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Slow-release oral morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence.

AIMS: To evaluate slow-release oral morphine (SROM) as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence. DESIGN: Open-label crossover study. SETTING: Out-patient methadone maintenance programme. PARTICIPANTS: Eighteen methadone maintenance patients. Intervention Participants were transferred from methadone to SROM (once-daily Kapanol trade mark ) for approximately 6 weeks before resuming methadone maintenance. MEASUREMENTS: Patient outcomes were assessed (1) during the transition between medications (dose requirements, withdrawal severity) and (2) after at least 4 weeks on a stable dose of each drug (treatment preference, patient ratings of treatment efficacy and acceptability, drug use, health, depression and sleep). FINDINGS: Transfer from methadone to SROM was associated with relatively mild withdrawal for the first 5 days; the final mean SROM : methadone dose ratio was 4.6 : 1. Compared to methadone, SROM was associated with improved social functioning, weight loss, fewer and less troublesome side-effects, greater drug liking, reduced heroin craving, an enhanced sense of feeling 'normal' and similar outcomes for unsanctioned drug use, depression and health. The majority of subjects preferred SROM (78%) over methadone (22%). CONCLUSIONS: These findings provide justification for further evaluation of SROM as a maintenance pharmacotherapy for opioid dependence.

Adult↗

Acquisition and use of needles and syringes by injecting drug users in Baltimore, Maryland.

Our objective was to determine how injection drug users (IDUs) in Baltimore, Maryland obtain and use needles and syringes (NS) for drug injection, before the opening of a needle exchange program (NEP). The method of this study was a cross-sectional structured interview survey in 1992 of active IDUs in a longitudinal study of human immunodeficiency virus (HIV) infection. For 466 IDUs (94.6% black, 83% male), usual sources of NS were "street" dealers (49.6%), pharmacies (29.8%), diabetics (16.3%), friends/neighbors (2.2%), and "shooting galleries" (1.9%). Half (53.5%) reported pharmacy purchase of NS, and 55.6% had diabetic friends/relatives. Twenty-three percent traded drugs, and 5% traded sex for NS. Eighty-eight and two-tenths percent would use a needle exchange program; 24.6% currently own no NS (median owned = 2.2). NS reuse was common (median = three times). Concern about (55.2%) or history of (33.9%) hassle/arrest for NS possession was typical; 81% kept NS at home, and 67% do not carry NS when purchasing drugs. Pharmacy purchasers (versus "street") were less likely to have been jailed, shared NS, or used shooting galleries during the preceding 6 months. In Maryland, although IDUs can legally purchase NS at pharmacist discretion, possession remains illegal; fewer than one-third of IDUs use pharmacies, and most obtain NS from illegal sources. Most IDUs reuse NS, but discard them after several uses. Current patterns of NS acquisition and use in Baltimore are likely to increase HIV transmission. Increased availability and decriminalization of NS possession could decrease the risk of injection-related HIV transmission.

Acquired Immunodeficiency Syndrome↗

The program of criminal undercover agents sources in the drug trade.

Information and intelligence have always been, and will remain the most essential components of policing, and indeed all law enforcement and security work, including the variety of drug control efforts. Sources of information are many and varied, ranging from everyday interactions of officers of the law with the public, anonymous reports, the use of paid and unpaid informants from the criminal underworld, to the law enforcement and security services' use of agents. This presentation, based on interviews with "handlers" of informants who are offenders and who supply information and evidence against other criminals, who may have been his former "comrades" explores: the dilemmas that the informer, and the handler face at each stage of the "operation" from recruitment to operation in the field, until the agent "fingers" the targets, and becomes a State witness. During each stage of the operation the "agents" motivations, fears, sense of betrayal (being betrayed and betraying others), being a "snitch", the need to protect identity as well as dependency upon the "handler" are the primary issues to be considered and resolved. The "handler" may have to tolerate the agent's commission of crimes during the operation and often may also have to "treat" the informant's spouse. Borrowed identity, which is the main meaning and dynamic of the informant's actions, and of any undercover work, will also be analyzed.

Crime↗

Forfeiture of illegally acquired assets of drug traffickers: the position in India.

Trafficking in drugs and other related crimes generates huge illicit funds which are used to support other criminal activity, corruption, illicit arms trading, the smuggling of goods and currency, and other economic offences. The traditional enforcement techniques aimed only at carriers and confiscation of the seized contraband no longer provide a sufficient deterrent. The problem is international in scope and requires close cooperation of all the agencies concerned. In 1976, India enacted specific legislation providing for the forfeiture of the property and assets of smugglers, including traffickers and foreign-exchange manipulators. This legislation, known as the "Smugglers and Foreign-Exchange Manipulators (Forfeiture of Property) Act, 1976", enables the enforcement authorities to confiscate all property, both movable and immovable, illegally acquired or accumulated, or for which investment is made from unlawful earnings resulting from smuggling and foreign exchange racketeering. It covers all such property held, not only in the names of smugglers and traffickers themselves, but their relatives and associates as well. The Act provides for principles of natural justice to be followed for all forfeiture proceedings and for appeals to a high tribunal. The legislation has enabled forfeiture action in 2,297 cases, covering properties valued at $US 40 million, during the last six years.

Crime↗

Assessing the trade-offs between crossover and parallel group designs in sleep research.

Sleep researchers invariably struggle with decisions regarding the optimal design for their studies. Whether such studies involve treatment for insomnia, obstructive sleep apnea, or any other sleep disorder, questions arise regarding the respective trade-offs between a parallel group and a crossover design. This study analyzed the variance structure of commonly measured polysomnographic variables in an effort to describe the statistical impact of these alternate designs. The study examined the effects of opioids on sleep and employed multiple crossovers between placebo, MS-contin, and methadone using a double-blind, randomized crossover design. Thirty-seven healthy subjects were studied. Four of the subjects were unable to complete the protocol for a variety of reasons, and polysomnogram data was unavailable for one subject. Data from 37 subjects provide the basis for this analysis. Despite dropouts, the crossover study was approximately four times as efficient as the parallel group design in terms of being able to recognize differences in deep sleep across these conditions. Other polysomnographic variables also favored the crossover design to varying extents. Despite the operational complexity of a crossover design, the statistical efficiency of this approach makes it a preferable approach for designing intervention studies in sleep research.

Adult↗

Compatibility of ropivacaine with morphine, sufentanil, fentanyl, or clonidine.

BACKGROUND: Ropivacaine hydrochloride (HCl) ('Naropin') is a long-acting local anaesthetic agent, administered epidurally to patients undergoing various surgical procedures. A combination of local anaesthetic and opioid is often administered for the management of severe pain to ensure that a minimal dose of each is used. Ropivacaine might be used in combination with an alpha2-adrenergic agonist for the management of visceral pain. Stability data have shown that ropivacaine is compatible with the systemic narcotic opioid analgesics morphine sulphate, sufentanil citrate and fentanyl citrate for 14 days in a Polybag (AstraZeneca-AB, Sweden), but no data have been obtained for the longer-term compatibility of ropivacaine with these opioids or with the alpha2-adrenergic agonist clonidine HCl. OBJECTIVE: This study used the Mark II Polybag (AstraZeneca-AB, Sweden) to test the physical and chemical compatibility of these products for up to 30 days. METHODS: Ropivacaine HCl solution for epidural infusion, 2 mg/mL, in 200 mL Mark II Polybag and commercially available additives in glass ampoules or vials were used as starting material. Appropriate admixtures were made and their appearance, pH, and drug concentrations were monitored on days 0, 7, 14, and 30. The appearance of the admixtures was examined with the aid of a stereomicroscope (Olympus, no. 220186, New York, USA) at 10x magnification. Drug concentration and enantiomeric purity were determined using high-performance liquid chromatographic analysis. RESULTS: All combinations at all doses stayed within the compatibility criteria (if no visible signs of physical changes in the admixture appeared throughout the 30 days of storage, and if pH and drug concentrations in each admixture did not vary by more than 10% between day 0 and days 7, 14, or 30 in storage). In addition, there were no important differences in the enantiomeric purity of ropivacaine with each combination. CONCLUSION: The study demonstrated that ropivacaine was suitable for use in combination with the opioids morphine sulphate, sufentanil citrate, and fentanyl citrate, or with the alpha2-adrenergic agonist clonidine HCl, for up to 30 days of storage before the management of severe or visceral pain. From a microbiological point of view, combinations not prepared under aseptic conditions should be used immediately. 'Naropin' is a trade mark of the AstraZeneca group of companies.

Adrenergic alpha-Agonists↗

Targeting pain-suppressed behaviors in preclinical assays of pain and analgesia: effects of morphine on acetic acid-suppressed feeding in C57BL/6J mice.

UNLABELLED: Pain increases the rate, frequency, or intensity of some behaviors (eg, withdrawal responses) and suppresses other behaviors (eg, feeding). Our laboratories are developing assays to test analgesic drug candidates using measurements of pain-suppressed rather than pain-elicited behaviors. Such assays may model important aspects of clinical pain and provide a means for distinguishing true analgesics from drugs that produce motor impairment. The present study compared effects of the mu opioid analgesic morphine and the nonanalgesic neuroleptic haloperidol on intraperitoneal acetic acid-induced writhing (a pain-elicited behavior) and suppression of feeding behavior (a pain-suppressed behavior). In feeding studies, C57BL/6J mice were given access to a dish containing 8 mL Ensure(trade mark) liquid food (0-100% in water) during daily sessions (7.5-120 min). Levels of consumption were dependent on both Ensure concentration and session duration. Intraperitoneal injection of acetic acid (0.10-0.56%) produced a time- and concentration-dependent decrease in Ensure consumption. Morphine (1 mg/kg) prevented both acid-induced writhing and acid-induced suppression of feeding, whereas the dopamine antagonist haloperidol inhibited writhing without preventing acid-induced suppression of feeding. The effects of morphine were time-dependent, selective for acid-suppressed feeding, and naltrexone-reversible. These results suggest that assays of pain-suppressed behaviors may complement assays of pain-elicited behaviors in preclinical studies of candidate analgesics. PERSPECTIVE: This paper presents a new preclinical strategy for assessing pain and analgesia in mice that is congruent with current methods of pain assessment in the clinic. This strategy may therefore be a useful complement to more traditional procedures for assessing pain and analgesia.

Acetic Acid↗

The profits of organized crime: the illicit drug trade in Canada.

Massive funds that are produced from street-level crime are laundered upwards into the criminal organizations for the benefit of their top-level members. The laundering systems used to distribute the proceeds of crime are designed to conceal the size of the organization as well as the identity of its members. Crime syndicates are attracted to criminal activity that produces the highest profits with the lowest risks. Although organized crime syndicates derive profits from a wide variety of criminal activity, their most sought after ventures principally involve the consensual type of crimes, such as drug trafficking, where no one individual can be readily identified as a legal victim for the purpose of recovering the proceeds of a criminal act. A recent survey indicated that illicit drug trafficking accounted for 87 per cent of the cash flow generated from organized crime. When the proceeds are disbursed, the criminals are free of the usual civil liability respecting the ownership of the proceeds. Canada currently has several laws which enhance the ability of law-enforcement authorities to trace the proceeds of crime and prosecute those who possess the assets. This legislation has some limitations with respect to seizure and forfeiture of certain types of proceeds. For example, forfeiture of the illegally acquired property is difficult when there is no original legal owner to initiate legal action, and even more difficult if the assets are located abroad.

Canada↗

Effect of flupirtine on Bcl-2 and glutathione level in neuronal cells treated in vitro with the prion protein fragment (PrP106-126).

Flupirtine, trade name Katadolon, is a centrally acting nonopioid analgesic that has recently been found to display cytoprotective activity in vitro and in vivo on neurons induced to undergo apoptosis. This report shows that the PrP106-126 fragment of the prion protein, which is the likely etiological agent for a series of encephalopathies, is toxic to cortical neurons in vitro. Simultaneously, PrP106-126 influences the molecular GSH content and the bcl-2 expression in neurons. Significant toxicity (32% reduction in cell viability) was observed at a concentration of 50 microM of the peptide after 9 days of incubation, while at higher concentrations toxicity increased to 70%. Neurotoxicity was greatly reduced following coincubation with 1 to 3 microg/ml flupirtine. Concomitant with PrP106-126-mediated cytotoxicity, glutathione (GSH) content fell by > 70% with respect to untreated controls. This decrease in GSH level was strongly blocked by flupirtine under incubation conditions that reduce cell toxicity. In addition to normalizing GSH content, flupirtine induced the expression of the anti-apoptotically acting proto-oncogene bcl-2. Based on these in vitro data and on the favorable pharmacokinetic profile of the drug, we strongly suggest that flupirtine may prove useful for treatment of patients with prion disease.

Amino Acid Sequence↗

Diversion of prescribed drugs by drug users in treatment: analysis of the UK market and new data from London.

AIMS: To review the available knowledge about the diversion to the illicit market of drugs prescribed to drug users in treatment in the United Kingdom, and to identify aspects of the London market in more detail. METHOD: An analysis of the literature and new data in terms of the extent and nature of the market, the practicalities of trade, motives for selling, reasons for demand and the influence of variations in prescribing practice on diversion. Prices of diverted prescription drugs and details of their availability in London are presented. FINDINGS: The size of the market is substantial and appears to involve a large number of individuals, each diverting small amounts of their own prescribed drugs. Major motives for selling prescribed drugs are to raise funds to buy other, preferred, drugs and/or to pay for a private prescription. Buyers in treatment appear to be motivated by a desire to supplement their own prescriptions because they are dissatisfied with the particular drug prescribed, dosage and formulation. Drug users in treatment can exploit the variations in prescribing practice--such as how much 'take-home' medication they are allowed and whether tests are conducted to ascertain if they are using it themselves--and divert their prescribed drugs. Prices of prescription drugs on the illicit market can fluctuate on a daily basis according to supply and demand. CONCLUSIONS: The results suggest that, to be effective, diversion control must simultaneously involve deterrents from prescribers, drug treatment services, law enforcement agencies and dispensing pharmacists. Finally, some suggestions for further research on this under-studied issue are suggested.

Benzodiazepines↗

[Tizanidine in the treatment of acute withdrawal symptoms in heroin dependent patients].

One of the treatment alternative of withdrawal symptoms of patients suffering from opiate dependence is to apply the clonidine in combination or itself. This remedy is not in commercial trade in our country. It is expectable according to the recent data analysing the effects of the alfa2 adreneregic agonist tizanidine that tizanidine has the similar protective effect as clonidine with the resembling target point. Based on this theory a research was done, in the course of which the i.v. heroin users who presented themselves at the Drug Outpatient Department of Buda between 1.10.1998-8.01.1999. were divided into two groups. The groups had got the usual detoxification treatment, but in the experimental group tizanidine were given in 3 x 8 mg/day dose too. Sixteen patients were in the tizanidine group, 10 patients were in the control group. The patients estimated the intensity of 7 symptoms of withdrawal (sweating, nervousness, insomnia, tremor, diarrhoea, muscle pain, drug craving) on a subjective scale day by day. The analysis showed that the tizanidine treatment decreased the intensity of the withdrawal symptoms in every symptom type examined. The ten days long acute withdrawal period were accomplished by all of the patients, but in the short course of the following (mean 9 and 11 weeks in the treated and the control groups respectively) there were three relapses in each group (3/16 in the treated and 3/10 in the control).

Acute Disease↗

[An analysis of the pharmaceuticals market in Vietnam].

This article sheds a light on the Vietnamese pharmaceutical market. The progress that has been made in the recent years following the opening of the Vietnamese regime to the western world, although not easy, brought a certain number of opportunities for domestic firms and foreign investors. The pharmaceutical Vietnamese industry started to emerge at the beginning of the 1990s. Although, the consumption of drugs is low, it does reach the sum of $ 5.5 per capita. As the majority of these products are imported, foreign companies tend to dominate the market both in volume and in diversity. The state has always played an important role with the implementation of a strict price control strategy and most national drug companies remain state-owned. The production and consumption of drugs were also largely influenced by state policies as the latter also control hospitals. In the second half of the eighties, the progressive liberalisation of the country allowed private drug pharmacies to appear and advertisement campaigns became legal. Because the lack of specific products like antibiotics was clear, the government increased the flow of imports, including private imports by citizens. Sources of imports have become more diverse, although France remains an important source of supply. Fournier, Lipha and Pierre Fabre are among the French drug manufacturers located in Vietnam. Other foreign companies include from India, South Korea, Thailand and Germany. Joint ventures were also created with French and Japanese companies. The import of medical materials is subjected to authorisations from the Ministry of Health and the Ministry of Foreign Trade as it is necessary to obtain a licence to do so. Licences are issued on the basis of the production of drugs that do not currently exist on the local market. But Vietnam also exports pharmaceutical products to Laos, Cambodia, and Cuba. Local resources constitute an important source of new products and have stirred a strong interest among pharmaceutical researchers. A strong decentralisation process characterises the pharmaceutical sector, with pharmacies in the provinces and districts while wholesalers remain located in Hanoi and Saigon. The presence of many middlemen has contributed to an increase in prices. Today, a concentration of pharmacies is still noted in inner cities while the suburbs and the villages still have difficulties supplying drugs for inhabitants. Solutions have been implemented such as the opening of new pharmacies and additional professional training for pharmacists. Prices were lowered while the quality of the supply chain was improved. Local production is encouraged as hospitals are prompted to prescribe Vietnamese products. The modernisation of the Vietnamese pharmaceutical industry is also visible through the importation of medical materials and an increase in the number of private hospitals financed with both the help of local and foreign investors, mainly through joint-ventures, most often in Saigon and Hanoi. The renovation of local hospitals was also possible with the help of France and Japan. Columbia Gia Dinh International, located in Saigon, is one of the very few US/Vietnamese medical institutions created with a local partner, the Gia Dinh hospital. The recovery of the economy will accelerate the creation of new projects designed to improve local medical infrastructures. Other private companies, some of which are based in Singapore, have been specifically designed to deliver care to expatriates working in Vietnam. Insurance coverage has been provided in Vietnam since in 1992. Other improvements concern the implementation of "Good Manufacturing Practices" (GMP) and "Good Laboratory Practices" and "Good Storage Practices". Most norms were implemented at the end of the 90s in joint companies linking foreign investors and local partners or in independent foreign drug manufacturers based in Vietnam. Special areas were created to receive high tech investments in the medical and pharmaceutical field. Prices should diminish as competition on the market increases and new products are placed on the market to achieve economies of scale. But investment in medical research is still strongly needed.

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