Predictors for the efficacy of naltrexone treatment in alcohol dependence: sweet preference.

AIMS: To analyse the possible associations between sweet preference and the efficacy of naltrexone treatment of alcohol dependence. METHODS: The preference for different concentrations of sucrose was evaluated in 78 participants diagnosed with alcohol dependence after treatment for 32 weeks with naltrexone or placebo without prior detoxification. RESULTS: A significant difference between naltrexone and placebo groups was found in the association between the preference for higher sucrose concentrations and relapses to heavy drinking. Higher sweet preference was significantly related to successful treatment measures in the naltrexone group but not in the placebo group. CONCLUSION: Sweet preference has a strong correlation to treatment outcomes with naltrexone, and sweet preference might be used as a predictor for better treatment results in alcoholics. Our study offers one possible new explanation of the clinical observation that naltrexone is not effective for every patient.

Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial.

Several studies have shown the opioid antagonist naltrexone to be effective when combined with psychosocial therapies for the treatment of patients who are dependent on alcohol with fixed medication and time (12 weeks). In this study, 121 nonabstinent outpatients with alcohol dependence (DSM-IV) were treated with sessions of cognitive coping skills (N = 67) or supportive therapy (N = 54) and either naltrexone 50 mg/day (N = 63) or placebo (N = 58) daily for the first 12 weeks and thereafter for 20 weeks only when craving alcohol (i.e., targeted medication) in a prospective one-center, dual, double-blind, randomized clinical trial. The dropout rate for all subjects was 16.5% during the first 12-week period and approximately twice that level by the end of the study. There were no significant group differences in study completion and therapy participation rates. After the continuous medication (12 weeks), the coping/naltrexone group had the best outcome, and coping/placebo had the worst. This difference remained during the targeted medication period (the following 20 weeks). Naltrexone was not better than placebo in the supportive groups, but it had a significant effect in the coping groups: 27% of the coping/naltrexone patients had no relapses to heavy drinking throughout the 32 weeks, compared with only 3% of the coping/placebo patients. The authors' data confirm the original finding of the efficacy of naltrexone in conjunction with coping skills therapy. In addition, their data show that detoxification is not required and that targeted medication taken only when craving occurs is effective in maintaining the reduction in heavy drinking.

Evidence about the use of naltrexone and for different ways of using it in the treatment of alcoholism.

Eight double-blind placebo-controlled clinical trials in five countries have demonstrated the safety and efficacy of naltrexone as an adjunct in alcoholism treatment. The efficacy depends, however, on how naltrexone is used. Three of the trials tested naltrexone in two ways: (1) with supportive therapy, i.e. support of complete abstinence; (2) with therapy tacitly accepting that relapses may occur and teaching how to cope with them. Although all found benefits from naltrexone with the coping therapy, none of them found any significant benefit of naltrexone over placebo when combined with support for abstinence. These results are consistent with our pre-clinical studies in which naltrexone, naloxone, and nalmefene were effective when paired with drinking but ineffective when given during abstinence. This supported the hypothesis that the primary mechanism involved is extinction (as had been concluded earlier for the effects of naltrexone in opiate addiction treatment), because extinction only weakens responses that are made while reinforcement is blocked. On this basis, it was proposed that: (1) naltrexone should be administered to patients who were still currently drinking; (2) the instructions should be to take naltrexone only when drinking was anticipated; (3) this treatment should continue indefinitely. Subsequently, clinical trials have found that naltrexone used in this manner is safe and effective.

Reduction of alcohol drinking and upregulation of opioid receptors by oral naltrexone in AA rats.

Rats of the high-drinking AA line were given 1 mg/kg naltrexone (NTX) or vehicle orally with a stress-free procedure just before 1 h of access to 10% ethanol daily for 8 days and again, 8 h later on the first 7 days. Forebrain homogenate binding studies using 0.03-6.00 nM [3H] naloxone were conducted from 1 to 4 days following treatment. NTX significantly suppressed alcohol intake, with the effect becoming progressively greater over days and continuing during the post-treatment period. Saturation binding studies in brain homogenate revealed that NTX had increased the B(max) for opioid receptors by 93%, 74%, 49%, and 28%, respectively, from post-treatment days 1 to 4 without altering K(d). B(max) was negatively correlated (r=-0.510, p=0.008) with alcohol intake during the preceding hour, but in control rats, it was positively correlated with changes in alcohol intake over time (r=+0.790, p=0.020). These results are consistent with the hypothesis that opioid receptors mediate reinforcement from alcohol and that NTX reduces subsequent alcohol drinking by extinction. Opioid receptor upregulation can develop simultaneously with suppression of drinking and may partially counteract the clinical benefits from NTX in the treatment of alcoholism.

Brain ethanol levels after voluntary ethanol drinking in AA and Wistar rats.

Brain ethanol was monitored in the nucleus accumbens with one minute microdialysis and headspace gas chromatography in male Wistar and alcohol preferring AA (Alko Alcohol) rats after voluntary limited access consumption without food restriction. The rats drank 0.93 +/- 0.14 (Wistar) and 0.73 +/- 0.07 g/kg (AA), with a resulting mean maximal brain ethanol level of 15.9 mM and 14.1 mM, respectively. Maximum brain ethanol levels for individual AA rats were in the range 9.4-33.6 mM, median 15.5 mM and for the individual Wistar rats in the range 2.5-35.2 mM, median 17.8 mM. There was a significant but not perfect correlation between the amount ethanol drunk and the resulting ethanol level in the nucleus accumbens, probably because of the rats not being food deprived before the experiment. The results show that rats drink pharmacologically meaningful doses in a voluntary limited access situation and that blood samples can give us a hint about the level attained in the brain, but to know the early brain concentration after drinking, microdialysis is an excellent tool.

Dopamine release during ethanol drinking in AA rats.

The dopamine overflow in the nucleus accumbens of rats from the high alcohol drinking AA line was measured by microdialysis before, during, and after one-half hour sessions of cued drinking of ethanol flavored with saccharin and peppermint or, as a control, saccharin-peppermint drinking. The animals had had extensive previous experience with ethanol drinking. Self-administration of the ethanol solution did not raise the dopamine level substantially: there was a small (17%) but significant increase only during the first 10 min after the onset of drinking. Giving the rats a cue for ethanol, which was part of their daily routine drinking regime, did not raise the dopamine level before ethanol was presented to the rats (i.e., during "anticipation"). The results are consistent with our previous studies showing a lack of a large ethanol-induced dopamine response in rats with previous experience of drinking ethanol and with the idea that although dopamine may play some role in alcohol drinking, it is not the central substrate producing the reinforcement from ethanol in AA rats.

Differential responses by psychosocial subgroups of fibromyalgia syndrome patients to an interdisciplinary treatment.

OBJECTIVES: To evaluate differential treatment responses among 3 empirically derived, psychosocial subgroups of patients with fibromyalgia syndrome to a standard interdisciplinary treatment program. METHOD: Patients were classified into 1 of 3 psychosocial groups on the basis of their responses to the Multidimensional Pain Inventory. Forty-eight patients completed a 6 one-half-day outpatient treatment program consisting of medical, physical, occupational, and psychological therapies spaced over a period of 4 weeks (3 sessions the first week followed by 1 session per week for the next 3 consecutive weeks). RESULTS: Statistically significant reductions were observed in pain, affective distress, perceived disability, and perceived inteference of pain in the patients characterized by poor coping and high level of pain ("dysfunctional" group). In contrast, individuals who were characterized by interpersonal difficulties ("interpersonally distressed" group) exhibited poor responses to the treatment. "Adaptive copers," the third group, revealed significant improvements in pain but due to low pretreatment levels of affective distress and disability showed little improvement on these outcomes. CONCLUSIONS: The results provided support for the hypothesis that customizing treatment based on patients' psychosocial needs will lead to enhanced treatment efficacy. They also emphasize the importance of using appropriate outcome criteria, as low levels of problems at baseline are not likely to show significant changes following any treatment.

New treatment options for substance abuse from a public health viewpoint.

Naltrexone is the first safe and effective pharmaceutical adjunct for use in the treatment of alcohol abuse. Theoretically it could be effective also as a means for terminating methadone maintenance and in the treatment of other forms of substance abuse. Two general types of protocols have been used with naltrexone. One protocol is similar to the protocol appropriate for use with disulfiram; it is designed to preclude use of the substance while on naltrexone. The other protocol is based on preclinical research showing that opioid antagonists can cause extinction of alcohol drinking; it is designed to maximize the effects from extinction. The results from the clinical trials are consistent with the conclusion that the major benefits from naltrexone treatment, regardless of protocol, are being caused by extinction. The extinction protocol is better from the position of public health, increasing the range of patients who can be treated, reducing the total cost and allowing patients to be treated with dignity. Pharmacological extinction is a new form of medicine, shown to be highly accessible and effective in treating excessive drinking and providing interesting possibilities for the treatment of other learned behavioural disorders.

Interdisciplinary treatment for fibromyalgia syndrome: clinical and statistical significance.

OBJECTIVES: The primary purposes of the study were to: evaluate the treatment efficacy of an outpatient, interdisciplinary treatment program for fibromyalgia syndrome (FMS); examine whether treatment gains would be sustained for 6 months following the treatment; assess whether improvements were clinically significant; and delineate the factors associated with clinically significant improvement in pain severity. METHODS: Sixty-seven FMS patients completed a 4-week outpatient program consisting of medical, physical, psychologic, and occupational therapies. Six-month followup data were available for 66% of treated patients. RESULTS: Comparisons between pretreatment and posttreatment measures revealed significant improvements in pain severity, life interference, sense of control, affective distress, depression, perceived physical impairment, fatigue, and anxiety; however, there was no improvement in interpersonal relationships or general activities. Clinically significant improvement in pain severity, using the Reliable Change Index, was obtained by 42% of the sample and was predicted by the pretreatment levels of depression, activity, perceived disability, solicitous responses of significant others, and idiopathic onset. Pretreatment level of pain severity was not a significant predictor of the degree of pain improvement. Comparisons among pretreatment, posttreatment, and 6-month followup data revealed that the patients maintained treatment gains in pain, life interference, sense of control, affective distress, and depression. However, the quadratic polynomial analysis revealed that relapse occurred in the subjective rating of fatigue. CONCLUSIONS: The results suggest that, overall, an outpatient interdisciplinary treatment program was effective in reducing many FMS symptoms. Treatment gains tended to be maintained for at least 6 months. However, there were large individual differences in response to treatment. These results suggest that identification of subgroups of FMS patients and their specific clinical characteristics may be useful for maximizing treatment efficacy.

Effects of naltrexone and ethanol on auditory event-related brain potentials.

Acute effects of ethanol (0.55 g/kg) and the opioid antagonist naltrexone (50 mg) on auditory event-related brain potentials (ERP) (i.e., electrical brain activity time-locked to sensory stimuli) were investigated in 13 healthy social drinkers, using a double-blind, placebo-controlled, design. The subjects' task was to attend to tones presented to a designated ear while ignoring tones to the other, and to detect deviant tones among the attended tones. When administered alone, naltrexone significantly reduced the amplitude of the later part of negative difference (Nd[l]), suggesting impaired selective attention. However, this effect might have been caused by naltrexone-induced nausea. Ethanol, when ingested alone, attenuated the amplitude of the N1, and increased the peak latencies of the mismatch negativity (MMN) and N2b that have been suggested to reflect automatic change detection in audition and allocation of attentional resources to processing of stimulus deviance, respectively. In contrast, the P1 amplitude was augmented by alcohol, but only when the tones were attended. When ethanol and naltrexone were simultaneously ingested, however, the alcohol-induced P1 amplitude augmentation was canceled, thus tentatively suggesting opioidergic mediation of this alcohol effect. In contrast, the MMN peak latency was increased significantly more in the interaction condition than in the ethanol condition, thus suggesting that the detrimental effects of alcohol on involuntary attention switching were augmented by naltrexone. Furthermore, the N2b amplitude was significantly suppressed in the interaction condition, suggesting attentional impairment.

A standardized manual tender point survey. I. Development and determination of a threshold point for the identification of positive tender points in fibromyalgia syndrome.

OBJECTIVE: To (a) develop a standardized tender point examination protocol [Manual Tender Point Survey (MTPS)] as a diagnostic procedure to evaluate the tender point (TP) criterion for fibromyalgia syndrome (FM) and (b) determine a threshold point for positive TP. METHODS: A standardized MTPS consisted of standardized components including (a) location of the survey sites, (b) patient and examiner positioning, (c) order of examination, (d) pressure application technique, and (e) pain severity rating scores [0 (no pain) - 10 (worst pain)]. Seventy patients with FM and 70 with chronic headache were examined using the MTPS protocol. RESULTS: A pain severity score of 2 (i.e., 0-1 = negative) was found to be an optimal threshold point for identifying positive TP, with sensitivity of 88.57% and specificity of 71.43%. These results are comparable to the sensitivity and specificity of the 1990 multicenter study. CONCLUSION: The MTPS provides a step-by-step, standardized TP examination protocol, which is sensitive and specific in discriminating patients with FM from patients with chronic headache.

Effects of type of symptom onset on psychological distress and disability in fibromyalgia syndrome patients.

The purpose of the study was to investigate the differences between two types of onset (post-traumatic versus idiopathic) in pain, disability, and psychological distress in patients with fibromyalgia syndrome (FS). Forty-six FS patients with post-traumatic onset and 46 FM patients with idiopathic onset, who were matched in age and pain duration, were included in the study. All participants completed self-report inventories assessing their adaptation to the pain conditions, and during the medical examination, an examining physician completed an inventory (Medical Examination and Diagnostic Information Coding System; MEDICS) to indicate the degree of physical abnormality. The analysis revealed that the degrees of physical abnormality of the patients were comparable in the two groups. However, controlling for the involvement with financial compensation issues (e.g. disability, litigation), the post-traumatic FS patients reported significantly higher degrees of pain, disability, life interference, and affective distress as well as lower level of activity than did the idiopathic FS patients. Furthermore, evaluation of the treatment history in these patients revealed that a significantly larger number of the posttraumatic FS patients were receiving opioid medications and had been treated with nerve block, physical therapy, and TENS. The results suggest that (1) post-traumatic onset is associated with high level of difficulties in adaptation to chronic FS symptoms and (2) FS patients are a heterogeneous group of patients.

Effect of prior ethanol experience on dopamine overflow in accumbens of AA and ANA rats.

The purpose of this study was to investigate the effect of repeated ethanol administration on dopamine overflow in the nucleus accumbens of alcohol-preferring AA (Alko Alcohol) and alcohol-avoiding ANA (Alko Nonalcohol) rats. Dopamine is a possible mediator of the reinforcing effects of ethanol, but it has previously been shown that ethanol-naïve alcohol-preferring AA and alcohol-nonpreferring ANA rats do not differ in their dopaminergic reaction to an intraperitoneal ethanol injection (0.5-2.0 g/kg), as assessed by measuring extracellular dopamine in the nucleus accumbens with in vivo microdialysis. Here a group of AA rats drank 10% (v/v) ethanol voluntarily-continual access for 5-15 days, limited access for 3 weeks-while a yoked group of AA rats and a yoked group of ANA rats received the same amount intragastrically by intubation. The rats were implanted with guide cannulas on the fourth week of limited access. Dopamine overflow was monitored in the microdialysis perfusate after 1 g/kg i.p. ethanol. The AA and the ANA rats that received ethanol non-contingently showed the same dopaminergic response to this as naïve animals have before. The group that had ingested the ethanol voluntarily showed, however, a significantly smaller increase in dopamine after 1 g/kg ethanol i.p. This suggests that the active behavior associated with obtaining the contingent drug may have an important impact on the reactions of the dopamine system to the drug, producing different results than when the same drug is administered by other routes. The hypothesis that dopamine mediates ethanol reinforcement in AA rats is not supported by the results.

Pain, disability, and physical functioning in subgroups of patients with fibromyalgia.

OBJECTIVE: To investigate (1) whether patients with fibromyalgia (FM) could be subgrouped on the basis of psychosocial and behavioral responses to pain, and (2) the relationships among pain severity, perceived disability, and observed physical functioning, as measured by cervical spinal mobility. METHODS: 117 patients with FM received a comprehensive examination, underwent physical performance tasks during the evaluation, and completed self-report inventories. RESULTS: About 87% of the patients could be classified into the Multidimensional Pain Inventory clustering groups identified and validated in patients with a range of chronic pain problems (Dysfunctional, Interpersonally Distressed, and Adaptive Copers). Although the 3 groups exhibited comparable levels of physical functioning, the Dysfunctional and Interpersonally Distressed patients reported higher levels of pain, disability, and depression. Interpersonally Distressed patients also reported significantly lower levels of marital satisfaction than the other 2 subgroups. There were significant associations between pain severity and perceived disability, and pain severity and physical functioning, defined by spinal mobility tests. The relationship between disability and physical functioning did not reach statistical significance. Correlational analyses by subgroups revealed a significant association between patient perceived disability and physical functioning in the Adaptive Copers, but not the Dysfunctional or Interpersonally Distressed patients. CONCLUSIONS: Patients with FM can be classified into 3 subgroups based on psychosocial and behavioral characteristics. These subgroups show substantial differences in clinical presentation of their symptoms. Although the results should be considered preliminary due to the narrow range of physical functioning, the differential relationships between perceived disability and physical functioning across cluster groups suggest the importance of FM syndrome as a heterogeneous disorder. Treating patients with FM as a homogeneous group may compromise research results, impede understanding of the mechanisms underlying this condition, and deter development of effective treatment.

Pain sensitivity and saccharin intake in alcohol-preferring and -nonpreferring rat strains.

The experiments were designed to study the association between consumption of palatable 0.1% (w/v) saccharin solution, voluntary drinking of 10% (v/v) ethanol solution, and pain sensitivity measured with the hot plate test. Rat lines that were genetically selected for high alcohol consumption (P and AA rats), alcohol-preferring Fawn Hooded (FH) rats and their F2[FH x FRL] hybrids, and the Maudsley Nonreactive strain (MNRA) had a high propensity to consume saccharin that resulted in a significant (almost twofold; p < 0.05) increase in their daily fluid intake when saccharin was available. These strains also had lower pain thresholds in the hot plate test than did their parallel strains [NP, ANA, Maudsley Reactive (MR)]. Most alcohol-nonpreferring strains [NP, ANA, and Flinders Resistant Line (FRL)] had preference ratios for saccharin about as high as those of the alcohol-preferring rats but, unlike the high alcohol drinkers, they did not increase their total fluid intake when saccharin was available. The mean saccharin intakes of the lines were strongly correlated with their alcohol drinking during the first 5 days, whereas their latencies on the hot plate were inversely related to their change in alcohol drinking with experience. The results are consistent with an endogenous opioid mechanism being involved in alcohol drinking.

Performance in the cross-maze and slip funnel tests of four pairs of rat lines selectively bred for divergent alcohol drinking behavior.

Alcohol naive rats from lines genetically selected for high and low alcohol drinking and founded on either Wistar (P/NP lines) and distinct heterogeneous stocks (AA/ANA and replicate HAD/LAD lines) were tested in the explorative cross-maze and the inescapable slip funnel. Rats of the low alcohol-consuming ANA, NP, LAD1 and LAD2 lines all exhibited a shorter latency before initiating exploration of the maze than did their high alcohol-consuming counterparts (66, 51, 33 and 51% of the values for AA, P, HAD1 and HAD2 lines, respectively). Significant line differences were also found with the slip funnel test (AA > ANA for time in a sprawling posture; P > NP but HAD1 < LAD1 and HAD2 < LAD2 for time escaping), but the directions of line differences were not consistently related to those in alcohol drinking.

Dose-related effect of alcohol on mismatch negativity and reaction time performance.

In a recent study, the mismatch negativity (MMN) component of auditory event-related potential, elicited by occasional frequency changes in a repetitive tone, was strongly attenuated by a low dosage of alcohol. We investigated the phenomenon in nine subjects with two different dosages of ethanol (0.35 and 0.55 g/kg), and with two magnitudes of frequency changes (5% and 10%), in a single-blind, placebo-controlled paradigm. Ethanol had no observable effect on the N1 and P2 deflections, nor on the reaction time to frequency changes measured in a separate session. However, the MMN was attenuated after administration of the larger dosage of alcohol, suggesting impaired preconscious processing of stimulus features outside the scope of attention. The results support the view according to which the automatic functions of human information processing are more sensitive than the controlled functions to the detrimental effects of alcohol. The fact that the MMN suppression was stronger when stimulus deviation was smaller indicates that at relatively low blood alcohol concentrations the detection of small deviations is especially hampered.

Effect of ethanol on extracellular dopamine in the nucleus accumbens of alcohol-preferring AA and alcohol-avoiding ANA rats.

The role of central monoamines in the genetically determined influences on voluntary ethanol consumption were examined by studying the extracellular levels of monoamines in the nucleus accumbens of the alcohol-preferring AA (Alko Alcohol) and alcohol-avoiding ANA (Alko Nonalcohol) rats with in vivo microdialysis. Dialysate samples for the assay of monoamines with small bore HPLC were collected from freely moving animals at 15 min intervals after administration of ethanol (0.5, 1, or 2 g/kg, i.p.). Ethanol significantly increased the extracellular levels of dopamine, DOPAC, and HVA, suggesting stimulation of dopamine release by ethanol, while the effect on 5-HIAA did not reach significance. No difference in the extent or time course of stimulation of dopamine release between the AA and ANA rats was found. The results could so far give no indication that the differential ethanol consumption by AA and ANA rats could be explained in terms of differences in ethanol-induced stimulation of dopamine release in the nucleus accumbens.

Low dose of ethanol suppresses mismatch negativity of auditory event-related potentials.

The acute effect of a low dose of ethanol (0.5 g/kg) on attention and auditory event-related potentials (ERPs) was investigated in 10 social drinkers using a single-blind, placebo-controlled cross-over design. A dichotic listening task, in which the subjects were instructed to attend selectively to stimuli to one ear while ignoring stimuli to the other, was used. The amplitudes of N1, P2, and the mismatch negativity (MMN) were significantly diminished by alcohol. The latencies of the MMN and N2b were also significantly increased after alcohol ingestion. The novel finding of the significant (> 60% reduction in amplitude) suppression of the MMN can be interpreted as indicating disturbed preconscious detection of acoustic changes outside the scope of attention. Because this is a prerequisite to an attentional shift, the MMN suppression may be related to increased risk for accidents after alcohol ingestion. The same dose of alcohol that suppressed the MMN left intact selective attention and conscious "target" detection, as reflected by the processing negativity and P3 deflections, thus suggesting that the automatic functions of human information processing are more sensitive to alcohol than the controlled, attentional functions.