanation of the improvements in performance obtained with smoking.     

Nicotine dependence, symptoms and oxidative stress in male patients with schizophrenia.

The high rate of smoking in schizophrenia may reflect patients' attempts to reduce the side effects of antipsychotic medications, and one mechanism for this reduction may be a reduction in oxidative stress and free radical-mediated brain damage that may contribute to schizophrenic symptoms and to complications of its treatment. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS), side effects were assessed with the Simpson and Angus Rating Scale (SAS), and malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were measured in plasma. All of these measures were compared in 130 male inpatients with DSM-IV schizophrenia: 104 smokers and 26 non-smokers. The results showed that the positive PANSS symptoms were lower in smokers than non-smokers (14.5 vs 17.5), while the negative symptoms were lower in those who smoked more cigarettes (r=-0.23). The SAS showed no differences. The CAT activity was correlated with both GSH-Px and SOD activities. Of the three enzymes only the CAT activity was significantly higher in smokers than non-smokers (2.9 vs 1.6 U/ml), but greater SOD activity correlated more cigarettes smoked (r=0.24). Consistent with some protection against oxidative stress, MDA also was significantly lower in smokers than non-smokers (9.2 vs 14.4 nmol/ml). The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be a selection bias, but appears to be associated with decreased oxidative stress and lipid peroxidation in schizophrenics who smoke tobacco.     

Attentional orienting towards smoking-related stimuli

According to incentive salience theory, conditioned stimuli (CS+) associated with drug reinforcement acquire the capacity to elicit a conditioned attentional orienting response, which controls drug-seeking and drug-taking behaviour. We sought evidence for this proposal by measuring visual attentional orienting towards smoking pictures presented briefly in the periphery of the visual field, versus control pictures likewise presented, in smokers versus non-smokers. In each trial, smokers and non-smokers responded manually to a dot probe stimulus that appeared in a location previously occupied by either a smoking picture or a control picture. Attentional bias scores were calculated by subtracting the median reaction time (RT) in the former condition from the median RT in the latter condition. In two experiments, light-smokers (smokers of fewer than 20 cigarettes/day) produced a mean bias score that was significantly greater than that of heavy-smokers (smokers of 20 or more cigarettes/day) and non-smokers. In addition, when smokers from the two experiments were pooled, a significant quadratic relationship was found between cigarettes/day and the attentional bias for the smoking stimuli. These findings are consistent with incentive salience theories and dual-process theories of addiction.     

Effect of acute deprivation of smoking on aggression and hostility

Smokers and non-smokers were tested on the Buss aggression-machine to determine their aggression scores and visual reaction times during two sessions. The mean aggression scores of the non-smokers did not differ significantly between sessions whereas there was a significant increase in aggression scores for the chronic smokers in their non-smoking (deprivation) session compared with their smoking session, This increase in aggression in deprived smokers is discussed as a factor in the continuance of the smoking habit and is positively correlated to rated hostility scores on the Buss-Durkee Hostility Inventory.Supported by a grant from the American Medical Association Education and Research Foundation.     

The smoking habits of New Zealand doctors: a review after ten years.

A second survey of New Zealand doctors' smoking habits in 1972 elicited an 83 percent response from 3113 doctors. 38.5 percent had never smoked compared with 23.8 percent in a 1963 survey; 29.2 had given up smoking, and 33.3 percent still smoked. Only 21.3 percent smoked cigarettes compared with 35.3 percent in 1963. There has been a sustantial increase in non-smokers among recent graduates. Both sexes now smoke cigarettes less frequently but pipe and cigar smoking by male doctors has risen sharply. Obstetricians smoke cigarettes more often than other groups of doctors, while pathologists, medical administrators and academics smoke the least. Giving up smoking was not difficult for most former smokers except for the heavy smokers who now make up most of the persistent smoker group.     

Appetitive nature of drug cues confirmed with physiological measures in a model using pictures of smoking

RATIONALE: In smokers, pictures of smoking that increase desire for a cigarette are described as pleasant rather than unpleasant. This suggests that these smoking cues may be appetitive and not withdrawal-like or aversive as held by traditional theories of drug cue formation. OBJECTIVE: Cues for smoking were examined using physiological measures of motivational valence. METHODS: Non-deprived smokers, deprived smokers and deprived smokers who expected to smoke (n=54) viewed a computer screen presenting experimental and control scenes (experiment 1). The acoustic startle reaction and activity of the corrugator and the zygomatic facial muscles were then measured after onset of smoking cues and standardized pleasant, neutral or unpleasant control scenes. Individuals who never smoked (n=18) were also used to test for cue effects on startle (experiment 2). RESULTS: No evidence was found that smoking cues were aversive in smokers. The smoking cues affected the startle responses and corrugator activity in a way similar to that of pleasant control material but significantly different from that of unpleasant material; the cue effects on zygomatic activity was most similar to that of neutral material. The general pattern of effects was not influenced by overnight smoke deprivation, expectancy to smoke or smoke repletion, but it was different in never smokers where the smoking scenes were found to be similar to unpleasant control scenes. CONCLUSIONS: Nonsubjective measures of motivational valence further suggest that drug cues are conditioned stimuli having appetitive effects. Startle response modulated by drug cues may be useful for probing motivational processes underlying dependence in the human.     

Comparison of the Analgesic Effects of Dronabinol and Smoked Marijuana in Daily Marijuana Smokers

Recent studies have demonstrated the therapeutic potential of cannabinoids to treat pain, yet none have compared the analgesic effectiveness of smoked marijuana to orally administered Δ⁹-tetrahydrocannabinol (THC; dronabinol). This randomized, placebo-controlled, double-dummy, double-blind study compared the magnitude and duration of analgesic effects of smoked marijuana and dronabinol under well-controlled conditions using a validated experimental model of pain. Healthy male (N=15) and female (N=15) daily marijuana smokers participated in this outpatient study comparing the analgesic, subjective, and physiological effects of marijuana (0.00, 1.98, or 3.56% THC) to dronabinol (0, 10, or 20 mg). Pain response was assessed using the cold-pressor test (CPT): participants immersed their left hand in cold water (4 °C), and the time to report pain (pain sensitivity) and withdraw the hand from the water (pain tolerance) were recorded. Subjective pain and drug effect ratings were also measured as well as cardiovascular effects. Compared with placebo, marijuana and dronabinol decreased pain sensitivity (3.56% 20 mg), increased pain tolerance (1.98% 20 mg), and decreased subjective ratings of pain intensity (1.98, 3.56% 20 mg). The magnitude of peak change in pain sensitivity and tolerance did not differ between marijuana and dronabinol, although dronabinol produced analgesia that was of a longer duration. Marijuana (1.98, 3.56%) and dronabinol (20 mg) also increased abuse-related subjective ratings relative to placebo; these ratings were greater with marijuana. These data indicate that under controlled conditions, marijuana and dronabinol decreased pain, with dronabinol producing longer-lasting decreases in pain sensitivity and lower ratings of abuse-related subjective effects than marijuana.     

Affective style among smokers: Understanding anxiety sensitivity, emotional reactivity, and distress tolerance using biological challenge

The present investigation evaluated affective style in terms of anxiety sensitivity, emotional reactivity, and distress tolerance in heavy smokers. Specifically, heavy smokers (> or = 20 cigarettes per day) were partitioned into those who were able to quit for at least 7 days (n = 10) and those who were able to quit for less than 7 days (n = 12). All participants completed measures of anxiety sensitivity and maximum breath-holding duration and then were exposed to a 20% carbon dioxide-enriched air challenge. Results indicated that heavy smokers who had not been able to remain abstinent from smoking for at least 1 week during a quit attempt demonstrated significantly greater cognitive-affective reactivity to the challenge relative to their counterparts but did not differ at a physiological level of analysis. Contrary to our hypotheses, neither anxiety sensitivity scores nor maximum breath-holding duration significantly differed between the groups. These findings are discussed in relation to better understanding affective style among heavy smokers.     

Ascorbic acid improves impaired venous and arterial endothelium-dependent dilation in smokers

AIM: To compare the acute effects of ascorbic acid on vasodilation of veins and arteries in vivo. METHODS: Twenty-six healthy non-smokers and 23 healthy moderate smokers were recruited in this study. The dorsal hand vein compliance technique and flow-mediated dilation were used. Dose-response curves to bradykinin and sodium nitroprusside were constructed to test the endothelium-dependent and -independent relaxation before and after acute infusion of ascorbic acid. RESULTS: Smokers had an impaired venodilation with bradykinin compared with non-smokers (68.3%+/-13.2% vs 93.7%+/-20.1%, respectively; P<0.05). Ascorbic acid administration in the dorsal hand vein significantly increased the venodilation with bradykinin in smokers (68.3%+/-13.2% vs 89.5%+/-6.3% before and after infusion, respectively; P<0.05) but not in non-smokers (93.7%+/-20.1% vs 86.4%+/-12.4% before and after infusion, respectively). Similarly, the arterial response in smokers had an impaired endothelium-dependent dilation compared with that in non-smokers (8.8%+/-2.7% vs 15.2%+/-2.3%, respectively; P<0.05) and ascorbic acid restored this response in smokers (8.8%+/-2.7% vs 18.7%+/-6.5% before and after infusion, respectively; P<0.05), but no difference was seen in non-smokers (15.2%+/-2.3% vs 14.0%+/-4.4% before and after infusion, respectively). The endothelium-independent dilation did not differ in both the groups studied. No important hemodynamic change was detected using the Portapress device. CONCLUSION: Smokers had impaired endothelium-dependent vasodilation responsiveness in both arterial and venous systems. Ascorbic acid restores this responsiveness in smokers.     

Theophylline kinetics in relation to age: the importance of smoking.

1 Single dose studies of theophylline kinetics were compared in groups of young and elderly smokers and non-smokers to assess the effect of age on theophylline absorption and the effect of smoking on drug metabolising enzyme activity in old age. 2 The rate and extent of absorption was not affected by age. Distribution and elimination kinetics were similar in young and elderly non-smokers. 3 In young subjects the elimination half-life of theophylline was shorter and clearance was significantly greater in smokers than in non-smokers. 4 In the elderly mean elimination half-life was significantly shorter in smokers and their plasma clearance was 40% higher than in non-smokers. The statistical difference for clearance was at the 7% level of significance. 5 These data indicate that ageing per se does not affect theophylline elimination and also that induction of theophylline metabolism due to smoking occurs in old age. Smoking is a variable that should be taken account of when assessing drug metabolism in elderly patients.     

The relationship of white blood cell and platelet counts to cigarette smoking in adult Nigerians

This study was undertaken to examine the relationship between cigarette-smoking and total white blood cell count (wbcc) and platelet count (pc) in adult Nigerians. We also studied the relationship of the white blood cell and platelet counts to the duration of the smoking habit and number of cigarette smoked per day. Three hundred and fifty-two healthy male adults, aged 18-52 years, were studied. They were randomly allocated to two groups--176 smokers and 176 non-smokers. The smoking habit was assessed from a minimum period of 1 year and a minimum number of 5 cigarettes per day. Results revealed that platelet count was higher for the regular Nigerian smoker than for non-smoker. The difference between mean platelet counts for smokers and non-smokers was statistically significant (t = 2.64 p = 0.0046). Man WBC count in smokers was slightly higher than for non-smokers. However, unlike in the case of platelet counts, the mean difference in WBC count between smokers and non-smokers is not statistically significant (t = 0.07, p value = 0.9442). Similar studies based on white population has showed statistically significant increases in wbcc and pc in smokers.     

Smoking modulates neuroendocrine responses to ipsapirone in patients with panic disorder.

Reduced 5-HT1A-receptor responsiveness has been reported in patients with panic disorder(PD) and/or agoraphobia (PDA). Although many of these patients are regular smokers, it has not been examined whether psychological or neurobiological effects induced by the selective 5-HT1A-receptor agonist, ipsapirone, are affected by the smoking status of the patients.In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone (0.3 mg/kg) and placebo were performed in 39 patients with PDA, and results were compared between patients who smoked (>10 cigarettes per day, n = 17) and patients who had been non-smokers for at least two years (n = 22).Patients who were smokers (but did not smoke during the challenge procedure) had significantly reduced baseline concentrations of cortisol and a significantly lower body temperature. In comparison to placebo, administration of ipsapirone was associated with significant increases of various psychological symptoms and plasma cortisol concentrations. The subgroup of PD patients who were smokers showed significantly higher cortisol responses to ipsapirone than non-smokers.In conclusion, smoking status has to be taken into account when assessing the responsiveness of 5-HT1A receptors in patients with psychiatric disorders. The prevention of smoking during challenge sessions might not be the ideal approach in heavy smokers, since sudden abstinence from smoking is likely to affect neurobiological and possibly psychological responses to ipsapirone.     

Does smoking influence the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine?

Twelve healthy habitual cigarette smokers and eight non-smokers participated in a double-blind placebo controlled study to determine the effect of smoking on the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine. In smokers, cigarette smoking was standardised and started 1 h before (A), or 2 h after (B) drug administration, or was prohibited (C). Intragastric pH-levels (IGpH) were measured with an ambulatory pH-recorder. Famotidine (40 mg orally) significantly raised median 22 h IGpH in non-smokers and smokers in all study periods. The smoking sequence (A, B, C) did not significantly influence median 22 h IGpH in both placebo-treated and famotidine-treated smokers, and no significant difference in median 22 h IGpH was shown between smokers and non-smokers. Plasma drug concentrations were similar in the various experiments, although famotidine was detected earlier in plasma from non-smokers compared with smokers (P less than 0.05). Smoking did not interfere significantly with the pharmacokinetics and pharmacodynamics of famotidine.     

Development of central and peripheral smoking effects over time

The present study compared for the first morning cigarettes CO and nicotine absorption as well as the effects on EEG and peripheral functions across a period of 90 min. Eighteen smokers participated in two sessions, one in which they smoked two cigarettes in succession and another in which they smoked three cigarettes at 30-min intervals. Smoking two cigarettes in succession produced a particularly wide range in nicotine absorption so that the subjects could be grouped into high (HN) and low (LN) nicotine absorbers, differing significantly in their CO and nicotine absorption. The smoking-induced cardioacceleration was greater and lasted longer in the HN than in the LN group. While the dominant alpha frequency increased to a significant extent in the HN group only, beta power increased in both groups, alpha power remained unaffected, theta power decreased in the HN group only and the effects on heart rate, dominant alpha frequency and beta power were significantly correlated with nicotine absorption across both groups. Smoking three cigarettes at 30-min intervals produced qualitatively similar but generally smaller effects. However, neither nicotine uptake nor any of the physiological parameters showed differential developments between the two groups, except the dominant alpha frequency, which increased in the HN group only. The development of acute tolerance to smoking across three cigarettes was observed only for finger vasoconstriction, craving to smoke and sickness after smoking, but not for cardioacceleration or any EEG parameters.