Buprenorphine and buprenorphine/naloxone soluble-film for treatment of opioid dependence

Introduction: Opioid dependence is a chronic relapsing disorder that shows excess mortality and comorbidity with somatic and psychiatric disorders. Methadone and buprenorphine/naloxone are widely accepted and are used as first-line maintenance treatments for opioid dependence. Fatal intoxications with these agents, risk of diversion, and accidental intoxications, especially in children, are apparent risks and are of increasing public concern. Buprenorphine/naloxone sublingual tablet is an established treatment for opioid dependence. A novel buprenorphine/naloxone film has been developed with improved pharmacokinetics and a hopefully lower risk of diversion and accidental intoxications.

Areas covered: This review evaluates the available preclinical and clinical data on the novel buprenorphine/naloxone film for the treatment of opioid dependence. Literature was identified though a comprehensive PubMed search and data sources included official FDA information.

Expert opinion: This is an interesting new formulation of a well-established medication in opioid dependence. However, few data have been published on its safety and efficacy. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal as expected. Results of an unpublished study made public by the FDA suggest a spectrum of adverse events similar to that of the conventional sublingual tablet. Some data show patients may prefer the novel film over the sublingual tablet. The estimated lower risk for diversion and especially for accidental poisoning in children cannot be assessed in clinical studies but requires data from emergency room visits.     

Opiate dependence following acute injections of morphine and naloxone: The assessment of various withdrawal signs

The injection of high dose of naloxone 15 minutes after a single injection of morphine in mice was found to produce a jumping response which was behaviorly similar to the jumping response observed during the withdrawal from chronic morphine administration. In addition the jumping response following the acute administration of morphine-naloxone was increased by the injection of atropine and attenuated by oxotremorine. These data are consistent with the reports of effect of these cholinergic drugs on the jumping response which occurred during withdrawal after chronic morphine administration. However, other symptoms associated with opiate withdrawal (hypothermia, weight loss and diarrhea) were not produced by the acute injection of morphine-naloxone. It is therefore suggested that this single injection paradigm is particular to the jumping response than a demonstration of the rapid development of opiate dependence.     

Buprenorphine in the treatment of opioid dependence.

Buprenorphine has become of increasing interest to be an alternative to methadone in the treatment of heroin addicts. The aim of the paper is to review, from a clinical perspective, the current status of what is known about the pharmacology of buprenorphine, with a particular emphasis on the issues of maintenance therapy in heroin addiction. A systematic review of published follow-up data, from observational and experimental studies was done. Electronic databases Medline and PSYNDEXplus were searched from their earliest entries. Buprenorphine appears to be a well-tolerated drug, with a benign overall side effect. Buprenorphine is an additional treatment option for heroin dependent patients, especially for those who do not wish to start or continue with methadone or for those who do not seem to benefit from adequate dosages of methadone.     

A self-administered questionnaire to measure dependence on cigarettes: the cigarette dependence scale.

A valid measure of dependence on cigarettes is a useful tool for clinicians and researchers. The aim of this study was to develop a new, self-administered measure of cigarette dependence, and to assess its validity. The content of the instrument was generated in qualitative surveys. A long version (114 items) was tested on the internet in 3009 smokers. Subsamples provided retest data after 18 days (n=578), follow-up data after 45 days (n=990) and saliva cotinine (n=105). The study resulted in a 12-item scale labelled the Cigarette Dependence Scale (CDS-12), and in a 5-item version of this scale (CDS-5). Except for tolerance, CDS-12 covers the main components of DSM-IV and ICD-10 definitions of dependence: compulsion, withdrawal symptoms, loss of control, time allocation, neglect of other activities, and persistence despite harm. CDS-5 has similar measurement properties but less comprehensive content. Both scales had a high test-retest reliability (r>or=0.83), and a high internal consistency (Cronbach's alpha>or=0.84). CDS-12 scores were higher in daily smokers than in occasional smokers (+1.3SD units), and were associated with the strength of the urge to smoke during the last quit attempt (R(2)>or=0.25), and with saliva cotinine (R(2)>or=0.17). CDS-12 and CDS-5 scores decreased in daily smokers who switched to occasional smoking at 18-day retest. Dependence scores did not predict smoking abstinence at follow-up. In conclusion, CDS-12 and CDS-5 are reliable measures of cigarette dependence which fulfill several criteria of content validity and construct validity and are sensitive to change over time.     

Buprenorphine Maintenance Treatment of Opiate Dependence: Correlations Between Prescriber Beliefs and Practices

Background: Despite the existence of evidence-based guidelines, different prescriber practices around buprenorphine maintenance treatment (BMT) of opiate dependence exist. Moreover, certain prescriber beliefs may influence their practice patterns. Objective: To understand community BMT practice patterns and discern their relationship to practitioner beliefs. Method: Survey of 30 local BMT prescribers about aspects of BMT, and analysis of correlations between practices and practitioner beliefs. Results: Practitioners generally followed standard treatment guidelines, though the most-common maintenances dosages of BMT (4–12 mg) were lower than recommended by some studies. Endorsement of belief in a “spiritual basis” of addiction correlated with lower average BMT doses and less frequent endorsement of the belief that BMT-treated patients are “in recovery.” Conclusions/Importance: These data suggest that relatively standardized, longer-term BMT of opiate dependence is accepted among the majority of surveyed prescribers, and certain provider beliefs about addiction may influence prescribing habits and attitudes. Future studies should: (1) assess these findings in larger samples; (2) examine how prescriber beliefs about addiction and BMT compare with those of other addiction treatment providers; and (3) ascertain whether individual prescriber beliefs influence patient outcomes.     

Buprenorphine: an alternative to methadone for heroin dependence treatment.

Eighty-five heroin addicts who were unwilling to receive methadone maintenance or enter therapeutic communities were assessed, single-blind, for the lowest sublingual dose of buprenorphine that blocked heroin craving (8.0 mg max). All doses were administered daily under observation. After maintenance for 4 to 12 weeks, abstinent subjects (confirmed by urine drug screens) entered a double-blind discontinuation trial and were randomly assigned to receive dose reductions (10% twice weekly for 5 weeks to zero dose, then placebo for 2 weeks) or a stable dose for 7 weeks. Subjects were terminated from discontinuation if heroin was used or they had increased craving/symptoms. Subjects completed the trial if they did not use heroin and had no increase in craving/symptoms. A wide dose range (1.5-8.0 mg/day) was effective in reducing heroin craving and use. Of 73 subjects who received buprenorphine for 4 to 52 weeks, 40 had no prior treatment, despite high levels (mean $/day heroin = 70.5 +/- 94.7) and many years (mean years = 10.7 +/- 8.6) of dependence. Subjects who received dose reductions developed abstinence symptoms, low energy most commonly, associated with drug-seeking behavior. Discontinuation trial outcome (n = 51) shows a highly significant difference between 29 subjects who received dose reductions (28 terminated, 1 completed) and 22 subjects who received no dose reductions (3 terminated; 19 completed) (chi-square = 36.08; p less than .00001). The findings suggest that buprenorphine could be an important medication for reducing demand for heroin by many heroin addicts who remain outside the present health-care system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Opiate receptor in praying mantis: Effect of morphine and naloxone

A praying mantis displays a “frightening reaction” called deimatic reaction (DR), any time that it is faced with a patterned visual stimulus that represents a potential damage for the insect. Results of the present paper show that the DR could be also elicited by an actual noxious (an electrical shock) and that this response is similar to that elicited by a potential nociceptive stimulus (a patterned visual stimulus). The DR elicited by the electric shock was used as a model for studying the analgesic effect of opiates. The mantis was placed in an apparatus that allowed us to give the insect an electrical shock and to measure the strength of its DR. During a first session the voltage threshold necessary to induce a full DR was determined, and then, the insect was injected with a certain solution. The voltage threshold was tested one, two and four hours after injection. Mantises that were injected with only distilled water showed no changes in their voltage threshold during the three tests. Injections of 300, 350 and 400 μg/g of morphine-HCl increased the voltage threshold in both a time-dependent and a dose related manner. A dose of 350 μg/g of morphine-HCl produced 50% of response inhibition after two hours of injections and is referred to as the median antinoxious dose (AD50). Sixteen μg/g of naloxone given in conjunction with an AD50 of morphine, partially blocked the effect of morphine during the first hour and fully blocked it during the second hour. Thirty-two μg/g of naloxone fully blocked the morphine effect during the first and the second hour. However, more than 48 μg/g of naloxone alone also increased the voltage threshold in insects, similar to those described for vertebrates.     

Atovaquone + proguanil: new preparation. Second-line antimalarial combination

(1) Quinine, halofantrine and mefloquine are effective treatments for most cases of uncomplicated Plasmodium falciparum malaria. (2) The choice of drug for prevention of P. falciparum malaria in highly endemic regions depends on the risk of chloroquine resistance, and possibly mefloquine resistance. The reference treatments are the chloroquine + proguanil combination, and mefloquine. (3) Marketing authorisation has been granted in France for the atovaquone + proguanil combination, in curative and preventive treatment of P. falciparum malaria. (4) The efficacy of the atovaquone + proguanil combination in uncomplicated malaria is similar to that of other treatments. Some strains of malaria seem to have reduced sensitivity. (5) The atovaquone + proguanil combination is also effective as prophylaxis, but there are no clinical trials showing whether it is equivalent to or better than other preventive treatments in non immune travellers. (6) According to the French licensing terms, atovaquone + proguanil prophylaxis can be stopped 7 days after leaving an endemic area, rather than 3-4 weeks with other drugs. This recommendation is based on weak evidence: mainly on theoretical arguments and on the absence of clinical malaria in some patients with evidence of P. falciparum infection. (7) The atovaquone + proguanil combination is less effective against other Plasmodium species (P. malariae, P. ovale and P. vivax). Chloroquine remains the reference treatment for these forms of malaria, which do not carry a risk of serious complications. (8) There were few adverse events in people taking the atovaquone + proguanil combination during clinical trials. During curative treatment, this combination caused more nausea and vomiting than reference treatments, while, in the prophylactic setting, it had slightly fewer adverse effects than the chloroquine + proguanil combination or mefloquine alone. But the drop out rate was not significantly different between treatment groups. (9) Atovaquone should be taken with food, to improve absorption. (10) The atovaquone + proguanil combination is expensive and is not refunded in France. In contrast, curative treatment with quinine is cheap, and is fully refunded. (11) Mefloquine and quinine remain the treatments of choice for uncomplicated malaria where there is chloroquine resistance. The atovaquone + proguanil combination is useful if mefloquine and quinine are contraindicated; unlike halofantrine, this combination does not carry the risk of serious drug interactions. In the prophylactic setting, the lack of experience with atovaquone means it should only be used as a second line option, after mefloquine, for short-term prophylaxis in areas with a high prevalence of chloroquine resistance.     

Buprenorphine in primary care: risk factors for treatment injection and implications for clinical management

AIMS: Though the introduction of office-based buprenorphine has greatly contributed to stem the HIV epidemic since 1995, concerns have been raised about the intravenous use of buprenorphine even in patients on substitution treatment. The aim of this study was to identify which factors are predictive of buprenorphine injection in patients receiving office-based buprenorphine. DESIGN AND SETTING: Subazur is a survey consisting of two longitudinal assessments of 111 stabilized patients receiving office-based buprenorphine in southeastern France. MEASUREMENTS: Patients were interviewed by phone at enrolment and 6 months later about social characteristics, addictive behaviors, treatment experiences, overdoses and suicide ideation or attempt. A logistic regression based on generalized estimating equations (GEE) was used to identify factors associated with buprenorphine injection at any interview. FINDINGS: Among the 111 patients (32% women, mean age 38 years), 36 reported buprenorphine injection after having started treatment initiation in 40 interviews. After adjustment for time since first injection, individuals perceiving their prescribed dosage as inadequate (OR=2.6 95%CI[1.2-5.7]) and those reporting a history of suicide ideation or attempt (OR=2.7 95%CI[1.1-7.0]) had approximately a three-fold higher risk of injecting buprenorphine. CONCLUSIONS: Providing adequate care for both drug dependence and psychiatric comorbidities in primary care is a major issue. Like heroin use during methadone treatment, buprenorphine injection should be regarded more as a response to inadequate care than simply as a "misuse". A re-assessment of the treatment efficacy through a possible dosage increase or a switch to methadone could potentially reduce diversion and assure sustained adherence to OST.     

Ethinylestradiol + norelgestromin: new preparation. Transdermal contraception: no tangible progress

(1) The reference hormone-based contraceptive for women is an oral contraceptive combining ethinylestradiol (about 30 micrograms) and a well-known progestin such as levonorgestrel or norethisterone. (2) A transdermal contraceptive patch delivering 20 micrograms of ethinylestradiol and 150 micrograms of norelgestromin over 24 hours, and designed to be left in place for a whole week, three weeks a month, has recently been marketed in France. (3) Norelgestromin is the active metabolite of norgestimate, which is already available in combined contraceptives but is less well evaluated than some other progestins. Norelgestromin is metabolised by the liver, notably into norgestrel. (4) The clinical evaluation dossier of the new transdermal contraceptive contains data from two comparative unblinded trials, one versus a triphasic combination of oral ethinylestradiol + levonorgestrel, and the other versus oral ethinyl estradiol (20 micrograms) + desogestrel. A third, non comparative trial offers weaker evidence. These three trials included about 3300 women in total, and lasted between 6 and 13 cycles. The patch was about as effective as the comparator contraceptives. (5) In the three main clinical trials, 4.7% of patches had to be replaced because they became unstuck, either completely (1.8%) or partially (2.9%). (6) More women dropped out of the groups using patches (19.9% of the patch group compared with 14.5% of the group taking oral contraceptives in one trial, 29.6% versus 24.3% in the other trial). Women using the patch were more likely than other women to stop their treatment because of adverse events (about 12% versus 5%). (7) Breast discomfort, breast tenderness or pain were reported by 22% of women using the patches and by 9% and 6% of women in the two comparator groups. Women using the patches had slightly longer menstrual periods (5.6 days versus 4.7 days). Reactions at the patch site were reported by 17% of women. (8) There is no evidence that the patch is any less likely than reference oral contraceptives to cause thromboembolism. The true thromboembolic risk associated with the new patches is unknown. (9) Used patches still contain large amounts of active substances, and must be placed in sachets (provided in the packet) and taken to a pharmacy for disposal. (10) In practice, the reference combined contraceptive for women is still oral ethinylestradiol (about 30 micrograms) plus a well-known progestin such as levonorgestrel or norethisterone. Ethinylestradiol + norelgestromin patches offer women no real benefits: they are probably less convenient and may be less safe.     

Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence

Buprenorphine is a semi-synthetic opioid derived from thebaine, a naturally occurring alkaloid of the opium poppy, Papaver somniferum. The pharmacology of buprenorphine is unique in that it is a partial agonist at the opioid mu receptor. Buprenorphine undergoes extensive first-pass metabolism and therefore has very low oral bioavailability; however, its bioavailability sublingually is extensive enough to make this a feasible route of administration for the treatment of opioid dependence. The mean time to maximum plasma concentration following sublingual administration is variable, ranging from 40 minutes to 3.5 hours. Buprenorphine has a large volume of distribution and is highly protein bound (96%). It is extensively metabolised by N-dealkylation to norbuprenorphine primarily through cytochrome P450 (CYP) 3A4. The terminal elimination half-life of buprenorphine is long and there is considerable variation in reported values (mean values ranging from 3 to 44 hours). Most of a dose of buprenorphine is eliminated in the faeces, with approximately 10-30% excreted in urine. Naloxone has been added to a sublingual formulation of buprenorphine to reduce the abuse liability of the product. The presence of naloxone does not appear to influence the pharmacokinetics of buprenorphine. Buprenorphine crosses the placenta during pregnancy and also crosses into breast milk. Buprenorphine dosage does not need to be significantly adjusted in patients with renal impairment; however, since CYP3A activity may be decreased in patients with severe chronic liver disease, it is possible that the metabolism of buprenorphine will be altered in these patients. Although there is limited evidence in the literature to date, drugs that are known to inhibit or induce CYP3A4 have the potential to diminish or enhance buprenorphine N-dealkylation. It appears that the interaction between buprenorphine and benzodiazepines is more likely to be a pharmacodynamic (additive or synergistic) than a pharmacokinetic interaction. The relationship between buprenorphine plasma concentration and response in the treatment of opioid dependence has not been well studied.The pharmacokinetic and pharmacodynamic properties of buprenorphine allow it to be a feasible option for substitution therapy in the treatment of opioid dependence.     

Pioglitazone + metformin: new drug. A combination product to avoid

More serious adverse effects, and still no tangible proof of efficacy.     

Schedule dependence of the interaction of naloxone and chlordiazepoxide.

Reports that the opiate antagonist, naloxone, blocks the anticonflict effects of diazepam and chlordiazepoxide suggest endogenous opioid involvement in the anxiolytic actions of the benzodiazepines. However, naloxone's ability to antagonize the anticonflict effects of the benzodiazepines is not universal, but schedule specific. The present experiments investigated the importance of the timing of conflict periods and control of reinforcement on the naloxone-benzodiazepine interaction. We tested the effects of naloxone (3 mg/kg, IP) and chlordiazepoxide (5 mg/kg, IP) on acquisition of a successive discrimination schedule, with nonreward periods similar in length and frequency to those of signalled DRL, and on an FI60-s schedule. Chlordiazepoxide increased rewarded responding and, unexpectedly, decreased nonrewarded responding during acquisition of successive discrimination. This reduction in nonrewarded responding was reversed by naloxone. Under the FI60 schedule, chlordiazepoxide increased nonrewarded responding, an effect that was totally blocked by naloxone at the beginning of the FI. Naloxone's ability to reverse the response-releasing effect of chlordiazepoxide decreased later in the FI. These results suggest endogenous opioid systems are involved in the anxiolytic actions of the benzodiazepines when the animal is adapting to recently introduced conflict. Once adaptation occurs, other neurotransmitter systems mediate the actions of the benzodiazepines.     

Opiate detoxification under anesthesia: no apparent benefit but suppression of thyroid hormones and risk of pulmonary and renal failure

INTRODUCTION: The new technique for opiate detoxification using anesthesia and high, repetitive doses of opiate-antagonists claims to detoxify addicts without withdrawal symptoms within 24-48 hours. We studied the method with 12 opiate addicts (5 L-polamidone, 4 dihydrocodeine, 3 heroin), using general anesthesia and the antagonists naloxone 0.5 mg/kg and naltrexone > 150 mg. Objective and subjective withdrawal symptoms were measured until urine was free of drugs and patients had no withdrawal symptoms. Thyroid hormones were measured before, during, and after the anesthesia period. RESULTS: All patients had moderate to severe opiate withdrawal symptoms. No detoxification was finished within 48 hours. The dihydrocodeine subjects were compared with conventionally detoxified controls; no difference was seen. The method suppressed thyroid hormones TT3, TT4, and TSH. The study was terminated because of side effects: 1 pulmonary failure and 2 renal failures. All patients survived without sequelae. CONCLUSION: There is no obvious benefit from this method, whereas the risks are high.     

Buprenorphine maintenance treatment of heroin dependence: the first experience from Iran

The aim of this study was to assess the efficacy of 1-, 2-, and 4-mg-per-day sublingual doses of buprenorphine in the maintenance treatment of heroin-dependent patients over a 17-week treatment period. Subjects were randomized to three dosage groups. Participants consisted of 105 heroin addicts (102 men and 3 women) who met the DSM-IV criteria for opioid dependence and were seeking treatment. Subjects received buprenorphine at a dose of 1, 2, or 4 mg per day and were treated in an urban outpatient clinic, including a weekly 1-hour individual counseling session. Days retained in treatment were measured. Overall, 49 patients (46.7%) completed the 17-week study. Completion rates by dosage group were 34.3% for the 1 mg dose group, 42.9% for the 2 mg dose group, and 62.9% for the 4 mg dose group. Retention in the 4 mg dose group was significantly better than in the 1 mg dose group (P = .017). None of the other comparisons was significant. The results support the efficacy and safety of buprenorphine for outpatient treatment of heroin dependence and seem to indicate that the highest dose (4 mg) of buprenorphine was the best of the three doses for Iranian heroin addicts to increase their retention in treatment.