Abstinence Response Research Articles

A sequential multiple assignment randomized trial for cocaine cessation and relapse prevention: Tailoring treatment to the individual

Drug addiction is a chronic, devastating, but treatable disorder. A core principle of drug addiction treatment states that no single treatment is appropriate for everyone (NIDA, 2012); treatments need to adjust based on patient characteristics and response in order to be maximally effective. For cocaine use disorders (CUD), specifically, the most potent intervention currently available for initiating abstinence is behavior therapy using contingency management (CM) procedures, with early cessation being a robust predictor of future abstinence. This raises two key questions for treatment development research: First, can we significantly improve initial CM response rates with targeted adjunctive interventions? Second, for individuals who fail to achieve initial abstinence with CM, is pharmacotherapy an effective augmentation strategy? This paper describes how a sequential, multiple assignment, randomized trial (SMART) design has advantages over a fixed-intervention approach when it comes to collecting data needed to answer both questions. The first aim will examine whether Acceptance and Commitment Therapy (ACT) in combination with CM increases initial abstinence response rates (i.e., 2 consecutive weeks of cocaine-negative urine screens). The second aim will examine whether ACT+CM in combination with modafinil promotes abstinence achievement in initial non-responders. Results are expected to inform how we tailor treatment of CUD to maximize outcomes.

What a difference a day makes: differences in initial abstinence response during a smoking cessation attempt.

To (1) identify distinct classes of smokers based on quit day withdrawal symptoms and (2) explore the relations between withdrawal classes and demographics, tobacco dependence, treatment and smoking outcomes. Secondary data analysis of participants (n=1504) in a randomized double-blind placebo-controlled multi-site smoking cessation trial who provided ecological momentary assessments of withdrawal symptoms on their quit day. Participants received smoking cessation counseling and were randomized to receive placebo or one of five active pharmacotherapies. Research offices in Madison and Milwaukee, Wisconsin, USA. Adult smokers (n=1236; 58% female, 86% white), recruited from the community via advertisements, who abstained on their quit day. Demographics and tobacco dependence were assessed at baseline and participants carried palmtop computers to record withdrawal symptoms (craving, negative affect, difficulty concentrating, hunger and anhedonia) on their quit day. Point-prevalence abstinence and latency to relapse were assessed at 8 weeks and 6 months post-quit. Latent class analysis identified four withdrawal classes [Akaike information criterion (AIC)=70.09]: Moderate withdrawal (64% of sample), high craving-anhedonia (8% of sample), affective withdrawal (13% of sample) and hunger (15% of sample). The high craving-anhedonia class reported significantly higher dependence (P<0.01), were less likely to have received combination nicotine replacement, reported lower week 8 abstinence rates and relapsed sooner than those in the moderate withdrawal class (P<0.05). The affective withdrawal class reported higher levels of baseline negative affect and life-time psychopathology (P<0.05) and relapsed more quickly than the moderate withdrawal class (P<0.01). While the majority of smokers report typical levels of withdrawal symptoms on their quit day, more than one-third report extreme craving or extreme negative affective or extreme hunger responses to initial abstinence. These distinct quit-day withdrawal symptom patterns are related to baseline characteristics, treatment and cessation success.

Effects of quitting smoking on EEG activation and attention last for more than 31 days and are more severe with stress, dependence, DRD2 A1 allele, and depressive traits.

Changes in physiology and attentional performance associated with smoking abstinence were characterized in 67 female smokers during low-stress and high-stress conditions. Abstinence was associated with decreases in cognitive performance, heart rate, and electroencephalographic (EEG) activation but with no change in serum estradiol or progesterone. Effects of quitting showed no tendency to resolve across the 31 days of abstinence. EEG deactivation and heart rate slowing were greater during a math task (high stress) than during relaxation (low stress). Individuals high in trait depression or nicotine dependence or with at least one dopamine D(2) receptor A1 allele experienced greater EEG deactivation following abstinence, especially in the right hemisphere during the stressful task. Thus, findings support the situation x trait adaptive response model of abstinence effects and emphasize the value of multiple dependent measures when characterizing abstinence responses.

Mood disturbance fails to resolve across 31 days of cigarette abstinence in women.

Smoking abstinence responses were characterized in 96 female smokers. Participants completed subjective state measures twice per week for 5 weeks and were then randomly assigned to a group required to abstain for 31 days or a control group that continued to smoke. Financial incentives for biochemically verified abstinence resulted in an 81% completion rate. Abstinence-related increases in depression, tension, anger, irritability, and appetite showed little tendency to return to prequit levels and remained significantly elevated above smoke-group levels. In contrast to psychological components of anxiety, physical components decreased to smoke group levels by the 2nd week of abstinence. Trait depression and neuroticism predicted larger increased abstinence-associated negative affect. The Big Five personality dimensions predicted variance not associated with depressive traits.

Preoperative alcoholism and postoperative morbidity.

Preoperative risk assessment has become part of daily clinical practice, but preoperative alcohol abuse has not received much attention. A Medline search was carried out to identify original papers published from 1967 to 1998. Relevant articles on postoperative morbidity in alcohol abusers were used to evaluate the evidence. Prospective and retrospective studies demonstrate a twofold to threefold increase in postoperative morbidity in alcohol abusers, the most frequent complications being infections, bleeding and cardiopulmonary insufficiency. Wound complications account for about half of the morbidity. The pathogenic mechanisms include preoperative immune incompetence, subclinical cardiac insufficiency and haemostatic imbalance. In addition, surgical trauma and/or postoperative abstinence result in an exaggerated stress response, which may further contribute to postoperative morbidity. Alcohol consumption should be included in the preoperative assessment of likely postoperative outcome. Reduction of postoperative morbidity in alcohol abusers may include preoperative alcohol abstinence to improve organ function, or perioperative alcohol administration to avoid the abstinence response.

Effects of smoking abstinence on mood and craving in men: influences of negative-affect-related personality traits, habitual nicotine intake and repeated measurements

A two-factor model of individual differences in smoking abstinence response was assessed. The two factors were nicotine bioadaptation (nicotine exposure and self-reported tolerance/dependence) and self-medication for negative affect/psychopathology. Bioadaptation was expected to promote transient increases in smoking abstinence-related negative affect, while self-medication was expected to be related to relatively permanent increases in negative affect. Of 56 male smokers starting, 50 completed the study, 30 of whom were randomly assigned to an immediate cessation group and 20 to a continuing-to-smoke control group. Mood and craving were repeatedly measured with the Profile of Mood States (POMS) and the Shiffman Withdrawal Questionnaire, administered twice per week during a three-week pre-quit baseline period and every 48 h during the 30-day abstinence phase. POMS negative moods decreased significantly across the six pre-quit baseline days even though there was no smoking cessation-related intervention during this time, a finding with implications for the question of whether quitters return to pre-quit levels of negative affect. Support for the two-factor model was provided by three of our findings. First, POMS Depression, Tension and Anger increased in the quit group after quitting and never returned to levels corresponding to the continuingto-smoke controls even after 30 days of abstinence. Second, trait depression assessed prior to smoking abstinence correlated with abstinence-related increases in POMS state depressive affect score shortly after quitting and during the last eight days of the study. Third, pre-quit cotinine concentration correlated with increases in negative affect during the first 48 h of abstinence. The findings suggest that previous studies should be interpreted with caution because of their failure to take into account the repeated-measures effect and selective attrition.

Further evidence that naloxone acts as an inverse opiate agonist: Implications for drug dependence and withdrawaL

To test if naloxone behaved as an inverse agonist rather than as an antagonist we evaluated its responses in guinea-pig ilea with and without morphine (480 nM, 24 h). In control ilea, naloxone (100 nM) had no effect. In morphine-treated ilea, naloxone as a bolus, but not as an infusion, elicited an abstinence response. Preadministration of naloxone blocked the response to subsequent administrations. Similarly, naloxone failed to produce an abstinence response in ilea pretreated with kappa compounds (bremazocine, U50488 or xorphanol 100 nM) or with kinase inhibitors (H7 or H8 30 μM). These findings can be interpreted in the light of the two-state receptor model if naloxone behaves as an inverse agonist: Incubation with morphine increased the active state of receptors making them susceptible to the inverse agonist (naloxone); exposure to naloxone favored the inactive conformation making them insensitive to further administration of naloxone; kappa compounds behaved as antagonists preventing the response to naloxone; and kinase inhibitors interfered with the active conformation making the system insensitive to naloxone. According to this model, dependence can be viewed as an overexpression of the active receptors and withdrawal as an abrupt change from the active to the inactive state.

Effect of temparature on opioid dependence and on the abstinence response in the isolated guinea pig ileum

This paper explores, in the isolated guinea-pig ileum, the effects of temperature on the acute development of opioid dependence and on the precipitation of the abstinence response, using as reference the effect of temperature on the response to a standard nicotine concentration. Additionally, the influence of temperature on acute morphine neurodepression was examined. Three experimental groups were included. In the first, the bath temperature was adjusted and maintained along the experimental session (2.5 h) at one of the following values: 28, 32, 36 or 40°C. In the second, the different values of bath temperature were applied only during the period of morphine exposure before testing the abstinence response at 36°C. In the third, all segments were initially incubated at 36°C for 1 h, and afterwards, abstinence and the nicotine response were elicited at the different temperatures mentioned. In all the series, a single challenge naloxone dose (3.1, 10, 31, 100, 316, 1000 or 3160 nM) was administered after 1h of morphine and complete naloxone concentration-response curves were obtained. The abstinence response was expressed as a percentage of the nicotine reference response. All segments showed robust nicotine responses at all the experimental protocols tested indicating that, at the temperature range studied, the contractile mechanisms were not impaired. This study showed that changes in bath temperature modify the magnitude of acute morphine neurodepression, and of the abstinence response but did no affect the development of acute opioid dependence. These data, along with several lines of evidence, strongly suggest that acute neurodepression, the development of opiate dependence and antagonist-precipitated abstinence are separable. Results are discussed on the basis of drug-receptor interactions.

A methodological basis for improving the reliability of measurements of opiate abstinence responses in the Guinea-Pig ileum made dependent in vitro

The purpose of this study was to find a neurogenic response of the isolated guinea-pig ileum that could serve as an internal standard to normalize abstinence responses, which are also neurogenic, during opiate dependence produced in vitro. The internal standard is required because of baseline variability in these responses of the ileum and a time-dependent decay in neuroeffector responsiveness with prolonged incubation. Systematic studies were made of the variability in the responses to neurogenic stimulation by 1) electrical field stimulation, 2) nicotinic stimulation, and 3) precipitation of opiate abstinence with opiate antagonists as well as studies of the time-dependent decay in responsiveness with prolonged incubation. The three neurogenic responses show covariation but the best correlation is found between the nicotinic and the abstinence responses. The nicotinic system presents a pharmacological sensitivity to specific acute opiate action and also shows an improving correlation with abstinence which develops with the progression of dependence. This correlation tends to a direct linear relation with a slope approaching 1.0. The nicotinic response of the ileum seems to be a valid internal control to normalize its abstinence responses after incubation with opiates for different intervals of time.

Nalbuphine.

Nalbuphine is a potent analgesic with a low side effect and dependence profile in animals and man. Nalbuphine is distinguished from other agonist/antagonist analgesics in having greater antagonist activity and fewer behavioral effects at analgesic doses than pentazocine, butorphanol or buprenorphine. At equi-analgesic doses, nalbuphine is quantitatively similar to nalorphine in regard to its large ratio of antagonist to analgetic activity. Clinical studies have confirmed this balance of strong antagonist to analgesic activity. Nalbuphine has been shown to effectively antagonize the respiratory depressant activity of narcotic analgesics while concomitantly adding to their analgetic responses. Unlike nalorphine or pentazocine, nalbuphine produces few overt behavioral or autonomic effects in animals at doses over 300 times its analgesic range. These findings are confirmed by clinical results which show that nalbuphine produces few psychotomimetic effects, even at elevated dose levels, in contrast to nalorphine or pentazocine. Nalbuphine produces limited respiratory depression in animals and in man. Significant cardiovascular effects have not been found. Nalbuphine was found to produce significantly less inhibition of gastrointestinal activity than any of the clinically useful narcotic or agonist/antagonist analgesics tested in animals. Nalbuphine's analgetic effects are reversed by naloxone doses similar to those which reverse nalorphine's agonist effects. Results in this and other tests suggest that nalbuphine is primarily a kappa-agonist/mu-antagonist analgesic. Unlike pentazocine or buprenorphine, nalbuphine does not suppress the narcotic abstinence syndrome in partly-withdrawn morphine-dependent animals or man. Rather, due to nalbuphine's strong antagonist activity, analgesic-range doses of nalbuphine severely exacerbate the withdrawal syndrome in partly-withdrawn mice, monkeys and humans. Nalbuphine also precipitates a strong abstinence response in non-withdrawn morphine-dependent animals and man. In post-addict humans, analgesic-range doses of nalbuphine are perceived as minimally morphine-like, but higher doses are judged to be progressively more nalorphine-like (i.e. dysphoric), which further limits nalbuphine's abuse potential in drug-seeking individuals. Primary dependence studies have demonstrated that physical dependence is possible at high dose levels that produce marked side effects. Other studies show that dependence is unlikely to be of significance within nalbuphine's usual analgesic range. Six-month studies in patients with chronic pain have confirmed that analgesic tolerance or physical dependence is uncommon.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of narcotic addiction by inhibition of craving: Contending with a cherished habit

The indefinitely repeated occurrence of powerful impulses to take drugs is the essence of drug addiction. These impulses are correlated with activity of the automatic nervous system. As early as 1941, Himmelsbach noted that the morphine abstinence syndrome (or craving) was “a disturbance affecting the autonomic division of the nervous system.” 1 The syndrome that results from repeated doses of narcotics has the features of a learned habit. Although narcotic habits always include motor acts that may have socially motivated components, treatment that concentrates on motor acts without attention to autonomic events inevitably misses the crux of the problem. The substantial failure of attempts to modify drug-taking behavior by measures directed at motor behaviors is exactly what was to have been expected. The evocations of the autonomic responses comprising the abstinence syndrome must be in response to some antecedent stimulus or stimuli. Lawrence Kolb, one of the earliest observers of addiction patterns stated: “… When we say a man relapses to drugs because he has a periodic craving …, we have stated only an end result and have left the primary cause of the craving undisclosed.” 2 Antecedent stimuli to craving may be in the external environment (exteroceptive), 2–11 or in a specific internal state (interoceptive). 2,5,6,12 In many cases, both external and internal antecedents can be identified. In this article we report our experiences in an experiment designed to weaken abstinence responses by systematically inhibiting them through the competition of aversive responses. The abstinence responses were induced by intravenous injections of naloxone and the aversive responses by electrical stimulation of the forearm. Our efforts achieved some success, but were largely thwarted by the subjects' almost universal disinterest in working towards change.

Comparative effects of synthetic enkephalinamides and morphine on abstinence responses in morphine-dependent mice

The effects of intracerebroventricular (ICV) administration of two synthetic enkephalinamides, D-Ala 2-Met 5-enkephalinamide and D-Met 2-Pro 5-enkephalinamide, were compared with those of morphine on abstinence responses in morphine dependent mice. Mice were rendered dependent by morphine pellet implantation for three days. When administered six hours after pellet removal, both enkephalinamides and morphine reversed the naloxone-induced abstinence jumping response. On a molar basis, D-Met 2-Pro 5-enkephalinamide was the most potent compound and morphine was the least potent. Thus, substitution of D-Methionine in the two-position and prolineamide in five-position of the naturally occurring enkephalins, methionine- and leucine-enkephalin resulted in potent compound. The enkephalinamides and morphine also prevented hypothermia when injected immediately after or six hours after morphine withdrawal (pellet removal).

Conditioning of narcotic abstinence symptoms in human subjects

Clinical evidence suggests the possibility of conditioning of narcotic abstinence symptoms. Addicts report subjective and objective signs of withdrawal/craving when exposed to certain stimuli. This may partially explain the high rate of relapse to drug seeking behavior when treated addicts return to their home environment. Conditioning of narcotic abstinence symptoms was produced experimentally in five of eight volunteer subjects. Brief naloxone precipitated abstinence was the unconditioned response. The conditioned stimulus was a tone and odor. After an average of seven training trials, the tone and odor produced a conditioned abstinence response. The conditioned response consisted of subjective components (feelings of sickness, nausea, cramps, craving) and objective components (yawning, tearing, rhinorrhea, irregular respiration and transiently increased blood pressure). These laboratory findings support the anecdotal evidence regarding the existence of conditioned abstinence phenomena.