Tramadol versus Methadone for Treatment of Opiate Withdrawal: A Double-Blind,Randomized, Clinical Trial

The aim of this study was to compare the efficacy and safety of tramadol versus methadone for treatment of opiate withdrawal. Seventy patients randomly were assigned in two groups to receive either prescribed methadone (60 mg/day) or tramadol (600 mg/day). The withdrawal syndrome of patients was evaluated before and after rapid opiate detoxification using the Objective Opioid Withdrawal Scale (OOWS). No significant differences existed in overall OOWS scores between two groups (P = 0.11). Dropout rates were similar in both groups. Side effects in the tramadol group were as or less common than in the methadone group, with the exception of perspiration. Tramadol may be as effective as methadone in the control of withdrawal and could be considered as a potential substitute for methadone to manage opioids withdrawal.     

Efficacy of buspirone in the treatment of opioid withdrawal

In an attempt to develop a new opiate detoxification approach, the authors assessed the efficacy of buspirone in the treatment of acute heroin withdrawal. Buspirone, a drug interacting with the serotonergic system, was selected because there is evidence that a decrease in serotonergic neurotransmission may be involved in opiate withdrawal symptoms. Twenty-nine hospitalized heroin addicts were randomized to 4 groups: (1) placebo; (2) methadone; (3) buspirone 30 mg daily; (4) buspirone 45 mg daily. The double-blind trial started in all patients with a 5-day methadone stabilization period ending with a 30-mg dose. This was followed from days 6 through 12 by placebo in group 1 and by a methadone taper in group 2. Because of its delayed action, buspirone was started on day 1 in groups 3 and 4 and was continued, after methadone discontinuation, through day 12. On day 13, drugs and placebo were discontinued and patients were observed through day 14. Withdrawal symptoms were assessed with the "Subjective Opiate Withdrawal Scale" (SOWS) and the "Objective Opiate Withdrawal Scale" (OOWS). The SOWS and OOWS scores were significantly higher in the placebo group than in the methadone, buspirone 30 mg, and buspirone 45 mg groups. There were no significant differences in SOWS or OOWS scores when the methadone group was compared with each of the two buspirone groups or when the two buspirone groups were compared with one another. In conclusion, buspirone, a nonopiate drug with no abuse potential, a safe side effect profile and no withdrawal symptoms, at doses of 30 and 45 mg, was as effective as a methadone taper in alleviating the withdrawal symptoms of heroin addicts stabilized for 5 days with, and then withdrawn from, methadone. The use of buspirone could be particularly helpful in outpatient settings where the duration of the methadone taper recommended for detoxification can be lengthy.     

Tramadol versus buprenorphine for the treatment of opiate withdrawal: a retrospective cohort control study

Various drugs have been used for the treatment of opioid withdrawal, e.g., methadone, buprenorphine, and clonidine. Tramadol is a centrally acting synthetic analgesic agent with opiate activity due to low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to mu opioid receptors. As a consequence, there may be a role for the use of tramadol in the treatment of opiate withdrawal. We attempt to assess the efficacy of tramadol in treating moderate heroin withdrawal through a retrospective cohort control study, conducted in a detoxification unit in a community teaching hospital. Out of 100 heroin abusers admitted for detoxification during the review period, 64 patients who were treated either with buprenorphine or tramadol, were included in this study, with 20 participants in the buprenorphine group and 44 in the tramadol group. Both groups were matched for age, sex, and self-reported average quantity of heroin used per day. In the tramadol group, the average CINA maximum was 9.0, and in the buprenorphine group it was 11.2 (P = 0.07). The use of oral clonidine per patient in the tramadol group was 1.6 tablets, and in the buprenorphine group 0.1 tablets (P = 0.002). The length of stay was 3.7 days in the tramadol group and 4.1 days in the buprenorphine group (P = 0.5). Four participants in the tramadol group received three or more doses of buprenorphine because their symptoms were not controlled, and were considered as treatment failures. These preliminary data suggest that tramadol may be comparable to buprenorphine in the management of mild to moderately severe heroin withdrawal. These findings, if reproduced in larger studies with stronger research designs, have potentially great implications for the management of opioid withdrawal in both the inpatient and outpatient setting.     

Intermittent naloxone attenuates the development of physical dependence on methadone in rhesus monkeys

Rhesus monkeys that received 15 daily injections of methadone (2 mg/kg i.m.) exhibited a characteristic opiate withdrawal syndrome after injection of naloxone (0.5 mg/kg i.m) on the 16th day. In comparison, injection of naloxone (0.5 mg/kg i.m.) once every 2 days during a similar 15 day methadone treatment period in these same monkeys significantly attenuated the severity of the opiate withdrawal syndrome exhibited after naloxone injection on the 16th day. Each naloxone administration during the 15 day methadone treatment period elicited an opiate withdrawal syndrome that did not significantly differ on each of the 7 days it was given and was less severe than the syndrome precipitated by naloxone following 15 days of methadone without intermittent naloxone. The lack of increments in the withdrawal response to the seven naloxone injections during the 15 days of methadone treatment and the attenuation of the withdrawal response to naloxone on day 16 after intermittent naloxone administration during the 15 day methadone treatment period support the hypothesis that naloxone modifies opiate receptor mechanisms so that they revert to an agonist-naive state following antagonist exposure. These findings suggest that various agonist and antagonist drugs opiate combinations or mixed agonist-antagonist drug could be clinically useful in the management of situations where physical dependence on opiates is a problem.     

Opioid detoxification with buprenorphine,clonidine, or methadone in hospitalized heroin-dependent patients with HIV infection

With the growing role of intravenous drug use in the transmission of HIV infection, HIV-infected patients frequently present with comorbid opioid dependence. Yet, few empirical evaluations of the efficacy and consequences of opioid detoxification medications in medically ill HIV-infected patients have been reported. In a randomized, double-blind clinical trial, we evaluated the impact of three medications on the signs and symptoms of withdrawal and on the pain severity in heroin-dependent HIV-infected patients (N=55) hospitalized for medical reasons on an inpatient AIDS service. Patients received a 3-day pharmacologic taper with intramuscular buprenorphine (n=21), oral clonidine (n=16), or oral methadone (n=18), followed by a clonidine transdermal patch on the fourth day. Observed and self-reported measures of opioid withdrawal and pain were taken 1-3 times daily for up to 4 days. Opiate administration used as medically indicated for pain was also recorded. Observer- and subject-rated opiate withdrawal scores decreased significantly following the first dose of medication and overall during treatment. Among all 55 subjects, self-reported and observer-reported pain decreased after treatment (on average observer-rated opioid withdrawal scale (OOWS) scores declined 5.6 units and short opioid withdrawal scale (SOWS) declined 4.8 units, P<0.001, for both) with no indication of increased pain during medication taper. There were no significant differences of pain decline and other measures of withdrawal between the three treatment groups. During the intervention period, supplemental opiates were administered as medically indicated for pain to 45% of the patients; only 34% of men versus 62% of women received morphine (P<0.05). These findings suggest buprenorphine, clonidine, and methadone regimens each decrease opioid withdrawal in medically ill HIV-infected patients.     

Chlordiazepoxide vs. methadone in opiate withdrawal: a preliminary double blind trial

A double blind trial of chlordiazepoxide vs. methadone in the management of the opiate withdrawal syndrome was conducted in a group of 24 regular heroin takers. Subjective and objective measures including physiological parameters were recorded to compare the severity of opiate withdrawal between the two groups. No significant difference was found in terms of subjective withdrawal distress between the two treatment conditions, although there was a tendency to a return of withdrawal symptoms in the methadone group towards the end of treatment. A nurse rating scale demonstrated a significantly higher level of withdrawal signs in the chlordiazepoxide group on day 3. Physiological measures suggested that neither group experienced a severe withdrawal illness. A similar number in each group (37%) became completely drug free.     

Coca and Cocaine: A Bibliography

Abstract

Using signs, symptoms and serum methadone levels to guide evaluation, the authors treated 164 patients in a methadone maintenance program with doses of methadone exceeding 100 mg/d. The mean dose of these higher dose (HD) patients was 211 mg/d (range 110–780 mg/d). A comparison group (C) of 101 patients was randomly selected from the general clinic population mean dose 65 mg/d). At intake the HD group reponed $153/day of heroin use versus $87/day in the C group. The HD group had more patients whose opiate of choice was an oral pharmaceutical (30% versus 2% of the C group). Sixty-three percent of the HD group had comorbid Axis I psychiatric diagnoses compared to 32% of the C group. Response to psychopharmacologic treatment was enhanced by increased methadone dose in HD patients with “refractory” psychiatric disorders. Urine toxicologies described as “before” were collected prior to increase over 100 mg/d in the HD group or at the first routine urine toxicology collection of the calendar year for the C group. These results were compared to the most recent urine toxicologies for both groups (“after”). The percentage of toxicologies positive for illicit drugs in the HD group dropped from 87% “before” to 3% “after”. The C group were 54% positive “before” and 37% positive “after”. We conclude that doses of methadone in excess of 100 mg/d (range 110—780 mg/d in our sample of 164 patients) are not only safe but necessary to prevent illicit opiate use, stabilize psychiatric symptoms, and diminish abuse of alcohol and benzodiazepines in many patients.     

Effects of ethnicity on low-dose opiate stabilization

In a recent randomized clinical trial using buprenorphine (2 and 6 mg) and methadone (35 and 65 mg), we compared low-level opiate withdrawal symptoms among Whites (n = 84), Hispanics (n = 20), and African Americans (n = 21). During the first 2 monthsof opiate stabilization, persistent low-level opiate withdrawal symptoms were significantly lower in African-Americans and Hispanics than in the white patients. As expected pharmacologically, this relative underreporting of low-level withdrawal by minority patients was greater for the low opiate doses (buprenorphine 2 mg and methadone 35 mg). This underreporting may reflect sociocultural as well as biological differences, because subjective, but not objective, withdrawal symptoms showed this ethnic difference.     

Propoxyphene napsylate compared to methadone for opiate dependence

When high single doses of propoxyphene napsylate (PN) were given to patients on a methadone maintenance program, results indicated that, to avoid undesirable side effects, the dose should not exceed 600 mg. However, when PN was given in divided doses (800 mg/day in two equal doses), no significant adverse reactions were noted. In the double-blind comparison of 800 mg PN in two divided doses versus 20 mg methadone, 10 mg methadone, or placebo methadone, it was found that PN (1) did not alleviate withdrawal symptoms in patients previously maintained on 20 mg methadone, (2) produced a slightly overmedicated effect in the detoxified group of ex-methadone patients, and (3) compared favorably to 10 mg methadone in suppressing withdrawal symptoms without producing evidence of overmedication in those patients previously stabilized on a methadone maintenance dose of 10 mg. It is concluded that on a mg for mg basis, PN at a dose of 80-times that of methadone will relieve withdrawal symptoms in the treatment of mildly addicted patients requiring 10 mg methadone or less per day.     

Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone treatment for in-patient opiate detoxification

This open study compares an accelerated 5-day lofexidine regimen with orthodox 10-day lofexidine and methadone regimens in the treatment of opiate withdrawal in 61 polysubstance abusing opiate addicts. Significant differences in levels of withdrawal symptoms were found on days 11, 13–15 and 17–20, symptoms resolving most rapidly in the 5-day lofexidine treatment group, whilst withdrawal responses in the 10-day lofexidine treatment group were intermediate between the 5-day lofexidine and standard methadone treatment conditions. When the two lofexidine regimens were separately compared with methadone the 5-day lofexidine treatment was significantly more effective on day 10, 11 and 13–20, whilst the 10-day lofexidine treatment was not significantly different from methadone. There were no significant differences in rates of completion of detoxification between the three treatments. Both the lofexidine treatment regimens had a similar effect on blood pressure. Five patients experienced side effects which resolved with dose reduction, all remaining in the study. An accelerated 5-day lofexidine regimen may attenuate opiate withdrawal symptoms more rapidly than conventional 10-day lofexidine or methadone treatment schedules without exacerbating hypotensive side effects.     

Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25–29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.     

Methadone combined with clonidine versus clonidine alone in opiate detoxification

The availability and use of a methadone/clonidine combination versus clonidine alone in opiate detoxification were studied. In Phase I of the study, a sequential combination of methadone followed by clonidine was utilized in those patients presenting with a primary diagnosis of opiate dependence. During the Phase II of the study, only clonidine was available. Medications were administered only if the history and clinical findings indicated impending or acute opiate withdrawal syndrome. Overall, there was no difference between the Phase I and Phase II groups when the number of opiate dependent admissions, patients completing detoxification, and the patients completing a follow-up rehabilitation program were compared. However, the patients in Phase I whose clinical symptomatology warranted the use of methadone were more likely to complete the detoxification program when compared to the patients in Phase II who received clonidine only. There was no difference between the two groups in completion of a follow-up rehabilitation. Detoxification with clonidine alone was more likely to be successful if the patient has had prior detoxification experience with methadone or if there was a secondary dependence of alcohol, sedative, or tranquilizer present coexisting with the primary opiate dependence diagnosis.     

Assessment of agonist and antagonist effects of tramadol in opioid-dependent humans

The subjective, behavioral, and physiologic effects of racemic tramadol, an analgesic with low abuse liability and dual mu-opioid agonist and monoamine reuptake actions, were evaluated in 2 clinical pharmacology studies in dependent opioid abusers. In the withdrawal precipitation study, participants (N = 8) were maintained on methadone 60 mg/day orally and challenged with intramuscular tramadol, hydromorphone, naloxone, and placebo 20 hr after methadone administration. In the withdrawal suppression study, participants (N = 6) were maintained on hydromorphone given orally 10 mg 4 times daily, and spontaneous opioid withdrawal was produced by withholding doses for 23 hr. During the experimentally induced withdrawal, oral tramadol, hydromorphone, naltrexone, and placebo were given. In both studies a comprehensive panel of participant-rated, observer-rated, and physiologic measures were collected. In both studies, naloxone and naltrexone significantly increased measures of opioid withdrawal, whereas tramadol showed no discernible antagonist effects. In contrast, tramadol's pattern of effects was more similar to that of hydromorphone and suggestive of mild opioid-agonist effects (withdrawal suppression), though not to a statistically significant degree.     

Comparison of buprenorphine and methadone in the treatment of opiate withdrawal: possible advantages of buprenorphine for the treatment of opiate-benzodiazepine codependent patients?

The study is a preliminary investigation to compare the effectiveness of buprenorphine and methadone as opiate detoxification treatments. The sample comprised 123 drug misusers who were dependent upon opiates only or who were codependent upon opiates and benzodiazepines. Drug misusers dependent upon methadone doses up to 70 mg were eligible for the study. Detoxification took place within a specialist inpatient drug-dependence unit. Withdrawal symptom severity was assessed on a daily basis by means of the Short Opiate Withdrawal Scale. Outcome was assessed for reductions in severity of withdrawal symptoms, treatment retention, and treatment completion. Buprenorphine detoxification was associated with less severe opiate withdrawal symptoms than methadone. Opiate/Benzodiazepine codependent patients reported less severe withdrawal symptoms during treatment with buprenorphine than with methadone and were also more likely to complete detoxification when treated with buprenorphine.     

Insomnia among addicts during supervised withdrawal from opiates: A comparison of oral methadone and electrostimulation

Measures of sleep disturbance were taken among drug-dependent inpatients being withdrawn from opiates using either a conventional oral methadone regime or electrostimulation (ES). Sleep was found to be disturbed in both groups. Subjects receiving ES showed the more marked sleep reduction and higher levels of night time waking during withdrawal: insomnia was most evident during the first 14 days of withdrawal. The degree of sleep disturbance among the methadone subjects was less severe but there were also sleep difficulties in this group. As late as 1 month after admission there was considerable night-to-night variability in sleep times with mean values between 4 h and 6 h in both groups. The ES procedure was unsatisfactory for managing insomnia during opiate withdrawal, but neither can methadone be regarded as fully satisfactory in this respect. An incidental finding to emerge from this study is that those subjects in the ES group who remained in treatment experienced more sleep disturbance than those who dropped out prematurely.     

Methadone tapering plus amantadine to detoxify heroin-dependent inpatients with or without an active cocaine use disorder: two randomised controlled trials

The efficacy of methadone tapering plus amantadine to detoxify heroin-dependent patients with or without an active cocaine use disorder was studied in a closed unit with two successive double-blind, placebo-controlled, 14-day trials. In the first trial, 40 heroin-dependent inpatients with an active cocaine use disorder were treated using methadone tapering, as well as amantadine (200-300 mg per day) or placebo. In the second trial, 40 heroin-dependent inpatients without an active cocaine use disorder received the same treatment. In both the trials, amantadine did not have a statistically significant effect on treatment completion, nor did it contribute, in completers, to a more rapid reduction in craving and opiate withdrawal. In the first trial, women were six times more likely than men to be non-completers, and on the last day of treatment, the first trial's completers and non-completers presented a comparable clinical state.     

Randomised double-blind comparison of lofexidine and clonidine in the out-patient treatment of opiate withdrawal

This study compares the clinical response to lofexidine and clonidine in the out-patient treatment of opiate withdrawal in 50 opiate addicts, using a randomised double-blind study design. Patients were taking 40 mg or less methadone daily, or equivalent amounts of other opiates. Fifty-eight percent of those starting treatment completed detoxification, and were opiate free at 4 weeks: more patients completed withdrawal in the lofexidine group, but the difference was not significant. Clonidine produced more hypotensive effects: more home visits were also required by medical staff. There was no other significant difference in side effects. Both drugs can be used successfully in out-patient detoxification, but lofexidine is more economical in regard to staff time.     

Pharmacokinetic-pharmacodynamic modeling of mood and withdrawal symptoms in relation to plasma concentrations of methadone in patients undergoing methadone maintenance treatment

ABSTRACT: 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.