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CORK Bibliography: Drug Interactions

79 citations. January 2009 to present

Prepared: March 2012

Babalonis S; Lile JA; Martin CA; Kelly TH. Physiological doses of progesterone potentiate the effects of triazolam in healthy, premenopausal women. Psychopharmacology 215(3): 429- 439, 2011. (50 refs.)

Gender plays a critical role in the effects of drugs and drug abuse liability. Biological factors, including ovarian hormones, may contribute to gender differences in drug abuse. Preclinical and some clinical research suggests that progesterone and its metabolites have activity at the GABA(A) receptor and may enhance the effect of GABAergic compounds (e.g., benzodiazepines). Because women are exposed to varying levels of progesterone from puberty until menopause, and appear more sensitive to the negative consequences of benzodiazepine use, it is important to understand the impact of progesterone on GABAergic drug effects. The purpose of this experiment was to characterize the behavioral effects of progesterone, alone and in combination with the short-acting benzodiazepine, triazolam, to determine if progesterone potentiates the behavioral effects of triazolam. Oral micronized progesterone (0, 100, and 200 mg) and oral triazolam (0.00, 0.12, and 0.25 mg/70 kg) were administered to healthy, premenopausal women (n = 11) under conditions of low circulating sex hormones. The subjective, performance and physiological effects of progesterone, alone and in combination with triazolam, were assessed. Triazolam alone produced prototypical sedative-like effects. Progesterone alone also engendered some sedative effects, although the time course of the effects was more limited than that of triazolam. Progesterone increased and extended the duration of triazolam effects and delayed the onset of triazolam peak effects, most notably at the 0.12 mg/70 kg dose. Progesterone potentiates the behavioral effects of benzodiazepines and may contribute to benzodiazepine use and abuse among women.

Albion C; Shkrum M; Cairns J. Contributing factors to methadone-related deaths in Ontario. American Journal of Forensic Medicine and Pathology 31(4): 313-319, 2010. (36 refs.)

To identify factors contributing to methadone-related deaths in Ontario in 2004, demographic factors, methadone blood levels, evidence of concurrent drug use, the source of methadone (prescribed or illicit), and its contribution in exacerbating preexistent disease were studied to identify users at risk for methadone toxicity and death. This retrospective study reviewed postmortem data, autopsy reports, police reports, hospital data, and postmortem toxicological analyses available in the Ontario Chief Coroner's Information Systemem. There were 54 cases with methadone detected in postmortem blood samples. Of total, 9 cases were not included in the study because of incomplete documentation. About 11 deaths were due to methadone toxicity alone; 25 deaths were due to combined methadone and other drug toxicity (notably cocaine and alcohol); 7 deaths were due to the exacerbation of a preexisting disease by methadone; 1 death was due to disease alone, and 1 death was due to trauma sustained in a motor vehicle collision. A significant number of methadone-related deaths were due to illicit methadone ingestion, which exceeded the opioid tolerance level. The source of methadone in these cases was unknown. Drug addicts, unaware of the hazard of consuming other illicit or prescription drugs concurrently, are at risk. This study demonstrated that methadone toxicity is enhanced by underlying disease, especially in individuals with underlying cardiac and pulmonary pathology.

Armstrong SC; Wynn GH; Sandson NB. Pharmacokinetic drug interactions of synthetic opiate analgesics. Psychosomatics 50(2): 169-176, 2009. (52 refs.)

Earlier reviews have covered pharmacokinetic drug interactions of natural and semi-synthetic opioid analgesics. This review will focus on the pharmacokinetic drug-drug interactions of methadone, propoxyphene, levomethadyl, meperidine, other phenylpiperidines (such as fentanyl), pentazocine, diphenoxylate, loperimide, and tramadol. The authors present an extensive review of the current literature. These drugs, with a few exceptions, are, at least partially, if not primarily, metabolized by the cytochrome P450 isoenzyme system (CYP) 3A4, and the action/interaction of these enzymes can have an effect on outcome. Therefore, these drugs are likely to produce drug-drug interactions when the CYP3A4 system is inhibited or induced. Knowledge of these drug-drug interactions is important because such interactions may decrease drug efficacy or result in adverse effects.

Baker J; Rainey PM; Moody DE; Morse GD; Ma Q; McCance-Katz EF. Interactions between buprenorphine and antiretrovirals: Nucleos(t)ide reverse transcriptase inhibitors (nrti) didanosine, lamivudine, and tenofovir. American Journal on Addictions 19(1): 17-29, 2010. (44 refs.)

To improve outcomes among injection drug users with HIV and/or chronic hepatitis B, it is important to identify drug interactions between antiretroviral and opiate therapies. We report the results of a study designed to examine the interaction between buprenorphine and the nucleos(t)ide reverse transcriptase inhibitors (NRTI) didanosine (ddI), lamivudine (3TC), and tenofovir (TDF). Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n = 27) participated in two 24-hour sessions to determine (1) pharmacokinetics of buprenorphine alone and (2) pharmacokinetics of both buprenorphine and either ddI, 3TC, or TDF. Among buprenorphine/naloxone-maintained study participants, no significant changes in buprenorphine pharmacokinetics were observed following ddI, 3TC, or TDF administration. Buprenorphine had no significant effect on NRTI concentrations. Concomitant use of buprenorphine with ddI, 3TC, or TDF results in neither a significant pharmacokinetic nor pharmacodynamic interaction.

Ballard ME; de Wit H. Combined effects of acute, very-low-dose ethanol and delta(9)-tetrahydrocannabinol in healthy human volunteers. Pharmacology, Biochemistry and Behavior 97(4): 627-631, 2011. (48 refs.)

Rationale: Previous studies examining the combined effects of ethanol and cannabis, or its primary psychoactive ingredient, Delta(9)-tetrahydrocannabinol (THC), have provided mixed results. Data from an in vitro study suggests that combined, sub-threshold doses of these drugs may interact to produce synergistic effects. Very low doses of the two drugs in combination have not been tested in humans. Materials and methods: This study assessed whether combinations of acute, very low doses of ethanol and THC produce synergistic effects on subjective, cognitive, and physiological measures. Healthy volunteers (n = 11) received capsules containing placebo or THC (2.5 mg), and beverages containing placebo or ethanol (0.1 and 0.2 g/kg) alone, and in combination, across separate sessions, in a within-subjects, randomized, double-blind design. During each session, participants completed measures of working memory, psychomotor ability, and simple reaction time, and provided subjective mood and drug effect ratings. Cardiovascular measures were obtained at regular intervals. Results: As intended, when administered alone, these very low doses of ethanol and THC had only moderate effects on isolated measures. The combined effects of these drugs were not synergistic, and in some cases appeared to be less-than-additive. Conclusions: Our data provide no evidence for synergistic effects of acute combinations of very-low-dose ethanol and THC on subjective or physiologic response, or on cognitive performance.

Bamashmus M; Othrob NY; Mousa A; Al-Tay W. Effect of khat (qat) consumption on pain during and after local anesthesia for patients undergoing cataract surgery. Medical Science Monitor 16(8): SR29-SR33, 2010. (37 refs.)

Background: The leaves of the Khat (Qat) plant (Catha edulis), which contain amphetamine-like compounds, are widely chewed in Yemen and East Africa for their pleasurable stimulant properties and for their psychostimulative effects. Khat consumption has a number of unwanted side-effects. This study investigates effects of Khat consumption on the quality of local anesthesia with peribulbar injection and patient perception of pain after administration of local anesthesia for routine cataract extraction. Material/Methods: This single-center, prospective trial included 323 consecutive patients undergoing routine cataract extraction for senile cataract. Cataract surgery was performed within 10 minutes of the administration of local anesthesia. The patients were divided into 2 groups: Group A for those who are consuming Khat on a regular basis and Group B for those who had not consumed Khat within the last 3 months. To assess pain experience during injection, intraoperatively, and postoperatively, each patient was asked to use a 10-point pain score chart. Results: The study included 164 males and 159 females. There were 121 patients (37.5%) in Group A and 202 patients (62.5%) in group B. All patients had peribulbar local anesthesia by 2-site injections. Group A had significantly greater pain scores during injection (p=0.000821) and intraoperatively (p=0.000001), but there was no difference in pain score postoperatively. Conclusions: Khat consumption decreases pain threshold and affects patients' comfort during local anesthesia and during surgery in routine cataract surgery. Patients consuming Khat need more care during local anesthesia to make the surgery comfortable.

Breitling LP; Arndt V; Drath C; Rothenbacher D; Brenner H. Smoking and gamma-glutamyltransferase: Opposite interactions with alcohol consumption and body mass index. PLoS ONE 5(9): e-article 13116, 2010. (32 refs.)

Background: Smoking has recently been suggested to synergistically interact with alcohol intake as a determinant of serum gamma-glutamyltransferase (gamma-GT), an emergent powerful predictor of disease and mortality. This study investigated whether this also applies to higher smoking and alcohol exposure ranges and to body mass index (BMI), which likewise is strongly associated with gamma-GT. Methodology/Principal Findings: Analyses were based on occupational health examinations of more than 15,000 German male workers aged 16-64 years, predominantly from the construction industry. Sociodemographics and other health-related information were collected during the exam. Joint associations of smoking and alcohol consumption or BMI with elevated or log-transformed gamma-GT were examined by tabulation and multiple adjusted regression models. Cigarette smoking exerted no effect on gamma-GT in teetotalers, but there was a statistically significant effect of smoking among participants with higher alcohol consumption intensity, odds of elevated gamma-GT being increased by 24% and 27% per additional 10 cigarettes smoked per day in subjects drinking 61-90 and > 90 gram alcohol per day, respectively (P for interaction = 0.039). The interaction was opposite for BMI, where no association was seen in obese subjects, whereas odds of elevated gamma-GT were increased by 24% per 10 cigarettes below 25 kg/m(2) (P for interaction = 0.040). This novel interaction was replicable in an independent cohort. Conclusion: The evidence for opposite interactions of smoking with alcohol and BMI as determinants of serum gamma-GT suggests that different physiological pathways are responsible for the associations between these factors.

Bruce RD; Altice FL; Moody DE; Morse GD; Andrews L; Lin SN et al. Pharmacokinetic interactions between buprenorphine/naloxone and once-daily lopinavir/ritonavir. Journal of Acquired Immune Deficiency Syndromes 54(5): 511-514, 2010. (13 refs.)

Background: This study was conducted to examine the pharmacokinetic interactions between buprenorphine/naloxone (BUP/NLX) and lopinavir/ritonavir (LPV/r) in HIV-seronegative subjects chronically maintained on BUP/NLX. Methods: This study was an open labeled pharmacokinetic study in twelve HIV-seronegative subjects stabilized on at least 3 weeks of BUP/NLX therapy. Subjects sequentially underwent baseline and steady-state pharmacokinetic evaluation of once-daily LPV/r (800/200 mg). Results: Compared to baseline values, BUP AUC0-24h (46.8 vs. 46.2 ng*hr/mL) and Cmax (6.54 vs. 5.88 ng/mL) did not differ significantly after achieving steady-state LPV/r. Similar analyses of norBUP, the primary metabolite of BUP, demonstrated no significant difference in norBUP AUC0-24 hours (73.7 vs. 52.7 ng.h/mL); however, Cmax (5.29 vs. 3.11 ng/mL) levels were statistically different (P < 0.05) after LPV/r administration. Naloxone concentrations were similarly unchanged for AUC0-24 hours (0.421 vs. 0.374 ng.hr/mL) and Cmax (0.186 vs. 0.186 ng/mL). Using standardized measures, no objective opioid withdrawal was observed. The AUC0-24 hours and Cmin of LPV in this study did not significantly differ from historical controls (159.6 vs. 171.3 mu g.hr/mL) and (2.3 vs. 1.3 mu g/mL). Conclusions: The addition of LPV/r to stabilized patients receiving BUP/NLX did not affect buprenorphine pharmacokinetics but did increase the clearance of norbuprenorphine. Pharmacodynamic responses indicate that the altered norbuprenorphine clearance did not lead to opioid withdrawal. Buprenorphine/naloxone and LPV/r can be safely coadministered without need for dosage modification.

Bruce RD; Moody DE; Fang WFB; Chodkowski D; Andrews L; Friedland GH. Tipranavir/ritonavir induction of buprenorphine glucuronide metabolism in HIV-negative subjects chronically receiving buprenorphine/naloxone. American Journal of Drug and Alcohol Abuse 37(4): 224-228, 2011. (34 refs.)

Background: Previous reports on the pharmacokinetic of tipranavir (TPV) and buprenorphine (BUP)/naloxone found that coadministration resulted in an 80% reduction in the area under the curve AUC of the primary BUP metabolite, norBUP, without any pharmacodynamic consequences. This study was conducted to characterize how tipranivir/ritonavir effects the glucuronide metabolites of BUP and may explain the reduction in the norBUP. Methods: HIV-seronegative subjects stabilized on at least 3 weeks of BUP/naloxone sequentially underwent baseline and steady-state pharmacokinetic evaluation of twice daily TPV 500 mg coadministered with ritonavir 200 mg (TPV/r). Results: Twelve subjects were enrolled and ten completed the study. The steady-state pharmacokinetics for BUP-3-glucuronide (BUP-3G) and norBUP-3-glucuronide (norBUP-3G) in the presence and absence of steady-state TPV/r were analyzed. The C(max) of BUP-3G was 8.78 +/- 5.23 ng/mL without TPV/r and increased to 12.7 +/- 11.7 after steady state of TPV/r was achieved. The AUC of BUP-3G was 31.1 +/- 19.4 (ng/mL) (h) without TPV/r and increased to 58. 6 +/- 49.5 after steady state of TPV/r was achieved (p = .0966). In contrast, steady-state norBUP-3G AUC(0-24 h) (p = .0216) and C(max) (p = .0088) were significantly decreased in the presence of steady-state TPV/r. Conclusions. and Scientific Significance: This study further elucidates the effects of TPV/r on glucuronidation. The current evaluation of glucuronide metabolites of BUP and norBUP are suggestive of combined inhibition of Uridine diphosphate (UDP)-glucuronosyltransferase of the 1A family and cytochrome P450 3A4 that spares UGT2B7 leading to a shunting of BUP away from production of norBUP and toward BUP-3G as seen by a statistically significant increase in the AUC of BUP-3G.

Burda K; Czubak A; Nowakowska E; Kus K; Metelska J; Nowakowska A. Interactions of nicotine and drugs used in the treatment of mental illnesses with respect to cognitive functions. (review). Drug Research 60(9): 527-543, 2010. (214 refs.)

Cognitive disorders in the course of mental illnesses are one of the most important and most difficult therapeutic problems related to those illnesses and they regard attention, memory, learning and sensory modulation. The limited number of nicotinic receptors (subtypes alpha 7 and alpha 4 beta 2) seems to cause the incidence and exacerbation of cognitive deficits in such patients. In patients with schizophrenia, the impairment of cognitive processes is also a side-effect of neuroleptics. The characteristics and intensity of the negative effect of antipsychotics on cognitive functions depends on the pharmacological action of those drugs and on the effect on dopamine and serotoninergic receptors in particular. Cognitive function deficits observed in various mental illnesses can be modified with the use of nicotine. A cholinergic neurotransmission system is a common transmission system in the central nervous system. The effect of nicotine on other neurotransmission systems - the dopaminergic and glutaminergic systems - seems to be significant for their efficacious cognitive effects in combination with antipsychotic drugs. Nicotine may also alleviate symptoms of depression, as it amplifies serotoninergic and noradrenergic neuronal activity. When studies on treating cognitive disorders with nicotine are carried out, nicotine's interactions with other drugs used in therapy of those disorders must be taken into account as well as the effect of this substance on neurotransmission systems.

Cabrera MAS; Dip RM; Furlan MO; Rodrigues SL. Use of drugs that act on the cytocrhrome P450 system in the elderly. Clinics 64(4): 273-278, 2009. (28 refs.)

OBJECTIVES: The objective of this study was to analyze medications that act on the cytochrome P450 (CYP450) enzymatic system and are used daily by non-institutionalized elderly individuals. METHODS: A cross-sectional population-based study of elderly individuals (>= 60 years old) was conducted. All continuously used medications with hepatic metabolism via CYP450 that are classified as substrates, inducers or inhibitors were considered. For the analysis, elderly individuals were stratified according to age groups, and hepatic metabolism activity due to daily alcohol consumption and smoking were considered. RESULTS: Elderly individuals (396 in total: 222 women and 174 men) between 60 and 95 years of age (mean: 72.1) were assessed. Use of drugs that act on CYP450 was identified in 61.6% of the subjects. Drug use was observed among 16.2% of the subjects: three drugs among 9.8% and four or more among 6.3% of the subjects. The metabolic activities of the drugs used were classified as substrates (58.8%), inhibitors (14.9%), and inducers (4.3%). The main drugs used were beta-blockers and statins (as substrates), proton pump inhibitors and fluoxetine (as inhibitors), and prednisone and carbamazepine (as inducers). CONCLUSIONS: The results demonstrate that the elderly use high levels of medications that act on CYP450, thereby increasing the risk of drug interactions in a group that is already vulnerable to adverse drug effects.

Caulkins JP; Reuter P; Coulson C. Basing drug scheduling decisions on scientific ranking of harmfulness: False promise from false premises. Addiction 106(11): 1886-1890, 2011. (20 refs.)

In recent years a number of studies have attempted to rank drugs by a single measure of harmfulness as the basis for decisions about scheduling and classification. These efforts are fundamentally flawed, both conceptually and methodologically. The effort to provide a single measure masks the variety of non-comparable dimensions that are relevant, the fact that benefits are ignored for most, but not all, drugs and that the harms of a drug are not invariant to the policy regime chosen. Methodologically, the most prominent recent effort ignores drug interactions and mixes aggregate and individual harms inappropriately. Instead we suggest that multiple dimensions of harm need to be displayed to inform human judgments of what drugs should be scheduled. Harm is not usefully reducible to a single dimension, and even perfect rankings would not constitute a 'sufficient statistic' for determining scheduling decisions.

Caulkins JP; Reuter P; Coulson C. Scales and blinkers, motes and beams: Whose view is obstructed on drug scheduling? (response). Addiction 106(11): 1896-1898, 2011. (7 refs.)

Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. The DAWN Report: Emergency Department Visits Involving Underage Alcohol Use in Combination with Other Drugs. (January 13, 2011). Rockville MD: Substance Abuse and Mental Health Administration, 2011. (6 refs.)

The National Survey on Drug Use and Health (NSDUH), show widespread use of alcohol among adolescents and young adults under the legal drinking age of 21. For example, 2009 NSDUH data showed that more than one half (52.2 percent) of young people aged 12 to 20 reported that they had consumed at least one alcoholic drink in their lifetime, 44.6 percent had consumed alcohol in the past year, 27.2% had consumed alcohol in the past month, and 18.1 percent reported binge alcohol use (i.e., drank five or more drinks on the same occasion on at least 1 day in the 30 days prior to the survey). In addition, 17.5 percent of underage drinkers reported that they had used illicit drugs within 2 hours of their last drinking occasion, a rate more than 3 times as high as that of drinkers aged 21 or older (5.0%). Among underage drinkers who reported illicit drug use within 2 hours of their last drinking occasion, marijuana was the most commonly reported drug used (16.9%). The use of alcohol in combination with illicit and other drugs is of particular concern given the potentially dangerous additive or interactive effects that may result. Research shows that the use of alcohol in combination with other drugs is associated with a variety of negative outcomes such as overdose, suicide, risky sexual behavior, alcohol dependence, depression, and social consequences such as legal, work, and health problems. Of the estimated 188,981 alcohol-related emergency department (ED) visits made by patients aged 12 to 20 in 2008, 70.0% involved alcohol only, and 30.0% involved alcohol in combination with other drugs. Illicit drug use was indicated in more than two thirds (68.4%), and pharmaceutical drugs were involved in more than one half (55.1 percent) of ED visits involving alcohol in combination with other drugs among patients aged 12 to 20. Among adolescents aged 12 to 17, 3 in 10 (30.2%) alcohol-related ED visits made by females involved other drugs, whereas more than 2 in 10 (22.9%) of such visits were made by males; among young adults aged 18 to 20, about one third of such visits made by both males (31.9 percent) and females (33.3 percent) involved other drugs. Of patients aged 12 to 20 who made alcohol-related ED visits involving other drugs, nearly two thirds (64.5%) had no evidence of follow-up care.

Public Domain

Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. The DAWN Report: Emergency Department Visits Involving Ecstasy. (March 24, 2011). Rockville MD: Substance Abuse and Mental Health Administration, 2011. (4 refs.)

The number of drug-related emergency department (ED) visits involving 3,4-methylenedioxymeth-amphetamine (MDMA), commonly known as "Ecstasy," increased significantly from 10,220 visits in 2004 to 17,865 visits in 2008, representing a 74.8%increase. Most ED visits involving Ecstasy in 2008 (69.3 percent) were made by patients aged 18 to 29. An estimated 77.8 percent of these ED visits involved Ecstasy in combination with alcohol or other drugs (including pharmaceuticals or illicit drugs); in fact, 31.3% involved one other drug, 15.0% involved two other drugs, 14.0 percent involved three other drugs, and 17.5 percent involved four or more other drugs. Ecstasy-related ED visits among patients aged 21 or older were more likely than those made by patients aged 20 or younger also to involve alcohol (50.1 vs. 20.4%) or cocaine (43.4 vs. 14.7%). Because it provides psychedelic and stimulant side effects, Ecstasy is associated with dynamic social environments, such as parties or raves, where there is loud music and dancing. Yet the benign nicknames and the lively social environments in which the drug often is used belie the serious health and mental consequences that can result from casual to heavy Ecstasy use. Aside from addiction, Ecstasy use can cause anxiety, agitation, recklessness, increased blood pressure, dehydration, heat stroke, muscle cramping, blurred vision, hyperthermia, heart failure, and kidney failure.2 The social and environmental contexts in which Ecstasy often is used�prolonged vigorous activity in warm environments, such as dancing at crowded parties�can amplify associated cardiovascular health risks.3 Because it also compromises metabolic functioning, Ecstasy taken in combination with other drugs may place users at increased risk for additional and life-threatening drug interactions.3

Public Domain

Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Administration. The DAWN Report: ED Visits Involving the Muscle Relaxant Carisoprodol. (October 27, 2011). Rockville MD: Substance Abuse and Mental Health Administration, 2011. (5 refs.)

This issue of The DAWN Report focuses on carisoprodol-related ED visits involving misuse or abuse in 2009 and trends between 2004 and 2009.The number of carisoprodol-related ED visits involving misuse or abuse doubled from 15,830 visits in 2004 to 31,763 visits in 2009. The number of carisoprodolrelated ED visits involving misuse or abuse by patients aged 50 or older tripled between 2004 and 2009 (from 2,070 to 7,115 visits). The majority of ED visits involving carisoprodol also involved other pharmaceuticals (77 percent); the most common combinations involved narcotic pain relievers (55 percent) and benzodiazepines (47 percent). Of all the carisoprodol visits classified as misuse or abuse, one third (35 percent) of the visits required hospitalization. Carisoprodol (i.e., Soma�, Soprodal�, Vanadom�) is a pharmaceutical typically prescribed to relieve symptoms of muscle pain or discomfort, but it can cause drowsiness and sedation in excess doses Carisoprodol is converted by the liver to meprobamate, a drug used to treat anxiety, that can result in physical and psychological dependence when used in excess. This conversion may account for some of the effects of carisoprodol and likely contributes to its potential for abuse. When carisoprodol is combined with drugs such as narcotic pain relievers, benzodiazepines (used to treat anxiety and insomnia), or alcohol, its sedation effects can be dangerously enhanced. Some users have combined carisoprodol with certain narcotic pain relievers and benzodiazepines to create an effect similar to that of heroin. The Food and Drug Administration (FDA) recommends using carisoprodol no longer than 2 to 3 weeks to avoid the risk for dependence, withdrawal, and abuse.

Public Domain

Dawkins L; Powell J. Effects of nicotine and alcohol on affective responses to emotionally toned film clips. Psychopharmacology 216(2): 197-205, 2011. (45 refs.)

Smoking abstinence can result in decreased affective reactions to positively valenced stimuli, and this can be reversed via smoking. Given their shared ability to trigger nucleus accumbens dopamine release, a priming dose of alcohol may likewise augment positive affective responses during abstinence. The purpose of this study is to replicate our previous finding that compared to satiation, abstinence from smoking will be associated with decreased 'happiness' responses to positively valenced film clips (Study 1) and to explore whether a priming dose of alcohol can substitute for nicotine by concomitantly enhancing such responses (Study 2). In both studies, 'sadness' responses to negatively valenced clips were also included. Thirty-two and 77 smokers, respectively, in Studies 1 and 2 were randomly allocated to abstain from smoking for 10 h (abstinent smokers) or smoke as usual (satiated smokers). Participants then rated the extent to which they felt a list of emotions in response to each of 16 film clips. In Study 2, participants were additionally allocated to an alcohol manipulation in which they received either alcohol or placebo. In Study 1, nicotine administration increased abstinent smokers' ratings of happiness and sadness to the corresponding film clips. In Study 2, nicotine and alcohol both enhanced positive reactivity to happy clips, and their effects were not additive. Alcohol but not nicotine likewise enhanced sadness responses to sad clips. Abstinence from smoking can result in blunting of affective responses to positively toned stimuli, an effect that can be ameliorated by both nicotine and alcohol. The impact of nicotine on negative reactivity appears to be less robust.

Deiss RG; Rodwell TC; Garfein RS. Tuberculosis and illicit drug use: Review and update. (review). Clinical Infectious Diseases 48(1): 72-82, 2009. (180 refs.)

Illicit drug users continue to be a group at high risk for tuberculosis ( TB). Here, we present an updated review of the relationship between TB and illicit drug use, and we summarize more than a decade of new research. Drug users, and injection drug users in particular, have driven TB epidemics in a number of countries. The successful identification and treatment of TB among illicit drug users remain important components of a comprehensive TB strategy, but illicit drug users present a unique set of challenges for TB diagnosis and control. New diagnostic modalities, including interferon-gamma-release assays, offer potential for improved diagnosis and surveillance among this group, along with proven treatment strategies that incorporate the use of directly observed therapy with treatment for drug abuse. Special considerations, including coinfection with viral hepatitis and the rifampin-methadone drug interaction, warrant clinical attention and are also updated here.

Desai NR; Mega JL; Jiang ST; Cannon CP; Sabatine MS. Interaction between cigarette smoking and clinical benefit of clopidogrel. Journal of the American College of Cardiology 53(15): 1273-1278, 2009. (28 refs.)

Objectives: The aim of this study was to examine the interaction between cigarette smoking and the clinical efficacy of clopidogrel in ST-segment elevation myocardial infarction (STEMI). Background: Cigarette smoking induces cytochrome P450 (CYP)1A2, which converts clopidogrel into its active metabolite, and prior studies suggest greater inhibition of platelet aggregation by clopidogrel in smokers of >= 10 cigarettes/day. Methods The effect of clopidogrel compared with placebo on angiographic and clinical outcomes was examined in 3,429 STEMI patients in the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28) randomized trial stratified by smoking intensity as follows: not current smokers (n = 1,732), and smokers of 1 to 9 (n = 206), 10 to 19 (n = 354), 20 to 29 (n = 715), and >= 30 cigarettes/day (n = 422). Logistic regression was used to adjust for other baseline characteristics and interaction terms to test for effect modification. Results: Although clopidogrel reduced the rate of the primary end point of a closed infarct-related artery or death/myocardial infarction before angiography in the CLARITY-TIMI 28 trial, the benefit was especially marked among those who smoked >= 10 cigarettes/day (adjusted odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.37 to 0.66; p < 0.0001) compared with those who did not (adjusted OR: 0.72, 95% CI: 0.57 to 0.91; p = 0.006; p(interaction) = 0.04). Similarly, clopidogrel was significantly more effective at reducing the rate of cardiovascular death, myocardial infarction, or urgent revascularization through 30 days among those who smoked >= 10 cigarettes/ day (adjusted OR: 0.54, 95% CI: 0.38 to 0.76; p = 0.0004) compared with those who did not (adjusted OR: 0.98; 95% CI: 0.75 to 1.28; p = 0.87; p(interaction) = 0.006). Conclusions: Cigarette smoking seems to positively modify the beneficial effect of clopidogrel on angiographic and clinical outcomes. This study demonstrates that common clinical factors that influence the metabolism of clopidogrel might impact its clinical effectiveness.

Dickson AJ; Vorce SP; Levine B; Past MR. Multiple-drug toxicity caused by the coadministration of 4-methylmethcathinone (mephedrone) and heroin. Journal of Analytical Toxicology 34(3): 162-168, 2010. (12 refs.)

An accidental death caused by the combined use of a new designer drug, 4-methylmethcathinone (mephedrone), and heroin is reported. A 22-year old Caucasian male was found unresponsive in his living quarters and transported to the hospital where he died. During autopsy, needle marks were found along the decedent's lower legs and ankles. Investigators discovered the decedent and his roommate had been using "Black Tar" heroin and mephedrone. Routine toxicological analysis detected morphine in the decedent's blood at 0.06 mg/L. Additionally, 6-adeylmorpone, morphine, codeine and doxylamine were detected in his urine. A designer drug screen, employing basic liquid-liquid extraction followed by pentafluropropionic anhydride derivatization, was used to isolate mephedrone from both blood and urine specimens. The derivatized extracts were analyzed by gas chromatography-mass spectrometry (GC-MS) operating in full-scan mode. Quantitative analysis of mephedrone was performed by GC-MS operating in selective ion monitoring mode using methampheatmine-d14 as an internal standard. Mephedrone was confirmed in the decedent's blood and urine at 0.50 and 198 mg/L, respectively. The physiological and pharmacological effects of mephedrone and any associated toxicity have not been reported. However, because of its structural similarities with methcathinone and the high concentration in the decedent's blood, the overall contribution of mephedrone to the death could not be minimized. Therefore the medical examiner reported the cause of death as multiple-drug toxicity and the manner of death as accidental.

Hallinan R; Crettol S; Agho K; Attia J; Besson J; Croquette-Krokar M et al. Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: A transnational study. European Journal of Clinical Pharmacology 65(11): 1113-1120, 2009. (45 refs.)

To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. Cannabis use and higher methadone doses in MMT could in part be a response to --or a cause of- more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Hsu WY; Chiu NY; Liao YC. Rhabdomyolysis and brain ischemic stroke in a heroin-dependent male under methadone maintenance therapy. Acta Psychiatrica Scandinavica 120(1): 76-79, 2009. (25 refs.)

Objective: There are several complications associated with heroin abuse, some of which are life-threatening. Methadone may aggravate this problem. Method: A clinical case description. Results: A 33-year-old man presented with rhabdomyolysis and cerebral ischemic stroke after intravenous heroin. He had used heroin since age 20, and had used 150 mg methadone daily for 6 months. He was found unconsciousness at home and was sent to our hospital. In the ER, his opiate level was 4497 ng/ml. In the ICU, we found rhabdomyolysis, acute renal failure and acute respiratory failure. After transfer to an internal ward, we noted aphasia and weakness of his left limbs. After MRI, we found cerebral ischemic infarction. Conclusion: Those using methadone and heroin simultaneously may increase risk of rhabdomyolysis and ischemic stroke. Patients under methadone maintenance therapy should be warned regarding these serious adverse events. Hypotheses of heroin-related rhabdomyolysis and stroke in heroin abusers are discussed.

Hurley LL; Taylor RE; Tizabi Y. Positive and negative effects of alcohol and nicotine and their interactions: A mechanistic review. (review). Neurotoxicity Research 21(1, special issue): 57-69, 2012. (246 refs.)

Nicotine and alcohol are two of the most commonly abused legal substances. Heavy use of one drug can often lead to, or is predictive of, heavy use of the other drug in adolescents and adults. Heavy drinking and smoking alone are of significant health hazard. The combination of the two, however, can result in synergistic adverse effects particularly in incidences of various cancers (e.g., esophagus). Although detrimental consequences of smoking are well established, nicotine by itself might possess positive and even therapeutic potential. Similarly, alcohol at low or moderated doses may confer beneficial health effects. These opposing findings have generated considerable interest in how these drugs act. Here we will briefly review the negative impact of drinking-smoking co-morbidity followed by factors that appear to contribute to the high rate of co-use of alcohol and nicotine. Our main focus will be on what research is telling us about the central actions and interactions of these drugs, and what has been elucidated about the mechanisms of their positive and negative effects. We will conclude by making suggestions for future research in this area.

Isaac T; Weissman JS; Davis RB; Massagli M; Cyrulik A; Sands DZ et al. Overrides of medication alerts in ambulatory care. Archives of Internal Medicine 169(3): 305-311, 2009. (25 refs.)

Background: Electronic prescribing systems with decision support may improve patient safety in ambulatory care by offering drug allergy and drug interaction alerts. However, preliminary studies show that clinicians override most of these alerts. Methods: We performed a retrospective analysis of 233 537 medication safety alerts generated by 2872 clinicians in Massachusetts, New Jersey, and Pennsylvania who used a common electronic prescribing system from January 1, 2006, through September 30, 2006. We used multivariate techniques to examine factors associated with alert acceptance. Results: A total of 6.6% of electronic prescription attempts generated alerts. Clinicians accepted 9.2% of drug interaction alerts and 23.0% of allergy alerts. High-severity interactions accounted for most alerts (61.6%); clinicians accepted high-severity alerts slightly more often than moderate- or low-severity interaction alerts (10.4%, 7.3%, and 7.1%, respectively; P < .001). Clinicians accepted 2.2% to 43.1% of high-severity interaction alerts, depending on the classes of interacting medications. In multivariable analyses, we found no difference in alert acceptance among clinicians of different specialties (P = .16). Clinicians were less likely to accept a drug interaction alert if the patient had previously received the alerted medication (odds ratio, 0.03; 95% confidence interval, 0.03-0.03). Conclusion: Clinicians override most medication alerts, suggesting that current medication safety alerts may be inadequate to protect patient safety.

Izzo AA; Ernst E. Interactions between herbal medicines and prescribed drugs: An updated systematic review. (review). Drugs 69(13): 1777-1798, 2009. (189 refs.)

The concomitant use of herbal medicines and pharmacotherapy is wide spread. We have reviewed the literature to determine the possible interactions between seven popular herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and conventional drugs. Literature searches were performed using MEDLINE, Cochrane Library and EMBASE and we identified 128 case reports or case series, and 80 clinical trials. Clinical trials indicate that St John's wort (Hypericum perforatum), via cytochrome P450 (CYP) and/or P-glycoprotein induction, reduces the plasma concentrations (and/or increases the clearance) of alprazolam, amitriptyline, atorvastatin, chlorzoxazone, ciclosporin, debrisoquine, digoxin, erythromycin, fexofenadine, gliclazide, imatinib, indinavir, irinotecan, ivabradine, mephenytoin, methadone, midazolam, nifedipine, omeprazole, oral contraceptives, quazepam, simvastatin, tacrolimus, talinolol, verapamil, voriconazole and warfarin. Case reports or case series suggest interactions of St John's wort with adrenergic vasopressors, anaesthetics, bupropion, buspirone, ciclosporin, eletriptan, loperamide, nefazodone, nevirapine, oral contraceptives, paroxetine, phenprocoumon, prednisone, sertraline, tacrolimus, theophylline, tibolone, tryptophan, venlafaxine and warfarin. Ginkgo (Ginkgo biloba) decreases the plasma concentrations of omeprazole, ritonavir and tolbutamide. Clinical cases indicate interactions of ginkgo with anti-epileptics, aspirin (acetylsalicylic acid), diuretics, ibuprofen, risperidone, rofecoxib, trazodone and warfarin. Ginseng (Panax ginseng) may interact with phenelzine and warfarin. Kava (Piper methysticum) increases the clearance of chlorzoxazone (a CYP2E1 substrate) and may interact with alprazolam, levodopa and paroxetine. Garlic (Allium sativum) interacts with chlorpropamide, fluindione, ritonavir and warfarin; it also reduces plasma concentrations of chlorzoxazone (a CYP2E1 probe). Echinacea might affect the clearance of caffeine (a CYP1A2 probe) and midazolam (a CYP3A4 probe). No interactions have been reported for saw palmetto (Serenoa repens). Numerous interactions between herbal medicines and conventional drugs have been documented. While the significance of many interactions is uncertain, several interactions, particularly those with St John's wort, may have serious clinical consequences.

Jain RB; Wang RY. Association of caffeine consumption and smoking status with the serum concentrations of polychlorinated biphenyls, dioxins, and furans in the general U.S. population: NHANES 2003-2004. Journal of Toxicology and Environmental Health. Part A: Current Issues 74(18): 1225-1239, 2011. (36 refs.)

Smoking appears to enhance the body's clearance of dioxins and dioxin-like polychlorinated biphenyls (PCB) by inducing CYP1A2 activity based on studies with a limited number of participants. This hypothesis was evaluated by using data from National Health and Nutrition Examination Survey. Specifically, adult participants were identified and the sums of their serum lipid-adjusted concentrations of 12 polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDD/PCDF) congeners, 33 PCB (total), 26 non-dioxin-like PCB, and 6 mono-ortho (dioxin-like) PCB were determined. In addition to evaluating the association of smoking, the association of caffeine consumption and the interaction between them was evaluated. Data analysis included regression models that were fitted with age, gender, race/ethnicity, and body mass index (BMI). R(2) varied from 34.8 to 66%. Smokers had significantly lower concentrations of total PCDD/PCDF than nonsmokers. New to this study, a siginificant interaction between caffeine consumption and smoking for total PCB was found. When caffeine was consumed less than once a day, smokers had higher concentrations of total PCB than nonsmokers. However, when caffeine was consumed at least once a day, smokers had lower concentrations than nonsmokers. A significant interaction between age and caffeine consumption frequency for each of the PCB groups was also observed. The differences in concentration between younger and older age groups were greater when caffeine was consumed at least once a day than when caffeine was consumed less frequently. Smoking and caffeine consumption need to be considered in the interpretation of human biomonitoring data because they appear to affect the serum concentrations of these chemicals.

Jamois C; Smith P; Morrison R; Riek M; Patel A; Schmitt C et al. Effect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. Addiction Biology 14(3): 321-327, 2009. (14 refs.)

This study was performed to determine the effect of two protease inhibitors. saquinavir (SQV, oral 1000 mg bid) boosted by ritonavir (RTV, oral 100 mg bid), on pharmacokinetics (PK) of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. This was a two-center, open-label. one-sequence cross-over, multiple-dose Study in 13 HIV-negative patients who were on stable methadone therapy (oral, 60-120 mg qd). All patients continued methadone treatment on days 2-15. All patients received SQV/RTV in combination with methadone from days 2-15. PK of methadone was assessed on day 1. (alone) and on day 15 when methadone treatment was combined with SQV/RTV at steady state. Twelve patients completed the study. Median age, body weight and height were 50 years (range: 24-54 years). 80 kg (range: 57-97 kg) and 174 cm (range: 1.63-189 cm). respectively. All patients were Caucasian. and 11 were smokers. Median methadone dose was 85 mg qd. Geometric mean area under Curve of the plasma concentration-time curve over 24 hour Closing interval (AUC(0-24) (hour)) ratio of methadone with and without SQV/RTV was 0.81%, (90% confidence interval: 71-91%). There was no significant plasma protein-binding displacement of methadone by SQV/RTV The combination of SQV/RTV and methadone was well tolerated. There were no clinically significant adverse events or significant changes in laboratory parameters, electrocardiograms or vital signs. The 19% decrease in R-methadone AUC(0-24) (hour) in the presence of SQV/RTV was not clinically relevant. There appears to be no need for methadone dose adjustment when methadone (60-120 mg qd) and SQV/RTV (1000/100 mg bid) are coadministered.

Kalichman SC; Amaral CM; White D; Swetsze C; Pope H; Kalichman MO et al. Prevalence and clinical implications of interactive toxicity: Beliefs regarding mixing alcohol and antiretroviral therapies among people living with HIV/AIDS. AIDS Patient Care and STDs 23(6): 449-454, 2009. (18 refs.)

Alcohol use is a barrier to medication adherence. Beyond the cognitive effects of intoxication, people living with HIV/AIDS who believe that alcohol should not be mixed with their medications may temporarily stop taking medications when drinking. To examine the effects of alcohol-treatment beliefs on HIV treatment adherence. People living with HIV/AIDS who were receiving treatment (n = 145) were recruited from community and clinical services during the period between January 2006 and May 2008 to complete measures of substance use and alcohol-antiretroviral (ARV) interactive toxicity beliefs (e.g., alcohol breaks down HIV medications so they will not work). Medication adherence was monitored using unannounced telephone-based pill counts. Forty percent of participants were currently using alcohol and nearly one in four drinkers reported stopping their medications when drinking. Beliefs that mixing alcohol and medications is toxic were common among drinkers and nondrinkers, with most beliefs endorsed more frequently by non-drinkers. Hierarchical regression analysis showed that stopping ARVs when drinking was associated with treatment nonadherence over and above quantity/frequency of alcohol use and problem drinking. Beliefs that alcohol and ARVs should not be mixed and that treatments should be interrupted when drinking are common among people living with HIV/AIDS. Clinicians should educate patients about the necessity of continuing to take ARV medications without interruption even if they are drinking alcohol.

Kaminer Y; Goldberg P; Connor DF. Psychotropic medications and substances of abuse interactions in youth. Substance Abuse 31(1): 53-57, 2010. (25 refs.)

The majority of youth with substance use disorders (SUDs) manifest one or more co-occurring psychiatric disorders. Consequently, many of these youths are being prescribed with psychotropic medications. As prescribing rates continue to increase for early-onset psychiatric disorders, potential risk for substance of abuse-psychiatric medication interactions may be enhanced. Because this type of drug-drug interaction has received little attention in the scientific literature, the authors conducted a systematic literature search examining the potential interactive adverse effects between psychotropic medications and substances of abuse in youth. Regardless of the scarcity of psychotropic medications-substance of abuse interactions found, it is important to stay vigilant due to the continued introduction of new classes of medications as well as the ever-changing map of street drugs.

Kapur BM; Hutson JR; Chibber T; Luk A; Selby P. Methadone: A review of drug-drug and pathophysiological interactions. (review). Critical Reviews In Clinical Laboratory Sciences 48(4): 171-195, 2011. (236 refs.)

Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to alpha(1)-acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone's fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.

Kaye S; Darke S; Duflou J. Methylenedioxymethamphetamine (MDMA)-related fatalities in Australia: Demographics, circumstances, toxicology and major organ pathology. Drug and Alcohol Dependence 104(3): 254-261, 2009. (51 refs.)

Aim: To examine the demographic characteristics, circumstances, toxicology and major organ pathology of MDMA-related deaths in Australia. Methods: Retrospective review of cases in which MDMA was a cause of death, as identified from the National Coronial Information System. Results: 82 cases over a 5-year period were identified. The majority of decedents were male (83%), with a median age of 26 years. Deaths were predominantly due to drug toxicity (82%), with MDMA the sole drug causing death in 23% of cases, and combined drug toxicity in 59% of cases. The remaining deaths (18%) were primarily due to pathological events/disease or injury, with MDMA a significant contributing condition. Cardiovascular pathology, typically atherosclerosis, was detected in 58% of decedents, with moderate-severe atherosclerosis in 23% of cases. The prevalence of such pathology is higher than that expected among similarly aged members of the general population. Cerebrovascular pathology, primarily cerebral haemorrhage and hypoxic damage, was present in 12% of cases. Conclusions: MDMA has contributed to a clinically significant number of deaths in Australia. The prevalence of cardiovascular pathology was similar to that among methamphetamine and cocaine fatalities. Whilst cardiovascular pathology may reflect the use of other stimulants, the cardiotoxic properties of MDMA have been well-documented. Future studies examining MDMA-related morbidity and mortality in the context of other risk factors are recommended. Overall, the current study highlights the need to educate users about the potential harms of MDMA use, particularly that in conjunction with other stimulants, opioids and alcohol, which are known to increase overall toxicity.

Khalsa JH; Elkashef A. Drug interactions between antiretroviral medications and medications used in the treatment of drug addiction: Research needs. American Journal on Addictions 19(1): 96-100, 2010. (32 refs.)

Today substance dependence is one of the major public health problems in the world with millions of people abusing legal and illegal drugs. In addition, almost one-third of the world's population suffers with one or more infections. Both drugs of abuse and infections are associated with serious medical and health consequences, some of which may be exacerbated by the occurrence of pharmacokinetic and/or pharmacodynamic interactions between medications used in the treatment of these conditions when they co-occur. This review briefly discusses issues surrounding clinical management related to drug interactions experienced by substance abusing patients. The emphasis of this paper is on the research needed to further study the extent, nature, and underlying molecular/genetic mechanism(s) of interactions between drugs of abuse, medications used in the treatment of drug addiction, and co-occurring infections.

Launiainen T; Vuori E; Ojanpera I. Prevalence of adverse drug combinations in a large post-mortem toxicology database. International Journal of Legal Medicine 123(2): 109-115, 2009. (40 refs.)

The prevalence of important adverse drug combinations was studied among the 37,367 cases included in the Finnish post-mortem toxicology database during 2000-2006. The new SFINX interaction database (Swedish, Finnish, INteraction X-referencing) was utilised to identify adverse drug combinations. Consequently, the 24 drugs chosen for the study generated 96 two-compound combinations possessing potentially severe interactions. The total number of hits for the combinations found in the post-mortem database was 267, which accounts for approximately 0.71% of all cases. The potential role of adverse drug interaction (ADI) in these cases was evaluated from the background information and death certificate. The possible ADI cases comprised 23% of all hits and 0.17% of all cases analysed. In cases with a pharmacodynamic mechanism, the most prominent combinations were medicines causing serotonin syndrome or a beta(1)-blocker with verapamil or diltiazem. In cases with a pharmacokinetic mechanism, half of the cases involved digoxin in combination with verapamil. In one third of the possible ADI cases, a forensic pathologist had noted the studied compounds as an underlying or contributing cause of death, although the agents' specific role in ADIs was rarely recognised.

Liang C; Chen J; Gu W; Wang H; Xue Z. Chronic alcoholism increases the induction dose of propofol. Acta Anaesthesiologica Scandinavica 55(9): 1113-1117, 2011. (16 refs.)

Background: The present study was designed to investigate the possible effect of chronic alcohol intake on propofol and remifentanil requirements, which was determined by quantifying the 50% (EC(50)) and 95% (EC(95)) effective effect-site concentrations for propofol and remifentanil at loss of consciousness (LOC) and after a painful stimulus. Methods: Thirty male patients (alcoholic group; n = 30) with chronic alcoholism and 30 patients (control group; n = 30) with a history of small alcohol intake were anaesthetized with propofol and remifentanil by target-controlled infusion. The predicted drug concentrations and Bispectral Index (BIS) values were recorded at LOC and after no response to painful stimuli. Results: The EC50 and EC95 of propofol at LOC in alcoholic group were 3.15 [95% confidence interval (CI), 2.77-3.37] and 4.05 (95% CI, 3.18-5.26) mg/ml, respectively, and those of the control group were 2.21 (95% CI, 1.92-2.86) and 3.04 (95% CI, 2.45-4.64) mg/ml, respectively. The EC50 and EC95 of remifentanil measured after no response to painful stimuli in the alcoholic group were 3.02 (95% CI, 2.70-3.38) and 4.98 (95% CI, 4.56-5.89) ng/ml, respectively, and those of the control group were 2.95 (95% CI, 2.68-3.33) and 4.86 (95% CI, 4.55-5.92) ng/ml, respectively. The EC50 and EC95 values of propofol at LOC in the control group were significantly lower than that of the alcoholic group. Conclusions: These findings suggest that the induction dose requirements of propofol are increased in alcoholic patients anaesthetized with propofol and remifentanil administered by target controlled infusion.

Lyne J; O'Donoghue B; Clancy M; Kinsella A; O'Gara C. Concurrent cocaine and alcohol use in individuals presenting to an addiction treatment program. Irish Journal of Medical Science 179(2): 233-237, 2010. (14 refs.)

National population surveys and information from the National Drug Treatment Reporting System indicate cocaine use is increasing. There is a paucity of studies focusing on comorbid cocaine and alcohol use in Ireland. The aims of the study are to examine comorbid cocaine and alcohol use patterns in those under 45 years, presenting to a national addiction treatment unit for alcohol and drug dependence. A retrospective review of the substance misuse behavior of 465 individuals participating in an addiction rehabilitation programme for alcohol dependence. Cocaine use among this population rose significantly between 1995 (8%) and 2006 (37.9%). There was a significant association between lifetime reported cocaine use and both psychotic disorders and deliberate self harm. Overall, the use was highest among younger age group and this declined steadily with age. Cocaine use among the alcohol-dependent population is an increasing problem in the Republic of Ireland, and poses a problem of higher toxicity associated with concurrent cocaine and alcohol use.

Maxwell JC; McCance-Katz EF. Indicators of buprenorphine and methadone use and abuse: What do we know? American Journal on Addictions 19(1): 73-88, 2010. (56 refs.)

Abuse of prescription opioids is a growing problem. The number of methadone pain pills distributed now exceeds liquid methadone used in opioid treatment, and the increases in buprenorphine indicators provide evidence of the need to monitor and intervene to decrease the abuse of this drug. The need for additional and improved data to track trends is discussed, along with findings as to the characteristics of the users and combinations of drugs. Data on toxicities related to methadone or buprenorphine, particularly in combination with other prescribed drugs, are presented and clinical implications and considerations are offered. These findings underscore the need for physicians to be aware of potential toxicities and to educate their patients regarding these issues.

McCance-Katz EF; Jatlow P; Rainey PM. Effect of cocaine use on methadone pharmacokinetics in humans. American Journal on Addictions 19(1): 47-52, 2010. (33 refs.)

Chronic cocaine use has been shown to significantly decrease buprenorphine concentrations in the blood with potential for adverse events and poor treatment response. In this study, we investigated whether a similar drug interaction occurred between cocaine and methadone. In a retrospective analysis, methadone pharmacokinetics were compared for those who were either regular cocaine users (N = 16) or with intermittent or no cocaine use (N = 23). Participants who used cocaine regularly showed a significant decrease in C-min (p = .04) and a trend for decreased AUC (p = .09) and more rapid methadone clearance (p = .08). Regular cocaine use may adversely impact treatment outcomes for opioid dependence in those receiving methadone maintenance by decreasing methadone exposure.

McCance-Katz EF; Mandell TW. Drug interactions of clinical importance with methadone and buprenorphine. American Journal on Addictions 19(1): 2-3, 2010. (2 refs.)

McCance-Katz EF; Moody DE; Morse GD; Ma Q; Rainey PM. Lack of clinically significant drug interactions between nevirapine and buprenorphine. American Journal on Addictions 19(1): 30-37, 2010. (34 refs.)

This study was conducted to determine whether drug interactions of clinical importance occur between buprenorphine, an opioid partial agonist medication used in treatment of opioid dependence, and the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n = 7) participated in 24-hour sessions to determine the pharmacokinetics of buprenorphine alone and of buprenorphine and nevirapine following administration of 200 mg nevirapine daily for 15 days. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined prior to and following nevirapine administration. Modest decreases were observed for AUC for buprenorphine and its metabolites. There was a trend for more rapid clearance of both buprenorphine (p = .08) and buprenorphine-3-glucuronide (p = .08). While no single effect reached statistical significance, the joint probability that the consistent declines in all measures of exposure were due to chance was extremely low, indicating that nevirapine significantly reduces overall exposure to buprenorphine and buprenorphine metabolites. Clinically significant consequences of the interaction were not observed. Buprenorphine did not alter nevirapine pharmacokinetics. Dose adjustments of either buprenorphine or nevirapine are not likely to be necessary when these drugs are coadministered for the treatment of opiate dependence and HIV disease.

McCance-Katz EF; Moody DE; Prathikanti S; Friedland G; Rainey PM. Rifampin, but not rifabutin, may produce opiate withdrawal in buprenorphine-maintained patients. Drug and Alcohol Dependence 118(2-3): 326-334, 2011. (43 refs.)

Background: This series of studies examines the pharmacokinetic/pharmacodynamic interactions between buprenorphine, an opioid partial agonist increasingly used in treatment of opioid dependence, and rifampin, a medication used as a first line treatment for tuberculosis; or rifabutin, an alternative antituberculosis medication. Methods: Opioid-dependent individuals on stable doses of buprenorphine/naloxone underwent two, 24-h blood sampling studies: (1) for buprenorphine pharmacokinetics and (2) following 15 days of rifampin 600 mg daily or rifabutin 300 mg daily for buprenorphine and rifampin or rifabutin pharmacokinetics. Results: Rifampin administration produced significant reduction in plasma buprenorphine concentrations (70% reduction in mean area under the curve (AUC); p = <0.001) and onset of opiate withdrawal symptoms in 50% of participants (p = 0.02). While rifabutin administration to buprenorphine-maintained subjects resulted in a significant decrease in buprenorphine plasma concentrations (35% decrease in AUC; p <0.001) no opiate withdrawal was seen. Compared with historical control data, buprenorphine had no significant effect on rifampin pharmacokinetics, but was associated with 22% lower rifabutin mean AUC (p = 0.009), although rifabutin and its active metabolite concentrations remained in the therapeutic range. Conclusions: Rifampin is a more potent inducer of buprenorphine metabolism than rifabutin with pharmacokinetic and pharmacodynamic adverse consequences. Those patients requiring rifampin treatment for tuberculosis and receiving buprenorphine therapy are likely to require an increase in buprenorphine dose to prevent withdrawal symptoms. Rifabutin administration was associated with decreases in buprenorphine plasma concentrations, but no clinically significant adverse events were observed.

McCance-Katz EF; Rainey PM; Moody DE. Effect of cocaine use on buprenorphine pharmacokinetics in humans. American Journal on Addictions 19(1): 38-46, 2010. (46 refs.)

The effect of chronic cocaine use on buprenorphine pharmacokinetics was investigated to identify drug interactions and potential toxicities. In a retrospective analysis, pharmacokinetics were compared for 16 studies completed on subjects who were regular cocaine users and 74 studies on subjects who used cocaine only occasionally or not at all. All participants were stably maintained on buprenorphine/naloxone 16/4 mg daily. Participants who used cocaine regularly had lower buprenorphine exposure (AUC 34% lower; C-max 27% lower and C-24 37% lower; p < .001 for all comparisons). Regular cocaine users were younger (p = .0007), and used more heroin (p = .004) and cocaine (p < .0001). Regular cocaine use may result in lower buprenorphine plasma concentrations with potential for adverse clinical outcomes.

McCance-Katz EF; Sullivan LE; Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: A review. American Journal on Addictions 19(1): 4-16, 2010. (92 refs.)

Drug interactions are a leading cause of morbidity and mortality. Methadone and buprenorphine are frequently prescribed for the treatment of opioid addiction. Patients needing treatment with these medications often have co-occurring medical and mental illnesses that require medication treatment. The abuse of illicit substances is also common in opioid-addicted individuals. These clinical realities place patients being treated with methadone and buprenorphine at risk for potentially toxic drug interactions. A substantial literature has accumulated on drug interactions between either methadone or buprenorphine with other medications when ingested concomitantly by humans. This review summarizes current literature in this area.

McNally L; Ratschen E. The delivery of stop smoking support to people with mental health conditions: A survey of NHS stop smoking services. BMC Health Services Research 10: article 179, 2010. (10 refs.)

Background: People with mental health problems exhibit smoking rates up to three times that of the general population. Metabolic interactions between hydrocarbon agents in tobacco smoke and some antipsychotic drugs account for a change in medication metabolism on stopping smoking, and potentially for increased blood levels. Nicotine withdrawal can mimic or exacerbate symptoms of mental illness. Therefore, appropriate screening for mental health problems and liaison with local mental health care providers should be a priority for NHS Stop Smoking Services. The present study aimed to examine this issue through surveys with NHS Stop Smoking Service staff in London. Methods: Semi-structured telephone interviews were conducted with one senior staff member from 27 of the 29 NHS Stop Smoking Services in London. Results: It was found that only a minority of services routinely check the mental health status or mental health service use of their clients. In addition, most services do not routinely implement special checks or actions when mental health problems are revealed. It was notable that respondents reported a lack of strategic drivers supporting work with mental health patients (such as targets relating to successful quits) as well as a low level of partnership working with local mental health care providers. Conclusions: NHS Stop Smoking Services may not be operating appropriate procedures for supporting people with mental health problems. There is a need for local protocols to be implemented that include routine screening for mental health issues and liaison with mental health care providers.

Mohamed WMY; Ben Hamida S; Cassel JC; de Vasconcelos AP; Jones BC. MDMA: Interactions with other psychoactive drugs. (review). Pharmacology, Biochemistry And Behavior 99(4): 759-774, 2011. (335 refs.)

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most widely abused illegal drugs. Some users self-report euphoria and an increased perception and feeling of closeness to others. When taken in warm environments. MDMA users may develop acute complications with potential fatal consequences. In rodents, MDMA increases locomotor activity and, depending on ambient temperature, may produce a dose-dependent, potentially lethal hyperthermia. Like most other recreational drugs, MDMA is frequently taken in combination with other substances including tobacco, EtOH, marijuana, amphetamines, cocaine and, caffeine. Although polydrug use is very common, the understanding of the effects of this multiple substance use, as well as the analysis of consequences of different drug-drug associations, received rather little attention. The purpose of this review is to summarize our current knowledge about the changes on MDMA-related behavior, pharmacology, and neurotoxicity associated with co-consumption of other drugs of abuse and psychoactive agents.

Molina DK; Hargrove VM. Fatal cocaine interactions: A review of cocaine-related deaths in Bexar County, Texas. American Journal of Forensic Medicine and Pathology 32(1): 71-77, 2011. (40 refs.)

Although cocaine is a widely abused illicit substance that is known to cause death, deaths due to its use appear to occur in a minority of those who use it. This report was designed to review drug-related deaths due to cocaine, and the concomitant use of other drugs/medications. A retrospective review of drug deaths at the Bexar County Medical Examiner's Office in San Antonio, Texas, was undertaken for cases where cocaine was one of the drugs implicated in causing death. Analysis was performed comparing the concentrations of cocaine and benzoylecgonine present and the absence or presence of other drugs. The data obtained showed that cocaine was toxic over a large range with deaths occurring at concentrations ranging from 0.01 to 78 mg/L. Analyses also indicated an increased lethality when cocaine is used in combination with ethanol, heroin, opiates, and antidepressant/antipsychotic medications, which is consistent with previous reports and research. Antihistamine data showed that there may be relationship between increased toxicity and coingestion, although more research is necessary.

Nathisuwan S; Dilokthornsakul P; Chaiyakunapruk N; Morarai T; Yodting T; Piriyachananusorn N. Assessing evidence of interaction between smoking and warfarin a systematic review and meta-analysis. (review). Chest 139(5): 1130- 1139, 2011. (29 refs.)

Background: Chronic smoking, theoretically, can interfere with warfarin metabolism through enzyme-inducing effects of polycyclic aromatic hydrocarbons. However, clinical evidence of interactions between warfarin and smoking are inconclusive. This study aimed to systematically review all relevant clinical evidence of this interaction. Methods: We performed a systematic search using computerized databases, including PubMedicine, Embase, Cochrane Central Register of Controlled Trials, CINAHL, Allied and Complementary Medicine, PsycINFO, International Pharmaceutical Abstracts, and ClinicalTrials.gov from 1966 to December 2008. Keywords included "warfarin" with "smoking," "tobacco," "cigarette," and "polycyclic aromatic hydrocarbons." Original articles reporting interaction between warfarin and smoking were included. All articles were reviewed independently by two investigators for study design, population, outcomes, and quality of evidence. Results: Of the 1,240 studies retrieved, one experimental pharmacokinetic study and 12 cross-sectional studies were included. The pooled analyses of multivariate studies suggested that smoking was associated with a 12.13% (95% CI, 6.999-17.265; P < .001) increase in warfarin dosage requirement and an additional 2.26 mg (95% CI, 2.529-7.042; P = .355) per week compared with nonsmoking. Additional sensitivity analysis of four multivariate studies with adjustment for pharmacogenomic factors suggested that smoking was associated with a 13.21% (95% CI, 8.59%-17.83%; P < .001) increase in warfarin dosage requirement compared with nonsmokers. Results of an experimental pharmacokinetic study lend theoretical support to the findings. Conclusions: Evidence suggests that smoking may potentially cause significant interaction with warfarin by increasing warfarin clearance, which leads to reduced warfarin effects. Close monitoring of warfarin therapy should be instituted when there is a change in smoking status of patients requiring warfarin therapy.

Ng W; Uchida H; Ismail Z; Mamo DC; Rajji TK; Remington G et al. Clozapine exposure and the impact of smoking and gender: A population pharmacokinetic study. Therapeutic Drug Monitoring 31(3): 360-366, 2009. (49 refs.)

The primary objective of this study was to evaluate the magnitude and variability of concentration exposure to clozapine and norclozapine in a real-world clinical setting, with a focus on smoking status, using population pharmacokinetic methodologies. A retrospective review of plasma clozapine and norclozapine concentrations taken from inpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007 was conducted. A nonlinear mixed-effects model was developed using NONMEM, including age, gender, weight, smoking status, and dosage formulation as covariates. Pharmacokinetic parameters and interindividual and residual variabilities were estimated with 1- and 2-compartment models. A total of 519 plasma clozapine concentrations from 197 patients (138 males; mean +/- SD age, 38 +/- 13 years; schizophrenia spectrum disorder 98.2%) were included for the analysis. A 1-compartment model with first-order absorption and elimination best described the data. Apparent volume of distribution was fixed to a previously reported value in the literature of 7 L/kg. The population-predicted oral clearance of clozapine and norclozapine was 18.0 and 39.0 L/h, respectively; both the predicted clearance values vary nearly 6-fold (range, 9.18-59.06 and 16.29-97.84 L/h, respectively). For clozapine; smokers and males showed increased oral clearance by 6.0 and 4.5 L/h, respectively. For norclozapine, smokers and male gender were associated with an increased oral clearance of 11.3 and 7.6 L/h, respectively. The formulation of clozapine administered had an impact on the absorption rate with a Ka of 0.14/h for tablet and 10.3/h for the suspension form. The data suggest that smoking and male gender are associated with lower exposure to clozapine and norclozapine due to the higher oral clearance. These findings may account for some of the variability in clozapine exposure and have important implications for individualized drug dosing and therapeutic drug monitoring.

Nieminen TH; Hagelberg NM; Saari TI; Neuvonen M; Neuvonen PJ; Laine K et al. Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir. European Journal of Clinical Pharmacology 66(10): 977-985, 2010. (49 refs.)

This study aimed to investigate the effect of antivirals ritonavir and lopinavir/ritonavir on the pharmacokinetics and pharmacodynamics of oral oxycodone, a widely used opioid receptor agonist used in the treatment of moderate to severe pain. A randomized crossover study design with three phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg, or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioral effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis. Ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-fold (range 1.9- to 4.3-fold; P < 0.001) and 2.6-fold (range 1.9- to 3.3-fold; P < 0.001). The mean (+/- SD) elimination half-life increased after ritonavir and lopinavir/ritonavir from 3.6 +/- 0.6 to 5.6 +/- 0.9 h (P < 0.001) and 5.7 +/- 0.9 h (P < 0.001), respectively. Both ritonavir (P < 0.001) and lopinavir/ritonavir (P < 0.05) increased the self-reported drug effect of oxycodone. Ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse effects.

Pearl PL; Drillings IM; Conry JA. Herbs in epilepsy: Evidence for efficacy, toxicity, and interactions. (review). Seminars in Pediatric Neurology 18(3): 203-208, 2011. (49 refs.)

Herbs and dietary supplements enjoy widespread use in the treatment of epilepsy although supportive data yielding efficacy and safety are lacking. Ten specific products, American hellebore, betony, blue cohosh, kava, mistletoe, mugwort, pipsissiwa, skullcap, valerian, and melatonin, have either multiple-cited recommendations for use in epilepsy or a rationale for antiepileptic action and are discussed in detail. These items paradoxically often have a proconvulsant effect in addition to potentially serious adverse effects. Herb-drug interactions also occur at the level of the P450 hepatic enzyme system of drug catabolism and the P-glycoprotein transport system regulating the entry of exogenous compounds into the vasculature or blood-brain barrier. Thus, significant pharmacokinetic interactions may occur, in addition to pharmacodynamic interactions and proconvulsant effects of alternative medications themselves. Patients should be inquired as to the nature of any alternative medicine products they are using, with the view that these products may be reasonable if traditional antiepileptic drug therapy is continued, potential adverse effects of the alternative agents are monitored, and the alternative and traditional agents do not conflict.

Penetar DM; Kouri EM; McCarthy EM; Lilly MM; Peters EN; Juliano TM et al. Nicotine pretreatment increases dysphoric effects of alcohol in luteal-phase female volunteers. International Journal of Environmental Research and Public Health 6(2): 526-546, 2009. (51 refs.)

The present report shows that nicotine enhances some of alcohol's positive and negative effects in women and that these effects are most pronounced during the luteal phase of the menstrual cycle. Ten low progesterone and 10 high progesterone/luteal-phase women received nicotine patch pretreatments (placebo or 21 mg) 3 hours before an alcohol challenge (0.4 g/kg). Subjective effects were recorded on mood adjective scales and the Addiction Research Center Inventory (ARCI). Heart rate and skin temperature were recorded. Luteal-phase women reported peak positive (e.g. "stimulated") and peak negative effects (e.g. "clumsy", "dizzy") almost twice as great as low progesterone women.

Price S; James C; Deighton C. Methotrexate use and alcohol. Clinical and Experimental Rheumatology 28(5, supplement 61): S114-S116, 2010. (26 refs.)

A literature review was performed to look at the interactions between alcohol and methotrexate in non-malignant disease. The evidence from research into psoriasis and inflammatory arthritis, and an overview of international and national guidelines, was amalgamated into some consensus recommendations.

Proenca P; Franco JM; Mustra C; Marcos M; Pereira AR; Corte-Real F et al. An UPLC-MS/MS method for the determination of valproic acid in blood of a fatal intoxication case. Journal of Forensic and Legal Medicine 18(7): 320-324, 2011. (50 refs.)

Valproic acid (VPA) has been used as an anticonvulsant for the treatment of epilepsy. The authors present a fatal case involving a 45-year-old female, found dead lying in bed with empty tablets of Diplexil (R) next to her. She was a chronic alcoholic and epileptic who had been under psychiatric treatment, having repeatedly demonstrated intent to commit suicide. A rapid method was developed and validated to determine VPA in blood by ultra-performance liquid chromatography (UPLC) coupled with tandem mass spectrometry (MS/MS) with electrospray ionization source in negative ion mode. The method involved sample treatment with phosphoric acid followed by solid-phase extraction. Chromatographic separation was achieved using an Acquity UPLC (R) BEH (2.1 x 50 mm id, 1.7 mu m) column and a mobile phase containing ammonium acetate and acetonitrile, at a 0.5 mL/min flow rate. Detection and quantification of VPA was achieved using multiple reaction monitoring (MRM). The MS/MS transitions used for monitoring were m/z 143.1-143.1 for valproic acid and m/z 296.1-205.0 for hydrochlorothiazide used as an internal standard (IS). The limit of quantification (LOQ) was 0.5 mu g/mL and the method was linear in the concentration range of 0.5-100 mu g/mL. The coefficients of variation obtained for accuracy and precision were less than 10% and the mean recovery was 95% for the three concentrations levels studied (5 mu g/mL,10 mu g/mL and 50 mu/mL). Toxicological results showed high concentration of VPA (556 mu g/mL) and therapeutic concentrations of tiapride, mirtazapine, oxazepam and nordiazepam. Blood sample analysis also revealed the presence of ethanol at a concentration of 1.34 g/L. A specific, selective and sensitive method for the determination of VPA in blood was developed and can be used in routine forensic investigation. Toxicological results led the pathologist to rule that death was due to an intoxication caused by the simultaneous ingestion of high VPA concentrations and alcohol, with a suicidal legal-medical etiology.

Quaak M; van Schayck CP; Knaapen AM; van Schooten FJ. Implications of gene-drug interactions in smoking cessation for improving the prevention of chronic degenerative diseases. (review). Mutation Research 667(1-2, Special Issue): 44-57, 2009. (137 refs.)

Tobacco smoking continues to be the major preventable cause of premature morbidity and mortality throughout the world. Recent research strongly suggests that genetic background is associated with several aspects of smoking (e.g. initiation, maintenance, cessation, number of cigarettes smoked, indicators of nicotine dependence (ND) and nicotine withdrawal). Variations in two broad classes of genes have been shown to influence smoking: (1) genes that may influence the response to nicotine (e.g. nicotine metabolism, nicotinic receptors) and (2) genes that may predispose to addictive behaviour via their effects on key neurotransmitter pathways (e.g. dopamine, serotonin and opioid). Since these genetic variants might also influence the response to smoking cessation pharmacotherapies, smoking cessation rates might be increased by determining which treatment would be most effective based on the smoker's genetic background. This is expected to result in a more efficient use of smoking cessation therapies, increased cessation rates and ultimately, in reduced deaths from smoking. Until now, most research on the influence of genetic variation on smoking cessation pharmacotherapy has been directed to the two most widely accepted and licensed forms of smoking cessation therapy: nicotine replacement therapy (NRT) and the antidepressant bupropion. overall, genotypes associated with increased dopamine availability seem to predict a better response to bupropion, while smokers with genotypes associated with reduced dopamine levels probably achieve better quit rates with NRT. A decreased metabolism for the drug used (e.g. bupropion or NRT), results in increased cessation rates as well. Furthermore, smokers with reduced dopaminergic and nicotinic receptor activity variants may experience greater benefit from nicotine spray, while smokers with increased activity variants in the opioid receptor may have greater success with transdermal patches. Thus it seems that genetic information may give directions in determining which treatment would be most effective for an individual smoker. However, several challenges will still have to be overcome before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.

Ray LA; MacKillop J; Tidey JW; Gwaltney C; Miranda R; McGeary J et al. A preliminary pharmacogenetic investigation of adverse events from topiramate in heavy drinkers. Experimental and Clinical Psychopharmacology 17(2): 122-129, 2009. (38 refs.)

Topiramate, an anticonvulsant medication, is an efficacious treatment for alcohol dependence. To date, little is known about genetic moderators of side effects from topiramate. The objective of this study was to examine 3 single nucleotide polymorphisms (SNPs) of the glutamate receptor GluR5 gene (GRIK1) as predictors of topiramate-induced side effects in the context of a laboratory study of topiramate. Heavy drinkers (n = 51, 19 women and 32 men), 75% of whom met criteria for an alcohol use disorder, completed a 5-week dose escalation schedule to a target dose of either 200 or 300 mg or matched placebo. The combined medication groups were compared with placebo-treated individuals for side effects at target dose. Analyses revealed that an SNP in intron 9 of the GRIK1 gene (rs2832407) was associated with the severity of topiramate-induced side effects and with serum levels of topiramate. Genes underlying glutamatergic neurotransmission, such as the GRIK1 gene, may help predict heterogeneity in topiramate-induced side effects. Future studies in larger samples are needed to more fully establish these preliminary findings.

Reddick AD; Hodge K; Morrison WG. Effect of concomitant opiate ingestion on paracetamol levels in acute overdose. Emergency Medicine Journal 27(10): 742-744, 2010. (11 refs.)

Aim: To assess whether the co-ingestion of opiates in acute paracetamol overdose has an effect on the paracetamol level 4 h after ingestion. Methods: A prospective observational study was performed in the emergency department of a teaching hospital. The paracetamol levels at 4 h of consecutive patients who had taken an overdose of either paracetamol alone or in conjunction with an opiate were collected over a 4-month period. The data were then analysed. Results: After exclusions, the results of 21 patients who took paracetamol alone and 20 who took paracetamol and an opiate showed that paracetamol levels were significantly lower at 4 h if there was co-ingestion of an opiate. Analysis shows that opiate ingestion is a predictor for paracetamol levels at 4 h. Conclusion: Co-ingestion of opiate decreases the serum paracetamol level at 4 h. If opiate and paracetamol are taken together, there is a case for a repeat measurement of the paracetamol level if the level at 4 h is lower than would be expected in selected patients.

Roache JD; Kahn R; Newton TF; Wallace CL; Murff WL; De La Garza R et al. A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram. Drug and Alcohol Dependence 119(1-2): 37-45, 2011. (32 refs.)

Background: A majority of cocaine addicts have a comorbid alcohol use disorder. Previous studies demonstrated efficacy of disulfiram in the treatment of cocaine dependence among patients with comorbid alcohol use disorder or opioid dependence. However, the cardiac risks of a disulfiram-ethanol reaction (DER) in individuals who drink, when coupled with the cardiac effects of cocaine, could result in significant toxicity or lethality due to the 3-way drug interaction. Aims: This study examined the safety of combining cocaine (30 mg i.v,) and ethanol (0.4 g/kg i.v.) in disulfiram-treated (0, 250, and 500 mg/d, p.o.) cocaine-dependent research volunteers. Results: The results showed that disulfiram did not enhance the cardiovascular effects of cocaine and may have reduced the subjective high from cocaine. In contrast, ethanol produced adverse ECG changes including QTc prolongation and a DER consisting of hypotension, tachycardia, nausea, and flushing in disulfiram-treated subjects. The severity of the DER was related to disulfiram dose and the trial with 500 mg/d was stopped prematurely due to safety concerns. The DER-related hypotension and tachycardia seen with ethanol infusion alone in disulfiram-treated subjects, was not exacerbated when combined with cocaine. In fact, cocaine tended to counteract the ethanol-related hypotension though it did exacerbate the tachycardia in two of seven subjects. Conclusions: Though conclusions are limited by the moderate doses of cocaine, ethanol, and disulfiram tested, the data do suggest that the risks of the moderate use of cocaine and ethanol in individuals treated with moderate doses of disulfiram (<= 250 mg/d) may not be as problematic as some may assume.

Rodeiro I; Donato MT; Jimenez N; Garrido G; Molina-Torres J; Menendez R et al. Inhibition of Human P450 Enzymes by natural extracts used in traditional medicine. Phytotherapy Research 23(2): 279-282, 2009. (21 refs.)

Different medicinal plants are widely used in Cuba and Mexico to treat several disorders. This paper reports in vitro inhibitory effects on the P450 system of herbal products commonly used by people in Cuba and Mexico in traditional medicine for decades. Experiments were conducted in human liver microsomes. The catalytic activities of CYPIA1/2, 2136, and 3A4 were measured using specific probe substrates. The Heliopsis longipes extract exhibited a concentration-dependent inhibition of the three enzymes, and similar effects were produced by affinin (an alkamide isolated from the H. longipes extract) and two catalytically reduced alkamides. Mangifera indica L. and Thalassia testudinum extracts, two natural polyphenol-rich extracts, diminished CYPIA1/2 and 3A4 activities, but not the CYP2D6 activity. These results suggest that these herbs inhibit the major human P450 enzymes involved in drug metabolism and could induce potential herbal-drug interactions.

Rossow I. Can harm ratings be useful? (editorial). Addiction 106(11): 1893-1894, 2011. (13 refs.)

Saber-Tehrani AS; Bruce RD; Altice FL. Pharmacokinetic drug interactions and adverse consequences between psychotropic medications and pharmacotherapy for the treatment of opioid dependence. (review). American Journal of Drug and Alcohol Abuse 37(1): 1-11, 2011. (138 refs.)

Background: Psychiatric comorbidities among opioid-dependent patients are common. Many medications used to treat both conditions are metabolized through complimentary cytochrome P450 isoenzymes. When medication-assisted treatment for opioid dependence is concurrently used with psychotropic medications, problematic pharmacokinetic drug interactions may occur. Methods: We reviewed relevant English language articles identified through the MedLine, Scopus, and Embase databases from 1950 to December 2009 using the specific generic names of medications and keywords such as pharmacokinetics and drug interactions with buprenorphine, methadone, and naltrexone. Selected references from these articles were reviewed. Additionally, a review was conducted of abstracts and conference proceedings from national and international meetings from 1990 to 2009. A total of 60 studies were identified and reviewed. Results: Clinical case series and carefully controlled pharmacokinetic interaction studies have been conducted between methadone, buprenorphine, or naltrexone and some psychoactive medications. Important pharmacokinetic drug interactions have been demonstrated within each class of medications affecting either methadone and buprenorphine or psychoactive drugs. Few studies, however, have been conducted with naltrexone. Conclusions and Scientific Significance: Several interactions between methadone, buprenorphine, or naltrexone and psychoactive medications are described and may have important clinical consequences. To optimize care, clinicians must be alerted to these interactions.

Schaffer SD; Yoon S; Zadezensky I. A review of smoking cessation: Potentially risky effects on prescribed medications. (review). Journal of Clinical Nursing 18(11): 1533-1540, 2009

To identify prescription drugs that require dosage adjustment or monitoring in patients who quit smoking and to provide recommendations for dosage adjustment based on available evidence. Health care providers are urged to facilitate smoking cessation for patients who smoke, but the effects of smoking cessation on the metabolism of some drugs is not routinely considered. A comprehensive literature review. The review was conducted in 2008 using a computerised drug interaction program and multiple PubMed and CINAHL searches to identify prescription drugs with clinically significant pharmacokinetic or pharmacodynamic changes caused by smoking cessation. Although much of the evidence is case report, dosage adjustments are clearly indicated for warfarin, olanzapine, clozapine and theophylline since they are metabolised by cytochrome P450 CYP1A2 and also have narrow therapeutic ratios. Careful monitoring is recommended for other CYP1A2 metabolised drugs, including those for hypertension and Alzheimer's disease. For many affected drugs, smoking cessation reverses smoking-induced CYP1A2 hepatic enzyme levels to normal, increasing plasma concentrations in patients whose dose was established while smoking. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, nicotine replacement will not alter the effect. The effects of smoking cessation on drugs metabolised by CYP1A2 have been under-appreciated by health care providers. Smoking cessation may increase plasma levels of some drugs to potentially toxic levels. Further research is warranted to clarify this effect. When patients stop smoking, providers should carefully review prescribed drug regimens and adjust or monitor drugs whose metabolism is affected by smoking cessation. This is particularly important for patients who abruptly stop smoking due to hospitalisation and for older patients who are likely to be taking multiple medications.

Schoffl I; Kothmann JF; Schoffl V; Rupprecht HD; Rupprecht T. "Vodka Energy": Too much for the adolescent nephron? Pediatrics 128(1): E227-E231, 2011. (20 refs.)

We report here the case of a 17-year-old boy who suffered acute renal failure after consuming 3 L of energy drink (ED) in combination with 1 L of vodka amounting to 4600 mg of taurine and 780 mg of caffeine mixed with 380 g of alcohol. The consumption of this mixture is extremely popular in adolescents, because the joint effects of caffeine and taurine reduce the effect of alcohol. Although there have been case reports of deaths linked to the consumption of EDs with and without alcohol, awareness of the possible dangers is still low. The fact that athletes and major sports events are sponsored by ED manufacturers implies that they may even be healthy and performance-enhancing.

Simkin DR; Grenoble S. Pharmacotherapies for adolescent substance use disorders. Child and Adolescent Psychiatric Clinics of North America 19(3): 591-+, 2010. (116 refs.)

There is a paucity of research on pharmacotherapies in adolescents with substance use disorders. This paucity is partly because of the fact that most people with substance dependence do not get diagnosed until early adulthood, that is, after 18 years of age. This article reviews pharmacotherapies used for aversion, substitution, anti-craving, and detoxification of alcohol, nicotine, cocaine, and opioids dependence. Adult research is referenced when applicable and generalized to adolescents with caution. Continued evaluation and development of pharmacotherapy for youth in controlled studies are needed to examine medication effectiveness, safety, potential for abuse, compliance, and potential interactions with other medications or substances of abuse.

Sinchai T; Plasen S; Sanvarinda Y; Jaisin Y; Govitrapong P; Morales NP et al. Caffeine potentiates methamphetamine-induced toxicity both in vitro and in vivo. Neuroscience Letters 502(1): 65-69, 2011. (25 refs.)

Ya-Ba, a combination of the two potent psychostimulants methamphetamine (METH) and caffeine (CAF), is commonly used by drug abusers in Thailand and neighboring countries. While the neurotoxic effects of METH are well documented, the toxicity of this combination is mostly unknown. This study aimed to elucidate the effects of this particular drug combination using both in vitro and in vivo models. We found that combined treatment of METH and CAF at individually non-toxic concentrations significantly decreased viability of human neuroblastoma SK-N-SH cells. The reduction in cell survival was accompanied by an increase in reactive oxygen species (ROS) formation and the Bax/Bcl-2 ratio. In vivo data showed that combined administration of METH and CAF increased the mortality rate of rats, with an increase in the level of thiobarbituric acid reactive substances (TBARS), the indicator of oxidative stress, in striatal tissues. The results indicate that caffeine potentiates the toxic effects of methamphetamine, possibly via a mechanism involving an increase in dopamine release and excess ROS generation.

Solarino B; Riesselmann B; Buschmann CT; Tsokos M. Multidrug poisoning involving nicotine and tramadol. Forensic Science International 194(1/3): E17-E19, 2010. (37 refs.)

A fatal case of multidrug poisoning by tramadol and nicotine is reported. Tramadol is a centrally acting analgesic used in the treatment of moderate to severe acute or chronic pain. Nicotine, a lipid-soluble alkaloid, is one of the most readily available drugs in modern society. A 46-year-old man was found dead in his bed, and a suicide note was discovered near the body. He had 25 transdermal nicotine patches attached to his thorax and abdomen. Two half emptied bottles were found on the bedside table; the toxicological examination revealed that they contained tobacco and nicotine as well as other drugs such as diphenhydramine. At autopsy, areas of fresh and old myocardial infarction as well as diffuse pulmonary congestion and edema were present. The tramadol concentration was 6.6 mu g/mL in femoral venous blood, while levels of nicotine and its primary metabolite cotinine were determined to be 0.6 and 2.0 mu g/mL in femoral venous blood. Based on these results, we determined the cause of death to be cardiorespiratory failure induced by the additive effects of tramadol and nicotine shortly after consumption.

Somala RK. Rhabdomyolysis and brain ischemic stroke in a heroin-dependent male under methadone maintenance therapy. (Comment). Acta Psychiatrica Scandinavica 120(1): 80-81, 2009. (10 refs.)

This is a commentary on an article in this issue, by WY Hsu et al., pages 76-79.

Susnjara IM; Smoljanovic A; Gojanovic MD. Drug related deaths in the Split-Dalmatia County 1997-2007. Collegium Antropologicum 35(3): 823-828, 2011. (40 refs.)

Drug overdoses are a major cause of mortality for drug users and, in many countries, are the leading cause of death in this group. The aim of the present study is to explore the frequency of all drug related deaths in the Split-Dalmatia County in the period between 1997 and 2007 and to analyze some of the characteristics of these deaths to help target preventive policies. The data on drug related deaths were collected using records from the Department of Forensic Medicine, Clinical Hospital Centre Split, University of Split, School of Medicine. There were 190 drug related deaths in the observed period of 11 years. Statistically significant difference (p=0.004, chi(2)-test for trend) was found in the number of deaths in 1997 in comparison with the number of deaths in 2007. The majority of 105 (55%) the decedents were 25-34 years old, and 92.1% (175) of them were male. There was a 94% higher probability of mortality in the 25-34 years group (chi(2)=5.55, p=0.064). Average age of all dead people was 31.01 +/- 7.59 years (median 31.0 years; range 18-49). Almost three quarters of the decedents were single and more than three fifths hadn't been employed. The most common location of death was at home. Approximately, 80% were autopsied followed by full histological and toxicological analyses. Out of all examined cases, the majority of drug related deaths (93 or 60.8%) were attributed to heroin. Heroin was the sole cause of death in 35(22.9%) cases. Methadone was cause of death in 24 (15.7%) cases. 3.4-methylenedioxy-methamphetamine (MDMA) deaths were rare (3.3%). Cocaine deaths were also rare (1.3%). Three fifths (55.6%) of the cases involved includes multi-substance use. During the investigation there was an evident trend towards multi-substance abuse patterns. These data suggest that interventions to prevent drug related mortality should address the use of drugs such as heroin and alcohol in combination.

Szymanska K; Hung RJ; Wunsch V; Eluf-Neto J; Curado MP; Koifman S et al. Alcohol and tobacco, and the risk of cancers of the upper aerodigestive tract in Latin America: A case-control study. Cancer Causes & Control 22(7): 1037-1046, 2011. (25 refs.)

Cancers of the upper aerodigestive tract (UADT; including oral cavity, pharynx, larynx and oesophagus) have high incidence rates all over the world, and they are especially frequent in some parts of Latin America. However, the data on the role of the major risk factors in these areas are still limited. We have evaluated the role of alcohol and tobacco consumption, based on 2,252 upper aerodigestive squamous-cell carcinoma cases and 1,707 controls from seven centres in Brazil, Argentina, and Cuba. We show that alcohol drinkers have a risk of UADT cancers that is up to five times higher than that of never-drinkers. A very strong effect of aperitifs and spirits as compared to other alcohol types was observed, with the ORs reaching 12.76 (CI 5.37-30.32) for oesophagus. Tobacco smokers were up to six times more likely to develop aerodigestive cancers than never-smokers, with the ORs reaching 11.14 (7.72-16.08) among current smokers for hypopharynx and larynx cancer. There was a trend for a decrease in risk after quitting alcohol drinking or tobacco smoking for all sites. The interactive effect of alcohol and tobacco was more than multiplicative. In this study, 65% of all UADT cases were attributable to a combined effect of alcohol and tobacco use. In this largest study on UADT cancer in Latin America, we have shown for the first time that a prevailing majority of UADT cancer cases is due to a combined effect of alcohol and tobacco use and could be prevented by quitting the use of either of these two agents.

Thompson J; Thompson JR. Acute myocardial infarction related to methylphenidate for adult attention deficit disorder. Journal of Emergency Medicine 38(1): 18-21, 2010. (17 refs.)

Adult Attention Deficit Disorder is increasingly diagnosed and treated. Psychostimulant medications, such as methylphenidate, are commonly prescribed for this condition, but the long-term safety of such medications in an adult population is unknown at present. Because these medications are closely related to amphetamines, it is expected that toxic side effects would be similar. We present the case of a 27-year-old man who suffered an acute myocardial infarction due to coronary vasospasm related to use of methylphenidate complicated by concomitant use of pseudoephedrine.

Trujillo KA; Smith ML; Guaderrama MM. Powerful behavioral interactions between methamphetamine and morphine. Pharmacology, Biochemistry and Behavior 99(3): 451-458, 2011. (50 refs.)

Use of drugs of abuse in combination is common among recreational users and addicts. The combination of a psychomotor stimulant with an opiate, known as a 'speedball,' reportedly produces greater effects than either drug alone and has been responsible for numerous deaths. Historically, the most popular speedball combination is that of cocaine and heroin. However, with the growing popularity of methamphetamine in recent years, there has been increased use of this drug in combination with other drugs of abuse, including opiates. Despite this, relatively little research has examined interactions between methamphetamine and opiates. In the current research, behavioral interactions between methamphetamine and the prototypical opiate, morphine, were examined across a variety of dose combinations in Sprague-Dawley rats. The combination of methamphetamine and morphine produced stimulation of behavior that was dramatically higher than either drug alone; however, the magnitude of the interaction was dependent on the dose of the drugs and the specific behaviors examined. The results demonstrate complex behavioral interactions between these drugs, but are consistent with the idea that this combination is used because it produces a greater effect than either drug alone.

Uchaipichat V; Raungrut P; Chau N; Janchawee B; Evans AM; Miners JO. Effects of ketamine on human udp-glucuronosyltransferases in vitro predict potential drug-drug interactions arising from ketamine inhibition of codeine and morphine glucuronidation. Drug Metabolism and Disposition 39(8): 1324-1328, 2011. (25 refs.)

In this study, the selectivity of UDP-glucuronosyltransferase (UGT) enzyme inhibition by ketamine (KTM) and the kinetics of KTM inhibition of human liver microsomal morphine (MOR) and codeine (COD) glucuronidation were characterized to explore a pharmacokinetic basis for the KTM-opioid interaction. With the exception of UGT1A4, KTM inhibited the activities of recombinant human UGT enzymes in a concentration-dependent manner. However, IC(50) values were < 100 mu M only for UGT2B4, UGT2B7, and UGT2B15. UGT2B7 catalyzes MOR 3- and 6-glucuronidation and the 6-glucuronidation of COD, with an additional substantial contribution of UGT2B4 to the latter reaction. Consistent with the effects of KTM on the activities of recombinant UGT2B enzyme activities, KTM competitively inhibited human liver microsomal MOR and COD glucuronidation. K(i) values for KTM inhibition of MOR 3- and 6-glucuronidation and COD 6-glucuronidation by human liver microsomes supplemented with 2% bovine serum albumin were 5.8 +/- 0.1, 4.6 +/- 0.2, and 3.5 +/- 0.1 mu M, respectively. Based on the derived inhibitor constants, in vitro-in vivo extrapolation was used to predict the effects of anesthetic and analgesic doses of KTM on MOR and COD clearances. Potentially clinically significant interactions (>50% increases in the in vivo area under the curve ratios) with MOR and COD were predicted for anesthetic doses of KTM and for a subanesthetic dose of KTM on COD glucuronidation.

van Nieuwenhuijzen PS; McGregor IS. Sedative and hypothermic effects of gamma-hydroxybutyrate (GHB) in rats alone and in combination with other drugs: Assessment using biotelemetry. Drug and Alcohol Dependence 103(3): 137-147, 2009. (80 refs.)

The recreational drug gamma-hydroxybutyrate (GHB) has euphoric effects and can induce sedation and body temperature changes. GHB is frequently combined with other recreational drugs although these interactions are not well characterised. The present study used biotelemetry to provide a fine-grained analysis of the effects of GHB on body temperature and locomotor activity in freely moving rats, and investigated interactions between GHB and 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH) and various antagonist drugs. GHB (1000 mg/kg) caused profound sedation for more than 2 h and a complex triphasic effect on body temperature: an initial hypothermia (5-40 min), followed by hyperthermia (40-140 min), followed again by hypothermia (140-360 min). A lower GHB close (500 mg/kg) also caused sedation but only a hypothermic effect that lasted up to 6 h. The dopamine D-1 receptor antagonist SCH 23390 (1 mg/kg), the opioid antagonist naltrexone (1 mg/kg), the benzodiazepine antagonist flumazenil (10 mg/kg), and the 5-HT2A/2C receptor antagonist ritanserin (1 mg/kg) did not prevent the overall sedative or body temperature effects of GHB (1000 mg/kg). However the GABA(B) antagonist SCH 50911 (50 mg/kg) prevented the hyperthermia induced by GHB (1000 mg/kg). Repeated daily administration of GHB (1000 mg/kg) produced tolerance to the sedative and hyperthermic effects of the drug and cross-tolerance to the sedative effects of the GABA(B) receptor agonist baclofen (10 mg/kg). A high ambient temperature of 28 degrees C prevented the hypothermia obtained with GHB (500 mg/kg) at 20 degrees C, while GHB (500 mg/kg) reduced the hyperthermia and hyperactivity produced by co-administered doses of MDMA (5 mg/kg) or METH (1 mg/kg) at 28 degrees C. These results further confirm a role for GABA(B) receptors in the hypothermic and sedative effects of GHB and show an interaction between GHB and MDMA, and GHB and METH, that may be relevant to the experience of recreational users who mix these drugs.

Vorspan F; Ksouda K; Bloch V; Laplanche JL; Peoc'h K; Hajj A et al. A case report of transient but clinically relevant interaction between methadone and duloxetine: A reply to McCance-Katz et al. American Journal on Addictions 19(5): 458-459, 2010. (5 refs.)

This short case report is a reponse to an article by McCance-Katz, et al. in the previous issue discussing interactions between methadone and commonly prescribed medication. It had been reported that while theoretically possible there were no reported adverse interactions between methadone and duloxetine, an SNRI antidepressant. This case report focuses upon a case of someone stabilized on methadone was prescribed duloxetine for a depressive episide, and several days later complained of subjective signs of opioid overdose. While the sympotms were minor, they continued until the methadone dose was reduced 14 days later. The authors suggest that there is an increasingly significant increase in methadone effects were observed and suggest that close monitoring is warranted with co-prescription.

Walley AY; Farrar D; Cheng DM; Alford DP; Samet JH. Are opioid dependence and methadone maintenance treatment (MMT) documented in the medical record? A patient safety issue. Journal of General Internal Medicine 24(9): 1007-1011, 2009. (24 refs.)

BACKGROUND: Opioid-dependent patients often have co-occurring chronic illnesses requiring medications that interact with methadone. Methadone maintenance treatment (MMT) is typically provided separately from medical care. Hence, coordination of medical care and substance use treatment is important to preserve patient safety. OBJECTIVE: To identify potential safety risks among MMT patients engaged in medical care by evaluating the frequency that opioid dependence and MMT documentation are missing in medical records and characterizing potential medication-methadone interactions. METHODS: Among patients from a methadone clinic who received primary care from an affiliated, but separate, medical center, we reviewed electronic medical records for documentation of methadone, opioid dependence, and potential drug-methadone interactions. The proportions of medical records without opioid dependence and methadone documentation were estimated and potential medication-methadone interactions were identified. RESULTS: Among the study subjects (n=84), opioid dependence documentation was missing from the medical record in 30% (95% CI, 20%-41%) and MMT documentation was missing from either the last primary care note or the last hospital discharge summary in 11% (95% CI, 5%-19%). Sixty-nine percent of the study subjects had at least 1 medication that potentially interacted with methadone; 19% had 3 or more potentially interacting medications. CONCLUSION: Among patients receiving MMT and medical care at different sites, documentation of opioid dependence and MMT in the medical record occurs for the majority, but is missing in a substantial number of patients. Most of these patients are prescribed medications that potentially interact with methadone. This study highlights opportunities for improved coordination between medical care and MMT.

Wannamethee SG; Shaper AG. Cigarette smoking and serum liver enzymes: The role of alcohol and inflammation. Annals of Clinical Biochemistry 47(Part 4): 321-326, 2010. (40 refs.)

Background and aims: Smoking may affect the liver through inflammatory pathways and may aggravate the pathogenic effects of alcohol on the liver. We have examined the relationship between cigarette smoking and liver enzymes and the role of alcohol and C-reactive protein (CRP), a marker of inflammation. Methods: The subjects consisted of 4595 men aged 40-59 y with no history of coronary heart disease drawn from general practices in 24 British towns. Results: Cigarette smoking was significantly associated with increased levels of gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) (P < 0.0001) and was inversely associated with increased aspartate aminotransferase (AST) after adjustment for alcohol intake, body mass index and physical activity. Compared with never smokers, heavy cigarette smokers (>= 40/day) were associated with increased odds of elevated GGT (>= 23 IU/L) (adjusted odds ratio [OR] 1.56 [1.08, 2.27]), which was abolished after adjustment for CRP (adjusted OR 1.27 [0.87, 1.86]). There was a significant interaction between smoking and alcohol on GGT. In the absence of heavy drinking, there was no association between smoking and GGT after adjustment for CRP. Among heavy drinkers, smoking was associated with increased levels of GGT independent of CRP. Smoking was associated with increased odds of elevated ALP (>= 11 IU/L) (adjusted OR 3.95 [2.77, 5.62]), which persisted after adjustment for CRP and white cell count (adjusted OR 2.90 [1.99-4.23]), possibly reflecting increased bone cell activity. Conclusion: The findings suggest that cigarette smoking does not cause liver injury, but may enhance the effects of alcohol on liver cell injury in heavy drinkers.

Wu CS; Lin YJ; Liu SK. Benzodiazepine use among patients with schizophrenia in Taiwan: A nationwide population-based survey. Psychiatric Services 62(8): 908-914, 2011. (28 refs.)

Objective: This study aimed to describe the pattern of benzodiazepine use in a representative sample of patients with schizophrenia in Taiwan. Methods: Data from the National Health Insurance Research Database in Taiwan were used to examine the prevalence and indices of benzodiazepine use in 2005. Demographic and clinical characteristics associated with long-term benzodiazepine use (more than 180 days of cumulated prescription in one year) were further explored by multivariate logistic regression analysis. Results: Among the 3,690 patients with schizophrenia, the one-year prevalence rate of benzodiazepine use was 79.2% (N=2,923). Among those who used benzodiazepines, 1,840 (62.9%) were long-term users. Use of benzodiazepines was associated with having a comorbid psychiatric disorder, use of concomitant psychotropic agents, and antipsychotic polypharmacy. Among benzodiazepine users, older age, longer duration of illness, and use of concomitant psychotropic agents were associated with significantly higher odds of being a long-term user. Conclusions: The study showed that benzodiazepine use was highly prevalent among patients with schizophrenia in Taiwan and that a substantial proportion of users (62.9%) were long-term users. Because long-term use was associated with longer duration of illness and with use of concomitant psychotropic medications, long-term users may be at higher risk of neurocognitive side effects caused by benzodiazepines and interactions with other psychotropic medications. Therefore, this group should be closely monitored for drug-drug interactions and the benefits and risks of benzodiazepine use.

Yamreudeewong W; Wong HK; Brausch LM; Pulley KR. Probable interaction between warfarin and marijuana smoking. Annals of Pharmacotherapy 43(7-8): 1347-1353, 2009. (34 refs.)

OBJECTIVE: To report a probable interaction between warfarin and marijuana smoking, resulting in increased international normalized ratio (INR) values and bleeding complications. CASE SUMMARY: A 56-year-old white male had been receiving chronic warfarin therapy for 11 years after mechanical heart valve replacement. He was admitted to the hospital with a diagnosis of upper gastrointestinal bleeding. Upon admission, his INR value was supratherapeutic at 10.41, and his hemoglobin level was 6.6 g/dL. He received 4 units of fresh frozen plasma and one 10-mg dose of oral vitamin K; his INR was 1.8 the next day. He was discharged 7 days after admission. Fifteen days after hospital discharge, he was readmitted with a constant nosebleed and increased bruising. His INR value was 11.55. After treatment, he was discharged with an INR value of 1.14. The patient smoked marijuana more frequently throughout the period of these 2 hospitalizations due to his depression. He was counseled by the pharmacist on the potential interaction of warfarin and marijuana. The patient decided to stop smoking marijuana after the third counseling session. During the 9 months that he did not smoke marijuana, his INR values ranged from 1.08 to 4.40 with no significant bleeding complications. DISCUSSION: Marijuana may increase warfarin anticoagulant effect by inhibiting its metabolism, and to a lesser extent, displacing warfarin from protein-binding sites. Other causes (eg, nonadherence) of the patient's increased INR were ruled out. Using the Horn Drug Interaction Probability Scale, our patient's warfarin-marijuana interaction appeared to be probable. CONCLUSIONS: To our knowledge, there have been no other reported cases of warfarin-marijuana interaction. While more clinical reports would be useful to confirm this interaction, clinicians should be aware of its probability so as to manage patients appropriately.

Zamparutti G; Schifano F; Corkery JM; Oyefeso A; Ghodse AH. Deaths of opiate/opioid misusers involving dihydrocodeine, UK, 1997-2007. British Journal of Clinical Pharmacology 72(2): 330-337, 2011. (58 refs.)

AIMS: Although its effectiveness is somewhat controversial, it appears that dihydrocodeine (DHC) is still prescribed in the UK as an alternative to both methadone and buprenorphine for the treatment of opiate addiction. METHODS: Data covering the period 1997-2007 voluntarily supplied by coroners were analysed. All cases pertaining to victims with a clear history of opiate/opioid misuse and in which DHC, either on its own or in combination, was identified at post-mortem toxicology and/or implicated in death, were extracted from the database. RESULTS: Dihydrocodeine, either alone or in combination, was identified in 584 fatalities meeting the selection criteria. In 44% of cases it was directly implicated in the cause of death. These cases represented about 6.8% of all opiate/opioid-related deaths during this period. Typical DHC cases identified were White males in their early thirties. Accidental deaths (96%) were likely to involve DHC in combination with other psychoactives, mainly heroin/morphine, hypnotics/sedatives and methadone. Both paracetamol and antidepressants were found in proportionately more suicide cases than in accidental overdoses. DHC had been prescribed to the decedent in at least 45% of cases. CONCLUSIONS: Opiate/opioid misusers should be educated about risks associated with polydrug intake. More in particular, co-administration of DHC with heroin, methadone and benzodiazepines may increase the risk of accidental fatal overdose. Prescribers should carefully consider pharmacological intervention alternative to DHC (e. g. methadone, buprenorphine) when managing and treating opiate addiction. More resources are required to do prospective research in this area.

Zhang JM; Kamdar O; Le W; Rosen GD; Upadhyay D. Nicotine induces resistance to chemotherapy by modulating mitochondrial signaling in lung cancer. American Journal of Respiratory Cell and Molecular Biology 40(2): 135-146, 2009. (28 refs.)

Continued smoking causes tumor progression and resistance to therapy in lung cancer. Carcinogens possess the ability to block apoptosis, and thus may induce development of cancers and resistance to therapy. Tobacco carcinogens have been studied widely; however, little is known about the agents that inhibit apoptosis, such as nicotine. We determine whether mitochondrial signaling mediates antiapoptotic effects of nicotine in lung cancer. A549 cells were exposed to nicotine (1 mu M) followed by cisplatin (35 mu M) plus etoposide (20 mu M) for 24 hours. We found that nicotine prevented chemotherapy-induced apoptosis, improved cell survival, and caused modest increases in DNA synthesis. Inhibition of mitogen-activated protein kinase (MAPK) and Akt prevented the antiapoptotic effects of nicotine and decreased chemotherapy-induced apoptosis. Small interfering RNA MAPK kinase-1 blocked antiapoptotic effects of nicotine, where as small interfering RNA MAPK kinase-2 blocked chemotherapy-induced apoptosis. Nicotine prevented chemotherapy-induced reduction in mitochondrial membrane potential and caspase-9 activation. Antiapoptotic effects of nicotine were blocked by mitochondrial anion channel inhibitor, 4,4'diisothiocyanatostilbene-2,2'disulfonic acid. Chemotherapy enhanced translocation of proapoptotic Bax to the mitochondria, whereas nicotine blocked these effects. Nicotine up-regulated Akt-mediated antiapoptotic X-linked inhibitor of apoptosis protein and phosphorylated proapoptotic Bcl2-antagonist of cell death. The A549-rho 0 cells, which lack mitochondrial DNA, demonstrated partial resistance to chemotherapy-induced apoptosis, but blocked the antiapoptotic effects of nicotine. Accordingly, we provide evidence that nicotine modulates mitochondrial signaling and inhibits chemotherapy-induced apoptosis in lung cancer. The mitochondrial regulation of nicotine imposes an important mechanism that can critically impair the treatment of lung cancer, because many cancer-therapeutic agents induce apoptosis via the mitochondrial death pathway. Strategies aimed at understanding nicotine-mediated signaling may facilitate the development of improved therapies in lung cancer.