Combination Of Methadone Research Articles

The perioperative combination of methadone and ketamine reduces post‐operative opioid usage compared with methadone alone

A synergy between ketamine and methadone (ME) to produce antinociception has been demonstrated in experimental neuropathy. We wanted to compare post-operative opioid requirements in patients undergoing multilevel lumbar arthrodesis after the administration combined ME-ketamine (MK) or ME alone. This was a randomised double-blind study. During sevoflurane-remifentanil anaesthesia, 11 patients in each group received the following: ketamine bolus (0.5 mg/kg) after tracheal intubation, followed by an infusion of 2.5 μg/kg/min in the MK or saline bolus plus infusion in the ME group. Post-operative analgesia - during 48 h - was provided by patient-controlled analgesia (PCA), delivering bolus containing the following: ME 0.25 mg plus ketamine 0.5 mg in the MK group or ME 0.5 mg in the ME group. Lockout was 10 min, maximum of 3 boluses/h in both groups. Before closing the wound, all the patients received intravenous (i.v.) ME 0.1 mg/kg, dexketoprophen and paracetamol. Pain intensity was evaluated by a numerical rating scale (NRS), on arrival at recovery room (RR) and 24 and 48 h after surgery. In the RR, i.v. ME was administered until NRS was 3 when PCA was started. Dexketoprophen and paracetamol were administered 48 h. Remifentanil requirements were higher in the MK group (P = 0.004). Patients in the MK group received 70% less ME by PCA at 24 h (MK vs. ME group, median and interquartile range) - 3.43 mg (1.9-6.5) vs. 15 mg (9.65-17.38) (P < 0.001) - and at 48 h - 2 mg (0.5-3.63) vs. 9.5 mg (3.5-13.75) (P = 0.001). Patients in the MK group also attempted less doses, at 24 h: 19.5 (12.75-79.5) vs. 98 (41.5-137) (P = 0.043). Both groups had similar NRS values and comparable side effects. Perioperative ketamine-ME combination significantly decreased opioid consumption by PCA.

Survey of methadone-drug interactions among patients of methadone maintenance treatment program in Taiwan

BackgroundAlthough methadone has been used for the maintenance treatment of opioid dependence for decades, it was not introduced in China or Taiwan until 2000s. Methadone-drug interactions (MDIs) have been shown to cause many adverse effects. However, such effects have not been scrutinized in the ethnic Chinese community.MethodsThe study was performed in two major hospitals in southern Taiwan. A total of 178 non-HIV patients aged ≥ 20 years who had participated in the Methadone Maintenance Treatment Program (MMTP) ≥ 1 month were recruited. An MDI is defined as concurrent use of drug(s) with methadone that may result in an increase or decrease of effectiveness and/or adverse effect of methadone. To determine the prevalence and clinical characteristics of MDIs, credible data sources, including the National Health Insurance (NHI) database, face-to-face interviews, medical records, and methadone computer databases, were linked for analysis. Socio-demographic and clinical factors associated with MDIs and co-medications were also examined.Results128 (72%) MMTP patients took at least one medication. Clinically significant MDIs included withdrawal symptoms, which were found among MMTP patients co-administered with buprenorphine or tramadol; severe QTc prolongation effect, which might be associated with use of haloperidol or droperidol; and additive CNS and respiratory depression, which could result from use of methadone in combination with chlorpromazine or thioridazine. Past amphetamine use, co-infection with hepatitis C, and a longer retention in the MMTP were associated with increased odds of co-medication. Among patients with co-medication use, significant correlates of MDIs included the male gender and length of co-medication in the MMTP.ConclusionsThe results demonstrate clinical evidence of significant MDIs among MMTP patients. Clinicians should check the past medical history of MMTP clients carefully before prescribing medicines. Because combinations of methadone with other psychotropic or opioid medications can affect treatment outcomes or precipitate withdrawal symptoms, clinicians should be cautious when prescribing these medications to MMTP patients and monitor the therapeutic effects and adverse drug reactions. Although it is difficult to interconnect medical data from different sources for the sake of privacy protection, the incumbent agency should develop pharmacovigilant measures to prevent the MDIs from occurring. Physicians are also advised to check more carefully on the medication history of their MMTP patients.

Dolor irruptivo refractario a ketamina y metadona resuelto con abordaje multimodal

We report the case of a 28 year-old patient with a giant cell sacral bone tumour with pelvic invasion for two years, who maintained an excellent functional status. During this time she was cared for by the Home Care Support Team, with two admissions to a chronic Palliative Care Unit. The patient was admitted to our acute Palliative Care Unit for the management of severe breakthrough pain in the right lower limb with 10/10 intensity, associated to severe toxicity induced by ketamine. The multiple pain crises were not adequately controlled with a combination of methadone, venlafaxine, gabapentin, acetaminophen, antiinflammatory drugs, steroids, diazepam, baclofen and ketamine. After an adequate clinical – radiological identification of the origins of the pain crises, the pain was successfully controlled with a multimodal therapeutic approach. This approach included discontinuation of ketamine, opioid rotation to morphine, titration of baclofen doses, palliative radiotherapy and biphosphonates.

The effects of concurrent administration of cytochrome P-450 inhibitors on the pharmacokinetics of oral methadone in healthy dogs

ObjectiveThe objective was to examine the effects of inhibiting cytochrome P450 (CYP) on the pharmacokinetics of oral methadone in dogs. Study designProspective non-randomized experimental trial. AnimalsSix healthy Greyhounds (three male and three female). MethodsThe study was divided into two phases. Oral methadone (mean = 2.1 mg kg−1 PO) was administered as whole tablets in Phase 1. In Phase 2 oral methadone (2.1 mg kg−1 PO) was administered concurrently with ketoconazole (13.0 mg kg−1 PO q 24 hours), chloramphenicol (48.7 mg kg−1 PO q 12 hours), fluoxetine (1.3 mg kg−1 PO q 24 hours), and trimethoprim (6.5 mg kg−1 PO q 24 hours). Blood was obtained for analysis of methadone plasma concentrations by liquid chromatography with mass spectrometry. The maximum plasma concentration (Cmax), time to Cmax (Tmax), and the area under the curve from time 0 to the last measurable time point above the limit of quantification of the analytical assay (AUC0–LAST) were compared statistically. ResultsThe Cmax of methadone was significantly different (p = 0.016) for Phase 1 (5.5 ng mL−1) and Phase 2 (171.9 ng mL−1). The AUC0–LAST was also significantly different (p = 0.004) for Phase 1 (13.1 hour ng mL−1) and Phase 2 (3075.2 hour ng mL−1). Conclusion and clinical relevanceConcurrent administration of CYP inhibitors with methadone significantly increased the area under the curve and plasma concentrations of methadone after oral administration to dogs. Further studies are needed assessing more clinically relevant combinations of methadone and CYP inhibitors.

Topical methadone and meperidine analgesic synergy in the mouse

Topical analgesics have many potential advantages over systemic administration. Prior work has shown potent analgesic activity of a number of topical opioids in the radiant heat tail-flick assay. The current study confirms the analgesic activity of morphine and extends it to two other mu opioids, methadone and meperidine. Combinations of topical morphine and lidocaine are synergistic. Similarly, the combination of methadone and lidocaine is synergistic. While there appeared to be some potentiation with the combination of meperidine and lidocaine, it did not achieve significance. Systemically, prior studies have shown that co-administration of morphine and methadone was synergistic. The combination of morphine and methadone was also synergistic when given topically. In contrast, the combination of morphine and meperidine was not synergistic systemically and it was not synergistic topically. Thus, the pharmacology of topical opioids mimics that seen with systemic administration. Their activity in the topical model supports their potential utility while the local limitation of their actions offers the possibility of a reduced side-effect profile.

The Biochemical Analysis of Methadone Modulation on Morphine-Induced Tolerance and Dependence in the Rat Brain

We have recently demonstrated that the combination of methadone and morphine enhances the ability of morphine to induce µ-opioid peptide (MOP) receptor endocytosis. As a result, rats receiving both drugs show reduced morphine tolerance and dependence. In the present study, we identify the biochemical basis for the protective effect of the drug combination. In rats treated with morphine alone, the inhibitory effect of DAMGO on forskolin-stimulated adenylyl cyclase activity was significantly reduced in a brain-region- selective manner. Importantly, these reductions were prevented in animals receiving the drug combination. We found that these changes were not due to alterations in MOP receptor density, or MOP receptor-G protein coupling, as no significant change in these parameters was observed. Together these data demonstrate that neither changes in receptor number nor function are required for morphine tolerance and dependence. Rather, brain-region-selective changes in adenylyl cyclase signal transduction are critical, and both these biochemical changes and the behavioral effects are prevented by facilitating endocytosis of the MOP receptor.

Mood and affect during detoxification of opiate addicts: a comparison of buprenorphine versus methadone

Twenty-six in-patients with Diagnostic and Statistical Manual version IV (DSM-IV) criteria for opioid dependence were selected at random to receive either a combination of an 11-day low-dose buprenorphine and a 14-day carbamazepine regimen (n = 14) or a combination of an 11-day methadone and a 14-day carbamazepine regimen (n = 12) in a double-blind, randomized 14-day in-patient detoxification treatment. Patients with buprenorphine and carbamazepine showed a significantly better psychological state after the first and second weeks of treatment. Above all, the buprenorphine-treated patients demonstrated a less marked tiredness, sensitiveness and depressive state as well as a more prominent elevated mood during the detoxification process. Seven non-completers (after 7 days: four of 12 = 33.3%; after 14 days: seven of 12 = 58.3%) were treated with methadone and carbamazepine and five non-completers (after 7 days: two of 14 = 14.3%; after 14 days: five of 14 = 35.7%) received buprenorphine and carbamazepine. The difference in the overall dropout rate after day 14 was not significant. The present study supports the hypothesis that the combination of buprenorphine and carbamazepine leads to a better clinical outcome than does a combination of methadone and carbamazepine in the detoxification of opioid addicts with additional multiple drug abuse. The buprenorphine and carbamazepine-regimen provides a more effective short-term relief of affective disturbances than does methadone and carbamazepine. No severe side effects occurred during the treatment period in both groups.

Neuroleptic Treatment of Opiate Addicts with a Comorbid Schizophrenia in a Methadone Maintenance Program

Methadon maintenance therapy with opiate addicts who suffer from a comorbid schizophrenia in an outpatient treatment setting of a psychiatric hospital is described. We examined five patients looking for periods of inpatient treatment, drug free urine tests, social integration and illegal activities before and after neuroleptic treatment. In comparison with standard neuroleptics patients show under the therapy with atypical neuroleptics better outcome in drug urine tests especially concerning cannabis and benzodiazepines. According to these findings, the best improvements seem to occur with a combination of methadone and clozapine.

Reinforcement by orally delivered methadone, cocaine, and methadone-cocaine combinations in rhesus monkeys: are the combinations better reinforcers?

Polydrug abuse is a problem that has been infrequently examined. In the present study, drug self-administration procedures were used to investigate the reinforcing effects of drug combinations. To determine the absolute and relative response rates maintained by orally delivered methadone, cocaine, and their combinations under sequential and concurrent access. Choice between drug combinations containing different concentrations of cocaine was also determined. Oral intake of methadone, cocaine, and their combinations was studied with rhesus monkeys during daily 3-h sessions. Lip contact (the operant response) was reinforced by delivery of liquid contingent upon completion of a fixed-ratio schedule. In one series, the drugs and drug combinations were studied sequentially with the water vehicle concurrently available. In the next series, the drugs and drug combinations were concurrently available. In the third series, pairs of drug combinations containing different concentrations of cocaine were also concurrently available. Methadone, cocaine and their combinations functioned as reinforcers. Under sequential access, response rates for the drug combinations and the component drugs were often similar. However, under concurrent access, response rates for the drug combinations were greater than response rates for the component drugs at the highest FR size for each condition. Also, drug combinations containing higher cocaine concentrations were preferred to combinations containing lower cocaine concentrations. Combinations of methadone and cocaine have relatively greater reinforcing effects than the component drugs, and these greater reinforcing effects are better detected with concurrent measures than with sequential measures.

Methadone deaths: a toxicological analysis

Aims—To perform a toxicological analysis of deaths involving methadone and to determine the fatal concentration of methadone in such deaths. Methods—Deaths in which methadone was mentioned in the cause of...

Reinforcing Effects of a Combination of Ethanol and Methadone Relative to Each Drug Alone

Studies report a high incidence of alcohol abuse in methadone maintenance patients. There is, however, little data on the reinforcing effects of combinations of ethanol and methadone. In the present study, oral self-administration of a combination of 1% (w/v) ethanol and 0.2 mg/ml methadone was compared to each drug alone in three rhesus monkeys in which methadone alone was not a reinforcer. In Experiment 1, ethanol and the combination, but not methadone alone, served as reinforcers. In Experiment 2, there was no preference for ethanol or the combination at fixed ratio (FR) 8 or 16. When the FR size was doubled (FR 16 or 32), all three animals preferred the combination to 1% ethanol. Experiment 3 further examined the effect of work requirement on preference for ethanol or the combination by varying FR values [1, 2, 4, 8, 16, or 32]. At lower FRs, ethanol was significantly preferred to the combination. As FR was increased, there was a significant reduction in preference for ethanol over the combination. The results show that an ethanol + methadone combination will be orally self-administered by monkeys and suggest that work requirement differenetially modifies preference for the combination and ethanol alone.

Development after prenatal exposure to cocaine, heroin and methadone

In Amsterdam a longitudinal, prospective and multidisciplinary study on the development of infants of drug-dependent mothers (IDDM) was started in 1983: 35 IDDM and 35 reference infants were originally enrolled. The drug-dependent women had used combinations of methadone, heroin, cocaine and other drugs during pregnancy. Of the IDDM, 80% had to be treated pharmaceutically for neonatal abstinence symptoms (NAS). Physical, neurological, cognitive and the socio-emotional development of the children were studied regularly from birth until 5.5 years of age. Differences between the reference group and the IDDM were found most clearly in cognitive development. The IDDM also had more behavioural problems at some of the ages studied. No group differences were seen in motor development. So far the results of the study show that IDDM and their caregivers need extra support in order to improve early communication and the children's cognitive development.

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.

Diazepam and methadone interactions in methadone maintenance.

Survey study data and high rates of diazepam use/abuse in methadone maintenance suggest that acute administration of diazepam with daily methadone doses may enhance methadone effects. Acute subjective and physiologic effects of single oral doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150%, and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose) were assessed under double-blind conditions. The subjects were five adult male patients on methadone maintenance with histories of diazepam abuse who were receiving 50 to 60 mg methadone a day. Physiologic measures were continuously monitored for 30 min before and for 2 hr after dosing. Pupil diameter and subjective responses were measured 15 min before dosing and 15, 30, 45, 60, 90, and 120 min after dosing. Methadone induced dose-dependent increases in pupil constriction and scores on a subjective opioid effects rating scale, but diazepam had no significant effect on either. The combination of methadone at 150% of the maintenance dose with 40 mg diazepam induced increases in these measures greater than those induced by either drug dose alone. Drug combinations, however, were more frequently identified as being benzodiazepine/barbiturate-like than as methadone-like. Thus although the subjective effects of the drug combination are distinguishable from those of methadone alone, diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioid effects that may be related to the relatively great use/abuse of diazepam in this population.

Methadone overdoses in a New York City hospital

Charts of the 81 methadone overdose patients admitted to Morrisania City Hospital from the Emergency Department during the eight month period between June, 1973 and January, 1974 were reviewed. There were 87 overdose cases in the 81 patients. All were treated successfully with naloxone hydrochloride administered intravenously. Four patients had pulmonary edema. In more than half, liver and muscle function studies showed abnormalities. Ninety percent (79) of the overdoses were associated with a combination of methadone and other non-opiate drugs, including alcohol.

Methadone—A Cause of Death

The past few years have seen a dramatic increase in the use of methadone in the United States, predominantly as a method of treating narcotic addiction. Concomitant with this has been a proportionate rise in the number of deaths in which methadone is either the cause of death or an incidental toxicologic finding. This indicates an increasingly wide-spread abuse of methadone. In Philadelphia, for example, there were only 4 deaths related to methadone between 1967 and 1969. The number rose dramatically in 1970 to 22, in 1971 to 27, and in the first 10 months of 1972 to 37. Of those deaths in 1972, 17 were directly attributable to methadone, 15 were attributable to a combination of methadone and one or more other narcotic and dangerous drugs, and 5 were due to causes other than drugs but methadone was found by postmortem toxicology.