A Conjugate Vaccine Attenuates Morphine- and Heroin-Induced Behavior in Rats

Background:

Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies.

Methods:

A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed.

Results:

After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse.

Conclusion:

These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin.     

Inhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients

AIMS

To compare the O- (CYP2D6 mediated) and N- (CYP3A4 mediated) demethylation metabolism of tramadol between methadone and buprenorphine maintained CYP2D6 extensive metabolizer subjects.

METHODS

Nine methadone and seven buprenorphine maintained subjects received a single 100 mg dose of tramadol hydrochloride. Blood was collected at 4 h and assayed for tramadol, methadone, buprenorphine and norbuprenorphine (where appropriate) and all urine over 4 h was assayed for tramadol and its M1 and M2 metabolites.

RESULTS

The urinary metabolic ratio [median (range)] for O-demethylation (M1) was significantly lower (P= 0.0002, probability score 1.0) in the subjects taking methadone [0.071 (0.012–0.103)] compared with those taking buprenorphine [0.192 (0.108–0.392)], but there was no significant difference (P= 0.21, probability score 0.69) in N-demethylation (M2). The percentage of dose [median (range)] recovered as M1 was significantly lower in subjects taking methadone compared with buprenorphine (0.069 (0.044–0.093) and 0.126 (0.069–0.187), respectively, P= 0.04, probability score 0.19), M2 was significantly higher in subjects taking methadone compared with buprenorphine (0.048 (0.033–0.085) and 0.033 (0.014–0.049), respectively, P= 0.04, probability score 0.81). Tramadol was similar (0.901 (0.635–1.30) and 0.685 (0.347–1.04), respectively, P= 0.35, probability score 0.65).

CONCLUSIONS

Methadone inhibited the CYP2D6-mediated metabolism of tramadol to M1. Hence, as the degree of opioid analgesia is largely dependent on M1 formation, methadone maintenance patients may not receive adequate analgesia from oral tramadol.     

Economic evaluation: A comparison of methadone versus buprenorphine for opiate substitution treatment

Background

The cost of opiate substitution is usually considered lower in cost when methadone is used, as compared to that of buprenorphine, however the overall cost effectiveness of substitution programmes comparing the two drugs remains largely unknown.

Methods

We evaluated the treatment cost and effectiveness of methadone and buprenorphine when used in an opiate substitution programme in Norfolk, UK. All programme costs, estimated from the perspective of the drug treatment clinic, were collected on 361 opiate-dependent participants over a six-month period. Total costs comprised medication (methadone or buprenorphine) costs, pharmacy supervision and dispensing costs, and drug service clinic costs. Effectiveness was measured in terms of (1) each programmes ability to retain participants in the programme for six months, and (2) the ability of the programme to accomplish complete abstinence from illicit opiate consumption.

Results

Overall, mean medication-only costs of methadone were lower than that of buprenorphine, however, pharmacy and clinic costs were lower for the buprenorphine programme. The covariate-adjusted mean total cost of the two programmes was not significantly different. Mean six-month retention rates were higher on the methadone programme, therefore, the methadone programme “dominates” the buprenorphine programme as it was slightly more effective for the same cost. Conversely, when ability to stop taking illicit opiates concomitant with opiate substitution medication was considered, the buprenorphine programme was more effective with an additional cost of £903 per individual who stopped illicit opiate use.

Conclusions

The provision of buprenorphine should be considered an appropriate treatment if cessation of illicit opiate use, concomitant with programme retention is considered an important outcome.     

Premature ejaculation and other sexual dysfunctions in opiate dependent men receiving methadone substitution treatment

Background

A significant number of men with opiate misuse have sexual problems. Premature ejaculation (PE) occurs predominantly on discontinuation of the opiate but seems to persist in some cases. The aims of this study were to determine the rates of PE and other sexual dysfunctions in patients maintained on methadone; to determine the time of onset of PE in relation to onset of opiate misuse; and to look at the patients' perception of the effect of heroin and methadone on PE.

Methods

Sixty five men attending a tertiary referral clinic for methadone maintenance treatment were assessed cross-sectionally using a semi-structured questionnaire, clinical interview, review of clinical records and the International Index of Erectile Function (IIEF).

Results

Thirty eight (58.5%) subjects reported a “lifetime” history of PE. Twenty (30.76%) of them reported “current” history of PE. Eleven (16.9%) people reported that PE preceded opiate misuse. Twenty four (63.2%) felt that heroin helped their PE and 7 (18.4%) felt that heroin worsened it. Fourteen (36.8%) felt that methadone helped PE, while 10 (26.3%) felt methadone worsened PE. Only 2 out of 65 (3.07%) reported that they had been asked about their sex life by the addiction services.

Conclusion

Prevalence of “current” premature ejaculation was almost 3 times greater than reported in the general population. A significant number of patients perceived heroin to be beneficial on PE. Presence of sexual dysfunction could therefore be a risk factor for relapse into heroin misuse. Most clinicians avoid asking patients questions of a sexual nature. Nevertheless, managing sexual difficulties among patients with opiate misuse could be a significant step in relapse prevention.     

Methadone and buprenorphine-naloxone are effective in reducing illicit buprenorphine and other opioid use,and reducing HIV risk behavior—Outcomes of a randomized trial

Aims

Determine the extent to which buprenorphine injectors continue treatment with buprenorphine-naloxone or methadone, and the impact of these treatments on substance use and HIV risk in the Republic of Georgia.

Methods

Randomized controlled 12-week trial of daily-observed methadone or buprenorphine-naloxone followed by a dose taper, referral to ongoing treatment, and follow-up at week 20 at the Uranti Clinic in Tbilisi, Republic of Georgia. Eighty consenting treatment-seeking individuals (40/group) aged 25 and above who met ICD-10 criteria for opioid dependence with physiologic features and reported injecting buprenorphine 10 or more times in the past 30 days. Opioid use according to urine tests and self-reports, treatment retention, and HIV risk behavior as determined by the Risk Assessment Battery.

Results

Mean age of participants was 33.7 (SD5.7), 4 were female, mean history of opioid injection use was 5.8 years (SD4.6), none were HIV+ at intake or at the 12-week assessment and 73.4% were HCV+. Sixty-eight participants (85%) completed the 12-week medication phase (33 from methadone and 35 from buprenorphine/naloxone group); 37 (46%) were in treatment at the 20-week follow-up (21 from methadone and 16 from the buprenorphine/naloxone group). In both study arms, treatment resulted in a marked reduction in unprescribed buprenorphine, other opioid use, and HIV injecting risk behavior with no clinically significant differences between the two treatment arms.

Conclusions

Daily observed methadone or buprenorphine-naloxone are effective treatments for non-medical buprenorphine and other opioid use in the Republic of Georgia and likely to be useful for preventing HIV infection.     

(R)- and (S)-methadone and buprenorphine concentration ratios in maternal and umbilical cord plasma following chronic maintenance dosing in pregnancy

AIMS

The aim of this study was to compare the transfer of buprenorphine and methadone between maternal and cord blood in women under chronic dosing conditions and to determine if differences exist in the transfer of the two methadone enantiomers.

METHODS

Maternal and cord blood samples were collected at delivery from women maintained on methadone (35, 25–140 mg day⁻¹) (median; range) or buprenorphine (6.00, 2–20 mg day⁻¹) during pregnancy. Plasma concentration ratios are presented as an indicator of foetal exposure relative to the mother.

RESULTS

Methadone was quantified in all samples, with cord : maternal plasma methadone concentration ratios (n = 15 mother-infant pairs) being significantly higher (P < 0.0001; mean difference (MD) 0.07; 95% confidence interval (CI) 0.048, 0.092) for the active (R)-methadone enantiomer (0.41; 0.19, 0.56) (median; range) compared with (S)-methadone (0.36; 0.15, 0.53). (R)- : (S)-methadone concentration ratios were also significantly higher (P < 0.0001; MD 0.24 95% CI 0.300, 0.180) for cord (1.40; 0.95, 1.67) compared with maternal plasma (1.16; 0.81, 1.38). Half the infant buprenorphine samples were below the assay lower limit of quantification (LLOQ) (0.125 ng ml⁻¹). The latter was four-fold lower than the LLOQ for methadone (0.50 ng ml⁻¹). The cord : maternal plasma buprenorphine concentration ratio (n = 9 mother-infant pairs) was 0.35; 0.14, 0.47 and for norbuprenorphine 0.49; 0.24, 0.91.

CONCLUSIONS

The transfer of the individual methadone enantiomers to the foetal circulation is stereoselective. Infants born to buprenorphine maintained women are not exposed to a greater proportion of the maternal dose compared with methadone and may be exposed to relatively less of the maternal dose compared with infants born to women maintained on methadone during pregnancy.     

Primary care patient characteristics associated with completion of 6-month buprenorphine treatment

Background

Opioid addiction is prevalent in the United States. Detoxification followed by behavioral counseling (abstinence-only approach) leads to relapse to opioids in most patients. An alternative approach is substitution therapy with the partial opioid receptor agonist buprenorphine, which is used for opioid maintenance in the primary care setting. This study investigated the patient characteristics associated with completion of 6-month buprenorphine/naloxone treatment in an ambulatory primary care office.

Methods

A retrospective chart review of 356 patients who received buprenorphine for treatment of opioid addiction was conducted. Patient characteristics were compared among completers and non-completers of 6-month buprenorphine treatment.

Results

Of the 356 patients, 127 (35.7%) completed 6-month buprenorphine treatment. Completion of treatment was associated with counseling attendance and having had a past injury.

Conclusions

Future research needs to investigate the factors associated with counseling that influenced this improved outcome. Patients with a past injury might suffer from chronic pain, suggesting that buprenorphine might produce analgesia in addition to improving addiction outcome in these patients, rendering them more likely to complete 6-month buprenorphine treatment. Further research is required to test this hypothesis. Combination of behavioral and medical treatment needs to be investigated for primary care patients with opioid addiction and chronic pain.     

Quality of life under maintenance treatment with heroin versus methadone in patients with opioid dependence

Background

There is increasing evidence that health-related quality of life (HRQOL) is associated with a successful treatment and better outcome in opioid addiction. The aim of the present study was the longitudinal investigation of HRQOL in patients with severe opioid dependence, who were randomly assigned to four groups of medical and psychosocial treatment: heroin (diacetylmorphine) versus methadone and case management (CM) versus psychoeducation (PSE) respectively.

Methods

HRQOL (MSQoL) and physical health (OTI) were investigated in 938 subjects, who participated in the German multi-centre study examining the effects of heroin-assisted treatment in patients with severe opioid dependence. Data for the present analysis were taken from baseline and 12-month follow up.

Results

Under both forms of maintenance and psychosocial treatment HRQOL improved significantly during the observation period. HRQOL improvement under maintenance with heroin exceeded improvement under methadone, especially with regard to subjective physical health. HRQOL improvement was significantly associated with better expert-rated physical health. Further analyses showed significant better improvement of HRQOL in subjects treated with PSE compared with CM.

Conclusions

The advantage of heroin with regard to the improvement of HRQOL may be partially explained by a better improvement of physical health under maintenance with heroin compared with methadone, which highlights the importance of a comprehensive model of health care for patients with severe opioid dependence. Future studies need to investigate the benefits of PSE for patients in maintenance therapy.     

Dosing and Monitoring of Methadone in Pregnancy: Literature Review

Background:

The pharmacokinetics of methadone is altered during pregnancy, but the most appropriate dosing and monitoring regimen has yet to be identified.

Objective:

To review dosing and monitoring of methadone therapy in pregnancy.

Methods:

A literature search was performed in several databases (PubMed, MEDLINE, Embase, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews) from inception to May 2012. The search terms were “methadone”, “pregnancy”, “pharmacokinetic”, “clearance”, “metabolism”, “therapeutic drug monitoring”, and “methadone dosing”. Additional papers were identified by searching the bibliographies of primary and review articles. All English-language primary articles related to methadone pharmacokinetics in pregnancy were included. Articles not related to maternal outcomes were excluded.

Results:

The literature search yielded 1 case report and 10 studies discussing use of methadone by pregnant women. Methadone pharmacokinetics in pregnancy has been studied in 3 pharmacokinetic trials, and split dosing of methadone in pregnant women has been described in 1 case report and 3 dosing trials. Only 4 trials evaluated monitoring of methadone concentration in pregnancy. The studies included in this review confirm that methadone pharmacokinetics is altered in pregnancy and is potentially correlated with increases in maternal withdrawal symptoms. Insufficient evidence is available to warrant routine monitoring of serum methadone concentrations in pregnant women with opioid dependence.

Conclusions:

Few studies of methadone pharmacokinetics and therapeutic drug monitoring are available for pregnant women with opioid dependence. Although it is known that methadone pharmacokinetics is altered in pregnancy, there is insufficient evidence to guide dosage adjustments and serum concentration monitoring. Until further studies are available, regular follow-up of maternal withdrawal symptoms and empiric dosage adjustments throughout pregnancy are still recommended.     

Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy

Purpose

Intravenous opioid use is a common route of hepatitis C virus (HCV) infection; consequently, the prevalence of HCV is high among patients on methadone or buprenorphine/naloxone. The authors evaluated the pharmacokinetic interaction of boceprevir with methadone or buprenorphine/naloxone in patients on stable maintenance therapy.

Methods

This was a two-center, open-label, fixed-sequence study in 21 adult volunteers on stable maintenance therapy. Oral methadone (20–150 mg once daily) or sublingual buprenorphine/naloxone (8/2–24/6 mg once daily) was administered alone or in combination with boceprevir (800 mg every 8 h) on days 2–7. Pharmacokinetic sampling occurred before and up to 24 h after the dose on days 1 and 7.

Results

Coadministration of boceprevir reduced the area under the concentration-time curve during a dosing interval τ (AUC _τ ) and maximum observed plasma (or serum) concentration (C _max) of R-methadone (geometric mean ratios (GMRs) [90 % confidence intervals (CIs)], 0.85 [0.74, 0.96] and 0.90 [0.71, 1.13]) and S-methadone (GMRs [90 % CIs], 0.78 [0.66, 0.93] and 0.83 [0.64, 1.09]). Boceprevir increased the AUC _τ and C _max of buprenorphine (GMRs [90 % CIs], 1.19 [0.91, 1.58] and 1.18 [0.93, 1.50]) and naloxone (GMRs [90 % CIs], 1.33 [0.90, 1.93] and 1.09 [0.79, 1.51]). Boceprevir exposure upon methadone or buprenorphine/naloxone coadministration was not clinically different from historical controls and there was no evidence of opioid withdrawal or excess.

Conclusions

There was no clinically meaningful impact of boceprevir on methadone or buprenorphine pharmacokinetics, suggesting that methadone/buprenorphine dose adjustments are not required upon coadministration with boceprevir. Individual patients may differ in their clinical experience and clinicians should maintain vigilance when coadministering these medications.

     

Addictive evaluation of cholic acid-verticinone ester,a potential cough therapeutic agent with agonist action of opioid receptor

Aim:

The purpose of this work was to search for potential drugs with potent antitussive and expectorant activities as well as a low toxicity, but without addictive properties. Cholic acid-verticinone ester (CA-Ver) was synthesized based on the clearly elucidated antitussive and expectorant activities of verticinone in bulbs of Fritillaria and different bile acids in Snake Bile. In our previous study, CA-Ver showed a much more potent activity than codeine phosphate. This study was carried out to investigate the central antitussive mechanism and the addictive evaluation of CA-Ver.

Methods:

Testing on a capsaicin-induced cough model of mice pretreated with naloxone, a non-selective opioid receptor antagonist, was performed for the observation of CA-Ver''s central antitussive mechanism. We then took naloxone-induced withdrawal tests of mice for the judgment of CA-Ver''s addiction. Lastly, we determined the opioid dependence of CA-Ver in the guinea pig ileum.

Results:

The test on the capsaicin-induced cough model showed that naloxone could block the antitussive effect of CA-Ver, suggesting the antitussive mechanism of CA-Ver was related to the central opioid receptors. The naloxone-urged withdrawal tests of the mice showed that CA-Ver was not addictive, and the test of the opioid dependence in the guinea pig ileum showed that CA-Ver had no withdrawal response.

Conclusion:

These findings suggested that CA-Ver deserved attention for its potent antitussive effects related to the central opioid receptors, but without addiction, and had a good development perspective.     

Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats

Aim:

Glutamatergic neurotransmission in the nucleus accumbens (NAc) is crucial for the relapse to heroin seeking. The aim of this study was to determine whether mGluR5 in the NAc core or shell involved in heroin seeking behavior in rats.

Methods:

Male SD rats were self-administered heroin under a fixed-ratio 1 (FR1) reinforcement schedule for 14 d, and subsequently withdrawn for 2 weeks. The selective mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 5, 15 and 50 nmol per side) was then microinjected into the NAc core or shell 10 min before a heroin-seeking test induced by context, cues or heroin priming.

Results:

Microinjection of MPEP into the NAc shell dose-dependently decreased the heroin seeking induced by context, cues or heroin priming. In contrast, microinjection of MPEP into the NAc core did not alter the heroin seeking induced by cues or heroin priming. In addition, microinjection with MPEP (15 nmol per side) in the NAc shell reversed both the percentage of open arms entries (OE%) and the percentage of time spent in open arms (OT%) after heroin withdrawal. Microinjection of MPEP (50 nmol per side) in the striatum as a control location did not affect the heroin seeking behavior. Microinjection of MPEP in the 3 locations did not change the locomotion activities.

Conclusion:

Blockade of mGluR5 in NAc shell in rats specifically suppresses the relapse to heroin-seeking and anxiety-like behavior, suggesting that mGluR5 antagonists may be a potential candidate for the therapy of heroin addiction.     

Levels of heroin and its metabolites in blood and brain extracellular fluid after i.v. heroin administration to freely moving rats

BACKGROUND AND PURPOSE

Heroin, with low affinity for μ-opioid receptors, has been considered to act as a prodrug. In order to study the pharmacokinetics of heroin and its active metabolites after i.v. administration, we gave a bolus injection of heroin to rats and measured the concentration of heroin and its metabolites in blood and brain extracellular fluid (ECF).

EXPERIMENTAL APPROACH

After an i.v. bolus injection of heroin to freely moving Sprague–Dawley rats, the concentrations of heroin and metabolites in blood samples from the vena jugularis and in microdialysis samples from striatal brain ECF were measured by ultraperformance LC-MS/MS.

KEY RESULTS

Heroin levels decreased very fast, both in blood and brain ECF, and could not be detected after 18 and 10 min respectively. 6-Monoacetylmorphine (6-MAM) increased very rapidly, reaching its maximal concentrations after 2.0 and 4.3 min, respectively, and falling thereafter. Morphine increased very slowly, reaching its maximal levels, which were six times lower than the highest 6-MAM concentrations, after 12.6 and 21.3 min, with a very slow decline during the rest of the experiment and only surpassing 6-MAM levels at least 30 min after injection.

CONCLUSIONS AND IMPLICATIONS

After an i.v. heroin injection, 6-MAM was the predominant opioid present shortly after injection and during the first 30 min, not only in the blood but also in rat brain ECF. 6-MAM might therefore mediate most of the effects observed shortly after heroin intake, and this finding questions the general assumption that morphine is the main and most important metabolite of heroin.     

Differential effect of opioid and cannabinoid receptor blockade on heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats

BACKGROUND AND PURPOSE

Opioids and cannabinoids interact in drug addiction and relapse. We investigated the effect of the opioid receptor antagonist naloxone and/or the cannabinoid CB₁ receptor antagonist rimonabant on cannabinoid-induced reinstatement of heroin seeking and on cannabinoid substitution in heroin-abstinent rats.

EXPERIMENTAL APPROACH

Rats were trained to self-administer heroin (30 µg·kg⁻¹ per infusion) under a fixed-ratio 1 reinforcement schedule. After extinction of self-administration (SA) behaviour, we confirmed the effect of naloxone (0.1–1 mg·kg⁻¹) and rimonabant (0.3–3 mg·kg⁻¹) on the reinstatement of heroin seeking induced by priming with the CB₁ receptor agonist WIN55,212-2 (WIN, 0.15–0.3 mg·kg⁻¹). Then, in a parallel set of heroin-trained rats, we evaluated whether WIN (12.5 µg·kg⁻¹ per infusion) SA substituted for heroin SA after different periods of extinction. In groups of rats in which substitution occurred, we studied the effect of both antagonists on cannabinoid intake.

KEY RESULTS

Cannabinoid-induced reinstatement of heroin seeking was significantly attenuated by naloxone (1 mg·kg⁻¹) and rimonabant (3 mg·kg⁻¹) and fully blocked by co-administration of sub-threshold doses of the two antagonists. Moreover, contrary to immediate (1 day) or delayed (90 days) drug substitution, rats readily self-administered WIN when access was given after 7, 14 or 21 days of extinction from heroin, and showed a response rate that was positively correlated with the extinction period. In these animals, cannabinoid intake was increased by naloxone (1 mg·kg⁻¹) and decreased by rimonabant (3 mg·kg⁻¹).

CONCLUSIONS AND IMPLICATIONS

Our findings extend previous research on the crosstalk between cannabinoid and opioid receptors in relapse mechanisms, which suggests a differential role in heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats.

LINKED ARTICLES

This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7     

Use of methadone for prevention of opioid withdrawal in critically ill children

Background

Opioids are commonly administered to critically ill children for analgesia and sedation, but many patients experience opioid withdrawal upon discontinuation. The authors’ institution developed a protocol for using methadone to prevent opioid withdrawal in children who have received morphine by continuous IV infusion for 5 days or longer in the pediatric intensive care unit (PICU).

Objectives

The primary objectives were to determine if opioids were tapered according to the protocol and to determine the conversion ratio for IV morphine to oral methadone that was used. Secondary objectives were to describe the methadone dosage used and the clinical outcomes, to evaluate adjustments to methadone dosing, and to report the incidence of adverse effects.

Methods

A retrospective analysis of charts was conducted for pediatric patients who had received morphine by continuous IV infusion for 5 days or longer followed by methadone in the PICU between May 2008 and August 2009. Validated scoring systems (the Withdrawal Assessment Tool and the State Behavioral Scale) were used to assess symptoms of withdrawal and degree of sedation, respectively.

Results

Forty-three patients were included in the study, with median age of 8 months (range 0.25–201 months). For 31 patients (72%), the protocol was not used, and there were no patients for whom the protocol was followed to completion. The median duration of weaning was 10 days (range 0–91 days). The conversion ratio for IV morphine to oral methadone was 1:0.78 for anticipated 5-day weaning and 1:0.98 for anticipated 10-day weaning. During the first 10 days of weaning, 18 patients (42%) experienced withdrawal symptoms. The methadone dose was increased for 11 (26%) of the 43 patients. Patients were sedated for a median of 1 day (range 0–9 days), were comfortable for a median of 6.5 days (range 1–64 days), and were agitated for a median of 2.5 days (range 0–23 days). Naloxone was required for 2 patients.

Conclusions

The institution’s methadone protocol was not followed consistently during the study period, and practices for transitioning from morphine by continuous IV infusion to methadone with tapering were also inconsistent. Further studies are needed to determine the optimal conversion ratio for morphine to methadone and the optimal tapering regimen to minimize withdrawal symptoms and adverse events.     

Retrospective Analysis of Opioid Medication Incidents Requiring Administration of Naloxone

Background:

Opioid analgesics are high-alert medications known to cause adverse drug events.

Objectives:

The purpose of this study was to determine the cause of opioid incidents requiring administration of naloxone, an opioid reversal agent. The specific objectives were to determine the number of opioid incidents and the proportion of incidents documented through occurrence reporting and to characterize the incidents by phase in the medication-use process, by type of incident, and by drug responsible for toxic effects.

Methods:

A retrospective chart analysis was conducted using records from 2 acute care centres in the Regina Qu’Appelle Health Region. The study included inpatients who received naloxone for reversal of opioid toxicity resulting from licit, in-hospital opioid use. Cases were classified as preventable or nonpreventable. Preventable cases were analyzed to determine the phase of the medication-use process during which the incident occurred. These cases were also grouped thematically by the type of incident. The drug most likely responsible for opioid toxicity was determined for each case. The proportion of cases documented by occurrence reporting was also noted.

Results:

Thirty-six cases involving administration of naloxone were identified, of which 29 (81%) were deemed preventable. Of these 29 preventable cases, the primary medication incident occurred most frequently in the prescribing phase (23 [79%]), but multiple phases were often involved. The cases were grouped into 6 themes according to the type of incident. Morphine was the drug that most frequently resulted in toxic effects (18 cases [50%]). Only two of the cases (5.6%) were documented by occurrence reports.

Conclusion:

Preventable opioid incidents occurred in the acute care centres under study. A combination of medication safety initiatives involving multiple disciplines may be required to decrease the incidence of these events and to better document their occurrence.     

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

Background:

Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT).

Methods:

Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect.

Results:

After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different.

Conclusions:

We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT.     

Combating opiate dependence: a comparison among the available pharmacological options

Pharmacotherapies for heroin addiction may target opiate withdrawal symptoms, facilitate initiation of abstinence and/or reduce relapse to heroin use either by maintenance on an agonist or antagonist agent. Available agents include opioid agonists, partial opioid agonists, opioid antagonists and alpha 2 -agonists for use during managed withdrawal and long-term maintenance. Experimental approaches combine alpha 2 -agonists with naltrexone to reduce the time of opiate withdrawal and to accelerate the transition to abstinence. Recently, buprenorphine has been introduced in the US for office-based maintenance, with the hope of replicating the success of this treatment in Europe and Australia. Naloxone has been added to buprenorphine in order to reduce its potential diversion to intravenous use, whilst facilitating the expansion of treatment. Although comprehensive substance abuse treatment is not limited to pharmacotherapy, this review will focus on the rationale, indications and limitations of the range of existing medications for detoxification and relapse prevention treatments. The two major goals of pharmacotherapy are to relieve the severity of opiate withdrawal symptoms during the managed withdrawal of the opioid and to prevent relapse to heroin use either after abstinence initiation or after being stabilised on a long-acting opiate agonist, such as methadone.     

Identification of an additional supraspinal component to the analgesic mechanism of action of buprenorphine

Background and purpose:

Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl.

Experimental approach:

The opioid receptor antagonist naloxone, Pertussis toxin (PTX), G_z protein antisense and nociceptin/orphanin-FQ receptor agonist nociceptin, and antagonist, JTC-801, were injected supraspinally (intracerebroventricular) and spinally (intrathecal). Also the cell-permeable Ser/Thr protein phosphatase inhibitor okadaic acid was given supraspinally.

Key results:

Spinal naloxone (20 µg) or PTX (1 µg) attenuated morphine, fentanyl and buprenorphine (s.c.) anti-nociception. Supraspinal naloxone or PTX attenuated morphine and fentanyl, but not buprenorphine anti-nociception. Spinal G_z protein antisense did not alter buprenorphine, morphine or fentanyl anti-nociception and supraspinal G_z-antisense did not alter morphine or fentanyl anti-nociception. However, supraspinal G_z-antisense (not random sense) reduced buprenorphine anti-nociception. Peripheral JTC-801 (1 mg·kg⁻¹, i.p.) enhanced the ascending (3 mg·kg⁻¹) and descending (30 mg·kg⁻¹) portions of buprenorphine''s dose–response curve, but only spinal, not supraspinal, nociceptin (10 nmol·L⁻¹) enhanced buprenorphine anti-nociception. Intracereboventricular okadaic acid (0.001–10 pg) produced a biphasic low-dose attenuation, high-dose enhancement of buprenorphine(3 or 30 mg·kg⁻¹, s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception.

Conclusions and implications:

Buprenorphine has an opioid component to its supraspinal mechanism of analgesic action. Our present results reveal an additional supraspinal component insensitive to naloxone, PTX and nociceptin/orphanin-FQ, but involving G_z protein and Ser/Thr protein phosphatase. These data might help explain the unique preclinical and clinical profiles of buprenorphine.