Subjective Withdrawal Research Articles

Effect of Ritonavir‐Boosted Danoprevir, a Potent Hepatitis C Virus Protease Inhibitor, on the Pharmacokinetics of Methadone in Healthy Subjects Undergoing Methadone Maintenance Therapy

To investigate the steady-state pharmacokinetics of methadone when coadministered with ritonavir-boosted danoprevir (DNVr). Open-label, two-period, single-sequence pharmacokinetic study. Two U.S. research centers. Eighteen methadone-maintained healthy adults. In Period 1 (Day -1), subjects received their daily methadone maintenance therapy (MMT). In Period 2 (Days 1-10), subjects received MMT plus DNVr 100/100mg twice/day. Pharmacokinetic parameters for the total concentrations of (R)- and (S)-methadone on Days -1 and 10 were determined using noncompartmental methods. Unbound (R)- and (S)-methadone concentrations at 3hours postdose were also assessed on Days -1 and 10. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare steady-state (R)- and (S)-methadone pharmacokinetics when MMT was administered with or without DNVr. Methadone withdrawal was assessed using the Subjective Opiate Withdrawal Scale. Compared with MMT alone, methadone AUCtau and Cmax GMR (90% CI) following coadministration with DNVr were 1.02 (0.91-1.15) and 1.01 (0.90-1.13) for (R)-methadone, and 1.01 (0.90-1.13) and 0.99 (0.89-1.10) for (S)-methadone, respectively. Unbound (R- and (S)-methadone concentrations were comparable with or without DNVr. No instances of methadone withdrawal were reported. MMT in combination with DNVr was well tolerated. Coadministration of DNVr with MMT resulted in no significant pharmacokinetic interactions or signs of methadone withdrawal. No dosage adjustment is needed for MMT when coadministered with DNVr.

Hab-o Shefa (an Iranian traditional medicine compound) in withdrawal syndrome and its effects in acute detoxification of opiates addict: A randomized, double blind, clinical trials

Hab-o Shefa is a natural traditional Iranian medicine (TIM) product that many centuries used as a replacement for opium addiction treatment. In this randomized, double blind, controlled, clinical trial the effect of Hab-o Shefa was studied in the treatment of opiates addiction. In a double-blind placebo-controlled clinical trial, 90 in-patients with opiates dependency that received an assisted self-help intervention, were randomly divided into the three groups. Hab-o Shefa was administered to the first group: 3 g/day four times daily on days 1 to 7, tapered down over 14 days. Clonidine was prescribed to the second group: 0.2 to 0.4 mg/day on days 1 to 2, 0.6 mg/day on days 3 to 18 and 0.4 to 0.2 mg/day on days 20 to 21. Placebo was administered to the third group. Studied variables included treatment retention, detoxification success rate, daily check of subjective, objective and clinical opiate withdrawal scale, depression scales, craving intensity, side effects, vital signs and electrocardiography (ECG) and biochemical tests at the beginning and end points of the study. Control of withdrawal symptoms and depression in Hab-o Shefa group was better than the other groups (P<0.05). Key words: Hab-o Shefa, acute detoxification, opiates addiction, traditional Iranian medicine, withdrawal symptoms.

Down-Regulation of Amygdala and Insula Functional Circuits by Varenicline and Nicotine in Abstinent Cigarette Smokers

Although the amygdala and insula are regarded as critical neural substrates perpetuating cigarette smoking, little is known about their circuit-level interactions with interconnected regions during nicotine withdrawal or following pharmacotherapy administration. To elucidate neurocircuitry associated with early smoking abstinence, we examined the impact of varenicline and nicotine, two modestly efficacious pharmacologic cessation aids, on amygdala- and insula-centered circuits using resting-state functional connectivity (rsFC). In a functional magnetic resonance imaging study employing a two-drug, placebo-controlled design, 24 overnight-abstinent smokers and 20 nonsmokers underwent ∼17 days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. We examined the impact of varenicline and nicotine (both alone and in combination) on amygdala- and insula-centered rsFC using seed-based assessments. Beginning with a functionally defined amygdala seed, we observed that rsFC strength in an amygdala-insula circuit was down-regulated by varenicline and nicotine in abstinent smokers. Using this identified insula region as a new seed, both drugs similarly decreased rsFC between the insula and constituents of the canonical default-mode network (posterior cingulate cortex, ventromedial/dorsomedial prefrontal cortex, parahippocampus). Drug-induced rsFC modulations were critically linked with nicotine withdrawal, as similar effects were not detected in nonsmokers. These results suggest that nicotine withdrawal is associated with elevated amygdala-insula and insula-default-mode network interactions. As these potentiated interactions were down-regulated by two pharmacotherapies, this effect may be a characteristic shared by pharmacologic agents promoting smoking cessation. Decreased rsFC in these circuits may contribute to amelioration of subjective withdrawal symptoms.

Comparison of efficacy between buprenorphine and tramadol in the detoxification of opioid (heroin)-dependent subjects

Tramadol is a synthetic opiate and a centrally acting weak m-opioid receptor agonist. The potential advantages of tramadol include ease of administration, low abuse potential, and being nonscheduled. This study compared tramadol and buprenorphine for controlling withdrawal symptoms in patients with opioid dependence syndrome. Consenting male subjects between 20 and 45 years of age who fulfilled the ICD-10-DCR criteria for opiate dependence syndrome were randomly assigned in a double-blind, double-dummy placebo-controlled trial for detoxification. Those with multiple drug dependence, abnormal cardiac, renal and hepatic functions, psychosis, or organic mental illness were excluded. Assessments included Subjective Opiate Withdrawal Scale (SOWS), Objective Opiate Withdrawal Scale (OOWS), Visual Analog Scale (VAS), and Side Effect Check List. Subjects were evaluated daily and study duration was 10 days. Sixty two subjects were enrolled. The mean SOWS and OOWS and VAS were significantly lower in the buprenorphine group on second and third day of detoxification as compared to the tramadol group. Although the retention rate was higher for buprenorphine group throughout the study, when compared with tramadol the difference was not significant on any day. Three subjects in the tramadol group had seizures. Tramadol was found to have limited detoxification efficacy in moderate to severe opioid withdrawal and substantial risk of seizures as compared to buprenorphine. Further studies are warranted to examine its efficacy in mild opioid withdrawal symptoms and its potential use in outpatient settings where its administration advantages may be valuable.

2801 – Effectiveness of electroacupuncture as adjunctive therapy in relieving opiate withdrawal symptoms among methadoe maintainance treatment (MMT) patient: a single blinded, randomized study

Over the last decades, acupuncture has been seen as an acceptable primary detoxification treatment for opiate dependence, and currently used to relieve the severity of opiate withdrawal symptoms among MMT patient. To investigate the effectiveness of electroacupuncture treatment in reducing opiate withdrawal symptoms among MMT patient. This was a pilot study with randomized, single-blinded, and parallel. Recruitment of 22 subjects, 11 in methadone treatment + acupuncture and 11 in methadone treatment without acupuncture. The severity of withdrawal reaction was assessed by Objective Opiate Withdrawal Scale (OOWS) and Subjective Opiate Withdrawal Scale (SOWS) at baseline, third, fifth, seventh, tenth and fourteenth day of treatment. One way Analysis of Variance (ANOVA) comparing the mean scores of the OOWS between treatment and control group has shown at tenth day of treatment p value is 0.026 and at fourteenth day p value is 0.022. One way ANOVA comparing the mean scores of the SOWS between treatment and control groups has shown at tenth day of treatment, p value is 0.015 and at fourteenth day, p value is 0.009. The study has shown the promising results, where electroacupuncture treatment had an effectiveness in relieving opiate withdrawal symptoms among MMT patient.

Pharmacokinetic-Pharmacodynamic Modeling of Mood and Withdrawal Symptoms in Relation to Plasma Concentrations of Methadone in Patients Undergoing Methadone Maintenance Treatment

The aims of the present study were to characterize the relationship between plasma racemic methadone and its enantiomers' concentrations with respect to their pharmacodynamic effects and to investigate the influence of potential covariates on the pharmacodynamic parameters in patients on methadone maintenance treatment (MMT). Eighty-eight regular subjects at the Sheffield Care Trust Substance Misuse Services were studied. Samples of blood and urine were collected before the daily dose of methadone. Blood samples were taken up to 5 hours after dose. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by liquid chromatography-mass spectrometry. The Total Mood Disturbance Score (TMDS), the Objective Opioid Withdrawal Scale (OOWS), and the Subjective Opioid Withdrawal Scale (SOWS) were used as measures of mood and withdrawal. Population pharmacokinetic/pharmacodynamic analysis and subsequent multiple regression analysis were used to determine the factors influencing the pharmacodynamic effects of methadone. Significant decreases (P ≤ 0.04) were observed in the scores for the TMDS, SOWS, and OOWS for 5 hours after methadone dosage. The TMDS had returned to baseline by 10 hours after dose (P = 0.98), at which time the SOWS remained significantly below baseline (P = 0.001). Multiple regression analysis revealed that 33% of the overall variation in unbound (R)-methadone EC50 was explained by 3 variables, namely CYP3A activity (9%), age (16%), and sex (8%). Age also accounted for 8% and 9% of the variation in total (rac)- and (R)-methadone EC50. The present study has confirmed that the duration of mood change in the present study was shorter than the effect of methadone in stabilizing withdrawal symptoms. Thus, it is likely that a once-daily dose of methadone, albeit effective for preventing withdrawal, may not be sufficient to improve mood in some patients. Finally, it was established that CYP3A activity, years of dependent use, sex, and age are major determinants of methadone EC50 with respect to TMDS.

Evaluation of Buprenorphine Dosage Adequacy in Opioid Receptor Agonist Substitution Therapy for Heroin Dependence

The dosing of opioid receptor agonist medications adequately and on an individual basis is crucial in the pharmacotherapy of opioid dependence. Clinical tools that are able to measure dose appropriateness are sorely needed. The recently developed and validated Opiate Dosage Adequacy Scale (ODAS) comprehensively evaluates the main outcomes relevant for methadone dose optimization, namely relapse, cross-tolerance, objective and subjective withdrawal symptoms, craving and overdose. Based on the ODAS, we developed a new assessment tool (BUprenorphine-naloxone Dosage Adequacy eVAluation [BUDAVA]) for evaluating dosage adequacy in patients in treatment with buprenorphine-naloxone. The main goal of this observational study was to explore whether the BUDAVA questionnaire could be used to assess buprenorphine-based, long-term substitution therapy for heroin addiction. The study included heroin-dependent patients who had been in treatment with buprenorphine-naloxone for at least 3 months. Patients (n = 196) were recruited from 11 drug abuse treatment centres in Italy. Dosage adequacy was assessed with the BUDAVA questionnaire. Patients classified as inadequately treated had their dosage modified. After 1 week, they were again administered the questionnaire to assess the adequacy of the new dosage. The buprenorphine-naloxone dosage was found to be inadequate in 61 of the 196 patients. In 13 patients, the treatment scored as inadequate only in the subjective withdrawal symptoms item of the questionnaire and therefore no dosage adjustment was made in the 2 weeks that have characterized this work. The remaining 48 inadequately treated patients had their dosage modified (42 dose increases and six dose decreases). After 1 week on the modified dosage, in 24 of these patients the new regimen was found by the assessment with the questionnaire to be adequate. These preliminary results suggest that the BUDAVA questionnaire may be useful for guiding buprenorphine-naloxone maintenance dose adjustments in heroin-dependent patients.

Relationship of Negative Affect and Outcome of an Opioid Therapy Trial Among Low Back Pain Patients

Patients with chronic noncancer pain frequently report symptoms of depression and anxiety (negative affect), which are associated with higher ratings of pain intensity and a greater likelihood of being prescribed chronic opioid therapy. The purpose of this secondary analysis was to test the hypothesis that initial levels of negative affect can predict treatment-related outcomes in a double-blind, placebo-controlled study of extended-release (ER) hydromorphone among opioid-tolerant patients with chronic low back pain. Four hundred fifty-nine (N = 459) patients participated in the titration/conversion phase of a multicenter study, of which 268 were randomized to receive once-daily hydromorphone or placebo. All patients completed the Hospital Anxiety and Depression Scale (HADS) at baseline and were divided evenly into Low (N = 157), Moderate (N = 155), and High (N = 147) negative affect groups based on their scores. Group differences in numerical pain intensity measures at home and in the clinic, Roland-Morris Disability ratings, and measures of symptoms from the Subjective Opiate Withdrawal Scale (SOWS) throughout the trial were analyzed. Two hundred sixty-eight of the initial 459 subjects who entered the 2 to 4-week titration/conversion phase (pretreatment) were successfully randomized to either placebo or ER hydromorphone; a total of 110 patients then completed this double-blind phase of the study. Those in the Moderate and High negative affect groups tended to drop out more often during the titration/conversion phase because of the adverse effects or lack of efficacy of their prescribed opioid than those in the Low negative mood group (P < 0.05). Overall, those patients in the Moderate and High groups reported significantly higher pain intensity scores in at-home and in-clinic pain intensity ratings (P < 0.05), greater disability on the Roland-Morris Scale (P < 0.01), and more withdrawal symptoms on the SOWS (P < 0.05) than those in the Low group. Higher negative affect scores also predicted less favorable ratings of the study drug during the titration phase (P < 0.05). Interestingly, the High negative affect group showed the most improvement in pain in the placebo condition (P < 0.05). Negative affect is associated with diminished benefit during a trial of opioid therapy and is predictive of dropout in a controlled clinical trial.

Withdrawal and psychological sequelae, and patient satisfaction associated with subcutaneous flumazenil infusion for the management of benzodiazepine withdrawal: a case series

Our group and others internationally have previously reported data on the use of low-dose flumazenil administered intravenously for the management of benzodiazepine withdrawal. This paper describes the first reported use of subcutaneous flumazenil infusion in the management of acute benzodiazepine withdrawal. Self-reported withdrawal symptoms and psychological state and anxiety sequelae were collected at baseline and then at intervals to 5 days following initiation of subcutaneous flumazenil infusion. Data indicate that patient subjective benzodiazepine withdrawal symptoms were well managed, with significant reduction in psychological distress seen over the duration of treatment. Perceived difficulty in performing everyday functions was positively correlated with withdrawal severity and improved over treatment. Patients reported high treatment comfort, willingness to undertake a future subsequent treatment using this technique, and willingness to recommend this treatment to a friend. This small proof-of-concept study indicates that subcutaneous flumazenil infusion has excellent tolerability, efficacy and improvement on measures of psychological distress. Given this technique is less invasive and requires fewer staff resources compared with intravenous administration, it may prove a significant asset in the management of benzodiazepine withdrawal.

The Combination Very Low-Dose Naltrexone–Clonidine in the Management of Opioid Withdrawal

Background: The management of withdrawal absorbs substantial clinical efforts in opioid dependence (OD). The real challenge lies in improving current pharmacotherapies. Although widely used, clonidine causes problematic adverse effects and does not alleviate important symptoms of opioid withdrawal, alone or in combination with the opioid antagonist naltrexone. Very low-dose naltrexone (VLNTX) has been shown to attenuate withdrawal intensity and noradrenaline release following opioid agonist taper, suggesting a combination with clonidine may result in improved safety and efficacy. Objectives: We investigated the effects of a VLNTX–clonidine combination in a secondary analysis of data from a double-blind, randomized opioid detoxification trial. Methods: Withdrawal symptoms and treatment completion were compared following VLNTX (.125 or .25 mg/day) and clonidine (.1–.2 mg q6h) in 127 individuals with OD undergoing 6-day methadone inpatient taper at a community program. Results: VLNTX was more effective than placebo or clonidine in reducing symptoms and signs of withdrawal. The use of VLNTX in combination with clonidine was associated with attenuated subjective withdrawal compared with each medication alone, favoring detoxification completion in comparison with clonidine or naltrexone placebo. VLNTX/clonidine was effective in reducing symptoms that are both undertreated and well controlled with clonidine treatment and was not associated with significant adverse events compared with other treatments. Conclusions and Scientific Significance: Preliminary results elucidate neurobiological mechanisms of OD and support the utility of controlled studies on a novel VLNTX + low-dose clonidine combination for the management of opioid withdrawal.Portions of this article were presented at the American Society of Addiction Medicine, 42nd Annual Medical Scientific Conference, April 14–17, 2011, in Washington, DC.

Gabapentin Effect on Pain Associated with Heroin Withdrawal in Iranian Crack: a Randomized Double-blind Clinical Trial.

Gabapentin seems to be a safe and well tolerated medication for treating heroine dependence. This study examined the efficacy of gabapentin for relieving withdrawal-related pain due to heroin use. Sixty men were recruited from an inpatient psychiatric ward of Fatemieh hospital in Semnan and randomized to receive either placebo (n = 30) or gabapentin (1800 mg/day) (n = 30) for 7 days. Subjective Opioid Withdrawal Scale (SOWS) was measured as a self-administered scale for grading body pain at baseline, and on days 1, 2, 3, 4, 6, and 7. Mean of pain score had a significant decrease trend in both gabapentin and placebo groups. Pain severity during the most of detoxification duration was significantly lower in gabapentin group compared with the placebo group. It is suggested that gabapentin may have an effective role in removing heroin withdrawal-related pain.

A Randomized Double-Blind Pilot Trial of Gabapentin versus Placebo to Relieve Iranian Crack-Related Withdrawal Pain

Objectives: Gabapentin seems to be a safe and well tolerated medication for treating cocaine dependence. This study examined the efficacy of gabapentin for withdrawal-related pain relief due to crack (the Iranian crack containing condensed heroin) use. Methods: Sixty subjects were recruited from either an inpatient psychiatric ward of Fatemieh hospital in semnan and randomized to either placebo (n=30) or gabapentin (1800 mg/day) (n=30) for 7 days, balanced for gender. Subjective Opioid Withdrawal Scale was measured as a self-administered scale for grading body pain at baseline, and days 1, 2, 3, 4, 5, 6, and 7. Results: Mean of pain score had a significant decreasing trend in both gabapentin and placebo groups. Pain severity during the first six days of detoxification was significantly lower in gabapentin group compared with the controls, while the severity of pain based on SOWS scale was measured similar in the two groups at seventh day of trial. Conclusion: We could confirm the effective role of gabapentin in removing Iranian crack-related withdrawal pain. However, this potential effect on pain removing was only observed in first six days of drug administration.

Effects of Acute Exercise on Opiate and Cigarette Craving in Methadone Patients

Acute aerobic exercise has been shown to reduce craving for cigarettes in smokers. Over 80% of patients enrolled in methadone maintenance treatment (MMT) programs for opiate addiction are smokers and 29% suffer from diabetes. Many MMT counselors believe that regular physical exercise helps their patients to be successful in the program; however, there have been no previous studies demonstrating that increased physical activity positively impacts MMT patients. Purpose: To determine if acute aerobic exercise changes opiate and cigarette craving in MMT patients. Methods: 9 MMT patients (Age = 45±2 years; BMI=27.5±1.9) completed 3 randomly applied experimental trials immedi- ately before receiving their daily methadone dose. The experimental trials consisted of 20 minutes of rest, moderate exer- cise (65% predicted maximal heart rate), or vigorous exercise (80% predicted maximal heart rate). Craving for opiates, cigarettes, and sweets was recorded before, immediately after (IPE), and 10 minute after exercise (10 Post). Subjects also completed the Subjective Opiate Withdrawal Scale (SOWS) before and 10 minutes after exercise. Results: Craving for opiates was reduced (p<0.05) as a result of vigorous exercise at IPE (-26.8+6.9%) and 10 Post (-5.5+0.5%); however, craving for opiates was unchanged following moderate exercise. Craving for cigarettes was reduced (p<0.05) following both moderate (IPE=-37.9+6.1%; 10 Post=-13.1+9.1%) and vigorous (IPE=-37.1 +7.1%; 10 Post=-8.8+9.2% exercise. Craving for sweets and the SOWS was unchanged as a result of exercise. Conclusion: The results of this investigation suggest that craving for opiates and cigarettes in patients participating in a MMT program may be influenced acute aerobic exercise.

Ultra-rapid opiate detoxification using dexmedetomidine under general anesthesia

In this study, ultra-rapid detoxification using dexmedetomidine under general anesthesia (GA) has been evaluated in preventing the withdrawal symptoms in patients addicted to opioids. Sixty male patients who were addicted to opioids were assigned to one of the two groups, in which anesthesia was induced and maintained using propofol infusion: group D = treated with dexmedetomidine during anesthesia and for 6 days after recovery from anesthesia; group C = control group treated after recovery from anesthesia with oral dose of lefoxidine 0.2 mg three times daily. Hemodynamic changes and withdrawal symptoms were assessed using Objective Opiate Withdrawal Scale (OOWS) during anesthesia and both the Objective Opiate Withdrawal Scale (OOWS) and Subjective Opiate Withdrawal Scale (SOWS) after recovery from anesthesia. Patient satisfaction was assessed using 101-point verbal rating scale. Hemodynamic data showed that there were statistically significant increases in heart rate and systolic blood pressure during anesthesia in control group. Control group had significantly higher OOWS score on the following 3 days than the dexmedetomidine group, with no significant changes between the two groups from the fourth day till the sixth day except for muscle twitches in the control group on the sixth day (Cd6). Control group had significantly higher SOWS score on the following 4 days than the dexmedetomidine group, with no significant changes between the two groups on the fifth and sixth days except for yawning, nausea, and muscle twitches in control group on the fifth and sixth days (Cd5, Cd6). Patient satisfaction was significantly greater in dexmedetomidine group than in control group. Dexmedetomidine had shown to decrease markedly the withdrawal symptoms when used during ultra-rapid opiate detoxification under GA, and the patients in this group were more satisfied.

Problem Drinking and Low-Dose Naltrexone-Assisted Opioid Detoxification

The influence of alcohol use on opioid dependence is a major problem that warrants a search for more effective treatment strategies. The addition of very-low-dose naltrexone (VLNTX) to methadone taper was recently associated with reduced withdrawal intensity during detoxification. In a secondary analysis of these data, we sought to determine whether problem drinking affects detoxification outcomes and whether symptoms are influenced by VLNTX use. Opioid-dependent patients (N = 174) received naltrexone (0.125 or 0.250 mg/day) or placebo in a double-blind, randomized design during methadone-based, 6-day inpatient detoxification. Alcohol consumption was assessed at admission using the Addiction Severity Index and selfreport. Outcome measures were opioid withdrawal intensity, craving, and retention in treatment. Problem drinking-opioid dependent patients (n = 79) showed episodic heavy alcohol use and reported increased subjective opioid withdrawal intensity (p = .001), craving (p = .001), and significantly lower rate of retention in treatment (p = .02). Individuals with problem drinking and opioid dependence who were treated with VLNTX (n = 55) showed reduced withdrawal (p = .05) and a lower rate of treatment discontinuation (p = .03), resuming alcohol intake in smaller numbers the day following discharge (p = .03). Treatment effects were more pronounced on anxiety, perspiration, shakiness, nausea, stomach cramps, and craving. There were no group differences in use of adjuvant medications and no treatment-related adverse events. Heavy drinking is associated with worse opioid detoxification outcomes. The addition of VLNTX is safe and is associated with reduced withdrawal symptoms and better completion rate in these patients. Further studies should explore the use of VLNTX in detoxification and long-term treatment of combined alcohol-opioid dependence and alcohol dependence alone.

A double-blind, double-dummy, randomized controlled study of memantine versus buprenorphine in naloxone-precipitated acute withdrawal in heroin addicts

To compare the efficacy of memantine with buprenorphine in the suppression of naloxone-precipitated acute withdrawal in heroin-dependent male subjects in an inpatient setting. Inpatient unit of tertiary level deaddiction facility. Forty-five treatment-seeking heroin-dependent males. Subjects stabilized on 650 mg of dextropropoxyphene for 5 days were randomly divided into two groups on the sixth day: group A (n=25) received 20 mg of memantine with buprenorphineplacebo, and group B (n=20) received 2 mg of buprenorphine with memantine placebo. Acute withdrawals were precipitated with naloxone (0.4 mg, intravenously) and were assessed using subjective and objective opioid withdrawal scales (SOWS and OOWS) and two separate visual analogue scales (VASs) for pain and dysphoria at baseline prior to test drug administration and again after the precipitation of acute withdrawal. Severity ofprecipitated opioid withdrawals. Baseline opioid withdrawal symptoms in both groups did not differ significantly. After the precipitation of acute withdrawal, there were no significant differences between subjects in both groups on OOWS and both VASs but showed significant difference on SOWS. When changes in ratings from baseline (and after naloxone-precipitated acute withdrawal) were compared between the two groups, a significant difference in the change in SOWS scores was observed with greater decrease in withdrawal scores in the buprenorphine group. Memantine has comparable efficacy to buprenorphine in the suppression of objective signs of naloxone-precipitated acute opioid withdrawal; however, its role in the suppression of subjective symptoms is debatable.

Program of the University Clinic of Toxicology, Skopje, Republic of Macedonia, in Treatment of Drug Addiction (Buprenorfin Treatment Protocol)

The program of our Clinic includes, not only treatment of acute intoxication with opioids and other drugs, but also comprehends clinical investigations and treatment of the somatic complications of this population. For the first time in our country our Clinic offers to this population the alternative way of treatment with Buprenorfin. The Clinic started with this protocol on August 1, 2009. During a period of two years, the treatment with Buprenorfine has been initiated in 353 patients, of which 211 regularly attend the medical check ups. This model is used according to the national clinical guidelines and procedures for the use of buprenorfine in the treatment of opioid dependence The dose of this medicament depends on the evolution of the withdrawal symptoms. We have used the objective and subjective opioid withdrawal scale for the observation of these symptoms (OOWS ; SOWS – Handelsman et al 1987). This protocol starts with a complete clinical investigations, (i.e. where all patients undergo the inclusion and exclusion criteria with a written consent). Afterwards, the patients are hospitalized and start with a Buprenorfin teratment. After period of 7-10 days hospitalization they come to our Clinic, like outpatients for a regular controls. We have precise evidence for every patient who comes for control (e.g. medical record with all biochemical and toxicological screenings). All patients are recommended a tight cooperation with psychiatrists who are specialized to treat the problematic drug addictions.

Morphine Sulfate and Naltrexone Hydrochloride Extended Release Capsules in Patients with Chronic Osteoarthritis Pain

Objective: To assess the efficacy and safety of morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®; MS-sNT), which contain morphine sulfate pellets with a sequestered naltrexone core, in treating patients with chronic, moderate-to-severe osteoarthritis (hip or knee) pain. Patients and Methods: This phase 3 study had an enriched-enrollment, randomized-withdrawal, double-blind, multicenter design. Patients (N = 547) were titrated to an effective dose of MS-sNT (20–160 mg/day). Responders (n = 344) were randomized to 12 weeks maintenance with an effective MS-sNT dose or were tapered to placebo over 2 weeks. The primary efficacy measure was the change from baseline (CFB) in diary average-pain scores (0–10 scale, Brief Pain Inventory [BPI]) from randomization to the last 7 days of the maintenance period. Secondary efficacy measures included the remaining BPI scores and Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. Opioid withdrawal symptoms were assessed by the Clinical Opiate Withdrawal Scale (COWS) and Subjective Opiate Withdrawal Scale (SOWS). The study ran from January 10, 2007 through November 8, 2007. Results: MS-sNT maintained pain control better than placebo (mean CFB, diary average-pain score, −0.2 ± 1.9 vs +0.3 ± 2.1; P = 0.045). Change from baseline for MS-sNT pain-diary score (worst, least, average, current) was superior during the maintenance period visits, weeks 2 to 12 (P < 0.05). WOMAC composite score CFB was superior at most visits. MS-sNT was generally well tolerated, with a typical morphine safety profile. No patient taking MS-sNT as directed experienced withdrawal symptoms. Conclusion: MS-sNT provided effective analgesia in patients with chronic, moderate-to-severe osteoarthritis pain, with a safety profile typical of morphine-containing products. Naltrexone sequestered in MS-sNT had no clinically relevant effect when MS-sNT was taken as directed.

Association of Race and Ethnicity With Withdrawal Symptoms, Attrition, Opioid Use, and Side-Effects During Buprenorphine Therapy

Some studies report differences in opioid withdrawal between racial/ethnic groups. However, it is not known if these differences are reflected in differential treatment response. Data from National Institute on Drug Abuse (NIDA) Clinical Trials Network-003 were used to examine racial/ethnic differences before and during stabilization with buprenorphine. At induction, non-Hispanic Caucasians had higher objective and subjective withdrawal scores and greater opioid craving than minority participants. No significant between-group differences were observed on these scales following buprenorphine. Non-Hispanic Caucasians and Hispanics reported more adverse events than African Americans. Although ethnic and racial differences were observed prior to buprenorphine treatment, scores following buprenorphine treatment were similar between groups.

Effects Of Acute Exercise On Opiate And Cigarrette Craving In Methadone Patients

Acute aerobic exercise has been shown to reduce craving for cigarettes in smokers. Over 80% of patients enrolled in methadone maintenance treatment (MMT) programs for opiate addiction are smokers. Many MMT counselors believe that regular physical exercise helps their patients to be successful in the program; however, some MMT patients believe that they will need to increase their daily methadone dose if they initiate an exercise program. PURPOSE: To determine if acute aerobic exercise changes opiate and cigarette craving in MMT patients. METHODS: 7 MMT patients (4 men, 3 women; Age = 45±2 years; BMI=27.5±1.9) completed 3 randomly applied experimental trials immediately before receiving their daily methadone dose. Subjects abstained from smoking for 6 hours prior to experimental trials. Experimental trials consisted of 20 minutes of rest, moderate aerobic exercise (65% predicted maximal heart rate), or vigorous aerobic exercise (80% predicted maximal heart rate). Craving for opiates, cigarettes, and sweets was recorded before, immediately post exercise (IPE), and 10 minutes after exercise (10 post). Subjects also completed the Subjective Opiate Withdrawal Scale (SOWS) before and 10 post. RESULTS: Craving for opiates was reduced (p<0.05) as a result of vigorous exercise at IPE (-26.8+6.9%) and 10 Post (-5.5+0.5%); however, craving for opiates was unchanged following moderate exercise. Craving for cigarettes was reduced (p<0.05) following both moderate (IPE=-37.9+6.1%; 10 Post=-13.1+9.1%) and vigorous (IPE=-37.1+7.1%; 10 Post=-8.8+9.2%) exercise. Craving for sweets and the SOWS was unchanged as a result of exercise. CONCLUSIONS: The results of this investigation suggest that craving for opiates and cigarettes in patients participating in a MMT program may be influenced by acute aerobic exercise.