Low Addictive Potential Research Articles

Role of zolpidem in the management of insomnia.

Insomnia is a common condition that affects one's ability to sleep comfortably and consequently to work effectively. Its etiology is multifactorial and involves plethora of risk factors. Consequences can vary from mild sleepiness to more sever psychiatric disturbances and ischemic stroke. Despite several diagnostic criteria it is poorly diagnosed and less often treated. Benzodiazepines formed the mainline therapy for many years till the advent of newer nonbenzodiazepine group of drugs including zolpidem. Zolpidem is an imidazo-pyridine compound that enhances the GABA(A) receptor function by interaction with Omega-1 receptor subtype. Its pharmacokinetic profile allows the patients to use it later in the night when having trouble falling asleep without any residual cognitive impairment the next morning. It has rapid onset of action, improves total sleep duration, and reduces night-time awakenings. Its adverse effect profile is satisfactory as it appears to have low addiction potential. This review will focus on the current role of zolpidem in the management of insomnia.

Risk assessment of khat use in the Netherlands: A review based on adverse health effects, prevalence, criminal involvement and public order

In preparing a decision about the legal status of khat in the Netherlands, the Dutch Minister of Health requested CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of khat in the Netherlands. The present paper is a redraft of a report which formed the scientific basis of the risk evaluation procedure (October 2007). This report reviews the scientific data about khat available in the international literature. In addition, the report contains some information specific for the Netherlands (prevalence, availability of khat and public order aspects). The main psychoactive compounds in khat leaves are cathine and cathinone, which are some 2- to 10-fold less active than amphetamine. Acute health problems are rarely seen, and are usually related with malnutrition, social and financial problems. Khat has a low addictive potential. Chronic toxicity of khat is modest when used in low amounts, whereas at high levels, khat use is associated with adverse effects, like hypertension, heart rhythm disorders, insomnia and loss of appetite. In addition, khat users show a higher prevalence of cancers in the digestive tract. At population level, khat does not lead to specific health risks in the Netherlands, as its use is confined to East-African immigrants. A relationship between khat use and psychiatric disorders has been suggested, but the reports are contradictory, and such studies are presumably heavily confounded by posttraumatic and social stress. In the Netherlands (and other countries), khat use occasionally leads to minor disturbance of civil order in the public domain (loud talking, spitting), but is not related to criminal activities. Following the assessment, CAM estimated the overall risk potential of khat use in the Netherlands as very low. A similar conclusion may be drawn for countries with a comparable prevalence of khat use and khat related public order disturbance.

A highly selective κ-opioid receptor agonist with low addictive potential and dependence liability

Buprenorphine analogs have been synthesized. In the studies of analgesic and addictive effects in mice and [35S]GTPγS binding assay in human brain tissue, an analog of buprenorphine where the tert-butyl is replaced by a cyclobutyl moiety (16) has been identified as a selective κ-partial agonist which gives antinociceptive effects, but has low abuse potential. The results may lead to lower degrees of dysphoria than full κ-agonists.

A Shift From Demerol (Meperidine) to Dilaudid (Hydromorphone) Improves Pain Control and Decreases Admissions for Patients in Sickle Cell Crisis

October 2004 30:5 eperidine was first synthesized in 1939 as an M agent and almost immediately became the most commonly prescribed opiate in the United States. At that time, morphine was available only in hypodermic tablets, which had to be dissolved and then injected. Meperidine, on the other hand, was available in solution, which made measuring relatively accurate and administration easier. Initially, it was thought that meperidine would not cause some of the problems associated with morphine such as respiratory depression, constipation, and urinary retention. Practitioners also believed that meperidine had a low potential for habituation and addiction. Enthusiasm for this drug was such that it was estimated in the late 1980s that as many as 60% of physicians in the United States were prescribing it for acute pain and 22% were prescribing it for chronic pain. Despite the popularity of meperidine, there are problems with its use. The metabolism of meperidine results in a neurotoxic metabolite, normeperidine. Normeperidine has half the analgesic strength of meperidine but 2 to 3 times the potency as a central nervous system excitatory agent. It has the propensity to induce anxiety, hyperref lexia, and mood changes. In large doses normeperidine can accumulate and has even been known to cause seizures. Meperidine also interacts unpredictably with monoamine oxidase inhibitors, phenelzine, tranylcypromine, and isocarboxazid. Some interactions are marked by agitation, tremors, fever, seizure, and even apnea and death. In populations where meperidine may be given over a period of several days, as with patients who have sickle cell disease, the potential for accumulation of

Oral triazolam sedation in implant dentistry.

Triazolam can be helpful for sedating dental implant patients when administered orally or sublingually in low dosages of 0.125 or 0.25 mg, but not exceeding 0.5 mg. It is a fast- but short-acting benzodiazepine with few side effects, and it has a long record of successful use. Its effects can be reversed with incremental intravenous flumazenil, although there is a risk of seizure. Triazolam has not been shown to be carcinogenic, and it has a low potential for abuse and addiction. It is contraindicated in patients who are pregnant, breast-feeding, and those concomitantly taking ethanol, macrolid antibiotics, some protease inhibitors, psychotropic medications, ketoconazole, itraconazole, nefaxodone, or other medications that impair oxidative metabolism mediated by cytochrome P450 3A (CYP 3A). Triazolam should be used with caution in patients taking grapefruit juice, cyclosporine, and other drugs such as calcium channel blockers including nifedipine, verapamil, and diltiazem. The lowest effective dose should be used.

What’s New in the Management of Pain in Children

What’s New in the Management of Pain in Children

Are scratchcards addictive? The prevalence of pathological scratchcard gambling among adult scratchcard buyers in the Netherlands.

To determine the prevalence of regular, potential problematic and pathological scratchcard gambling (PSG) 5 years after the introduction of scratchcards in the Netherlands. A non-proportional stratified random sample of 12,222 scratchcard buyers was approached. Regular scratchcard buyers (n = 3342) were asked to fill out the South Oaks Gambling Screen (SOGS). Those with a SOGS score of 3 or more (n = 340) were interviewed with the gambling section of the DSM-IV Diagnostic Interview Schedule (DIS-T). Weighted data were used to obtain unbiased prevalence estimates. The estimated prevalence of regular and potential problematic scratchcard gambling were 28.4% and 2.68%, respectively. Only 0.24% met DSM-IV criteria for PSG. Of those, only 0.09% were addicted uniquely to scratchcards. The remaining 0.15% were also addicted to other games of chance. Demographic and gambling characteristics of these 'combined' PSG (young men, mainly slot-machine players) resembled characteristics of pathological gamblers in general. In contrast to these 'combined' PSG, 'unique' PSG were mainly women between 25 and 34 years who spent relatively small amounts of money on scratchcards (equivalent to one scratchcard a day). Scratchcards have a very low addiction potential among adults in the Netherlands. Given the specific characteristics of the unique PSG and the relatively small amount of money they spent, the appropriateness of DSM criteria for this particular form of gambling can be questioned.

The use of buspirone in primary care.

1. Although clinical trials have demonstrated the effectiveness of buspirone in treating generalized anxiety disorder, more studies are needed to confirm its efficacy in treating other anxiety disorders, depression, behavior disorders, substance abuse disorders, movement disorders, and other medical conditions. 2. Clinicians prescribing buspirone must know its basic pharmacology, adverse effects, and dosing guidelines. 3. Buspirone appears to be an alternative attractive medication to traditional benzodiazepines due to its low addictive potential and lack of lethality.

Behavioral pharmacology of buprenorphine, with a focus on preclinical models of reward and addiction.

Buprenorphine is a potent mu-receptor partial agonist and is widely used as an analgesic drug. It is also increasingly considered to be an alternative to methadone in the maintenance and eventual detoxification of heroin addicts, and also in the treatment of cocaine addiction. So far, buprenorphine has been available as a sublingual tablet and as a solution for IV injection. Recently, a new transdermal formulation of buprenorphine in slow-release matrix patches has been introduced (Transtec) for the treatment of intermediate to severe pain. The aim of this paper is to review, from a preclinical perspective, the current status of what is known about the behavioral pharmacology of buprenorphine, with a particular emphasis on the issues of reward, addiction, and dependence. It will also point to open questions that should be addressed in the future to improve our understanding of the effects and the mechanisms of action of this drug. Since buprenorphine is a potent opioid drug, the issue of addiction and dependence in this context is an important one. Although there are still some gaps in the behavioral pharmacological characterization of buprenorphine, the general conclusion that can be drawn from the reviewed literature is that despite the high affinity of buprenorphine for the mu receptor it appears to be a remarkably safe drug, with a benign overall side effect profile and low addictive and dependence-inducing potential. This favorable side effect profile appears to be due, to a large extent, to the partial agonistic properties of the drug, in combination with its particular receptor kinetics (i.e. very slow dissociation from the mu receptor after binding).

Comparative biotransformation of morphine, codeine and pholcodine in rat hepatocytes: identification of a novel metabolite of pholcodine

1. Pholcodine (3-morpholinoethylmorphine), a semi-synthetic alkaloid, is widely used as an antitussive agent. 2. Norpholcodine [7,8-didehydro-4,5 α -epoxy-3-(2-morpholinoethoxy)morphinan-6 α -ol] (NP) and pholcodine-N-oxide [1(9a)-dehydro-(4aR,5S,7a R,9c S,12S)-4a,5,7a,8,9,9a-hexahydro-5-hydroxy-12-methyl-3-morpholinoethoxy-1 H -8,9,c-(iminoethano)phenanthro[4,5-bcd] furan-12-oxide] (PNOX) were identified in incubations of pholcodine with freshly isolated rat hepatocytes by liquid chromatography/electrospray-mass spectrometry (LC/ESI-MS). 3. Synthesized NP and PNOX were characterized by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. 4. N -oxidation was the major metabolic pathway for pholcodine, producing a previously unreported metabolite. 5. The metabolism of morphine and codeine was also determined using freshly isolated hepatocytes. 6. For morphine, 3-glucuronidation was the major metabolic pathway, whilst for codeine it was dealkylation (O - and N -). 7. Neither morphine nor its metabolites were metabolites of pholcodine. 8. This observation supports the hypothesis that the absence of analgesic activity with pholcodine may be due to less O -dealkylation in vivo. 9. Together with the slow biotransformation of pholcodine (k met = 0.021 µM min -1) in comparison with morphine (k met = 0.057 µM min -1) and codeine (k met = 0.112 µM min -1), the results obtained were consistent with its low addiction potential and suggest that its antitussive efficacy is mediated by the parent drug or one of its metabolites other than morphine.

Opioids in chronic pain management: is there a significant risk of addiction?

In the last decade there has been significant controversy about the appropriateness, efficacy, safety, and wisdom of treating chronic pain patients (CPPs) with opioids. Arguments against their use have included concerns about tolerance, dependence, addiction, persistent side effects, and interference with physical or psychosocial functioning. However, considerable experience and research with long-term cancer pain treatment suggests that in appropriately selected patients, opioids have a low morbidity, and a low addiction potential, and in addition to the primary analgesic action, can facilitate reduction in suffering, enhance functional activity level, and improve quality of life without significant risk of addictive behaviors. Some patients, however, are at risk. Risk factors for addiction are discussed in this article.

Dose-response study of caffeine effects on cerebral functional activity with a specific focus on dependence.

Caffeine is a behavioral stimulant consumed on a worldwide basis. The question of whether caffeine is addictive has been debated for over a decade. Caffeine acts as a mild positive reinforcer but is not consistently self-administered in humans or animals. With [14C]2-deoxyglucose autoradiography, we studied the effects of increasing doses of caffeine on cerebral glucose utilization in rats. At 1 mg/kg, caffeine activated the caudate nucleus mediating locomotion, and the raphe nuclei and locus coeruleus involved with mood and sleep. After 2.5 and 5 mg/kg caffeine, metabolic activation spread to other components of the nigrostriatal dopaminergic system, the thalamus, ventral tegmental area and amygdala. The functional activation of the shell of the nucleus accumbens, an area involved in addiction and reward, was only induced by the highest dose of caffeine, 10 mg/kg. At this dose, the activation of the shell of the nucleus accumbens occurred together with that of the core of the nucleus accumbens and of most other brain regions. These data correlate well with the known sensitivity of locomotion, mood and sleep to low doses of caffeine. They also show that low doses of caffeine which reflect the usual human level of consumption fail to activate reward circuits in the brain and thus provide functional evidence of the very low addictive potential of caffeine.

Acute injection of drugs with low addictive potential (Δ9-tetrahydrocannabinol, 3,4-methylenedioxymethamphetamine, lysergic acid diamide) causes a much higher c-fos expression in limbic brain areas than highly addicting drugs (cocaine and morphine)

It is regarded as a common pharmacological property responsible for the addictive potential of drugs of abuse that they are able to activate brain areas involved in the sensation of pleasure, especially the nucleus accumbens. To investigate the connection between addictive potential and stimulation of critical brain areas in more detail, we studied c-fos accumulation in response to various addicting drugs in direct comparison. The substances were injected into drug-naive rats, and c-fos mRNA levels were measured throughout the brain by in situ hybridization. Cocaine in a high dose of 50 mg/kg yielded only a discrete c-fos expression in the medial and central striatum. Morphine (50 mg/kg) caused a weak c-fos synthesis in the lateral septum. THC (Δ9-tetrahydrocannabinol), 25 mg/kg, induced c-fos mRNA again in the lateral septum and furthermore in large parts of the striatum including the nucleus accumbens. LSD (lysergic acid diamide), 1 mg/kg, elicited a similar c-fos expression pattern as THC, but there was additionally a very strong hybridization signal in the cerebral cortex, especially in the upper layers, and in the ventral part of the periaqueductal gray. The widest range of brain areas was activated by MDMA (3,4-methylenedioxymethamphetamine, `ecstasy'), 6 mg/kg. In addition to the regions that responded to LSD, there was a very pronounced c-fos signal in the nucleus accumbens core and shell and in the mammillary nuclei. Taken together, our study revealed that the drugs with the highest addictive potential, cocaine and morphine, yielded a very low c-fos synthesis throughout the brain whereas the brain regions closely linked to pleasure (especially the nucleus accumbens) responded strongly to drugs with an apparently lower addictive potential (THC, LSD, MDMA).

Excessive morphine requirements after pre-hospital nalbuphine analgesia.

Nalbuphine hydrochloride is an opioid agonist-antagonist that has gained acceptance as a pre-hospital analgesic agent. Nalbuphine has equal analgesic properties to morphine, has a low addiction potential, and can be...

Ecstasy (MDMA) in Recreational Users: Self‐Reported Psychological and Physiological Effects

Twenty recreational drug users were asked to describe the psychological and physiological effects they experienced under MDMA (3,4-methylenedioxymethamphetamine). The subjects comprised 11 males and nine females, in the age range 18–31 years. Five subjects had taken MDMA once, nine had taken it 2–9 times, while six subjects had taken it +10 times. Each subject completed a modified Profile of Mood States Questionnaire (POMS), an Ecstasy Effect Questionnaire, and a structured interview, covering past experience with MDMA. Increased feelings of elation, agreeableness, energy, and mental confusion were reported on-drug (p < 0·001), together with faster heart rate, feeling hot, increased sweating and dehydration, dilated pupils, and tight jaw (trismus). Coming off-Ecstasy led to feelings of lethargy, moodiness, insomnia, depression, irritability, and paranoia. Bad MDMA trips were reported by 25 per cent of the sample, following a variety of unpleasant experiences. Chronic pharmacodynamic tolerance was not apparent, since although regular users all described their first MDMA experience as ‘the most intense’, later trips were affected by knowledge and expectancy, rather than any diminution in drug response. Acute pharmacodynamic tolerance was, however, evident, with a period between drugs being described as necessary in order to maintain drug effectiveness. This may help explain the low addiction potential of MDMA. © 1997 John Wiley & Sons, Ltd.

Ecstasy (MDMA) in Recreational Users: Self-Reported Psychological and Physiological Effects

Twenty recreational drug users were asked to describe the psychological and physiological eAects they experienced under MDMA (3,4-methylenedioxymethamphetamine). The subjects comprised 11 males and nine females, in the age range 18‐31 years. Five subjects had taken MDMA once, nine had taken it 2‐9 times, while six subjects had taken ita10 times. Each subject completed a modified Profile of Mood States Questionnaire (POMS), an Ecstasy EAect Questionnaire, and a structured interview, covering past experience with MDMA. Increased feelings of elation, agreeableness, energy, and mental confusion were reported on-drug (p< 0001), together with faster heart rate, feeling hot, increased sweating and dehydration, dilated pupils, and tight jaw (trismus). Coming oA-Ecstasy led to feelings of lethargy, moodiness, insomnia, depression, irritability, and paranoia. Bad MDMA trips were reported by 25 per cent of the sample, following a variety of unpleasant experiences. Chronic pharmacodynamic tolerance was not apparent, since although regular users all described their first MDMA experience as ‘the most intense’, later trips were aAected by knowledge and expectancy, rather than any diminution in drug response. Acute pharmacodynamic tolerance was, however, evident, with a period between drugs being described as necessary in order to maintain drug eAectiveness. This may help explain the low addiction potential of MDMA. #1997 by John Wiley & Sons, Ltd.

Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl

Chronic pain remains a problem because it is often misdiagnosed and undertreated. Adverse effects and safety concerns associated with many analgesics have limited the use of these agents and contributed to the undertreatment of pain. With regard to the pharmacologic agents most commonly used to manage pain, centrally acting analgesics (e.g., morphine, codeine) are associated with respiratory depression, tolerance, and dependence, and most nonsteroidal anti-inflammatory drugs (NSAIDs) produce adverse gastrointestinal effects. New to the United States, tramadol HCl, which has been prescribed for almost 2 decades in Europe, is a single-entity, centrally acting analgesic that is effective for the management of moderate to moderately severe pain. Although the mechanism of action of this analgesic is not completely understood, animal models suggest that at least two complementary modes of action appear applicable: (1) binding of parent compound and mono- O-desmethyltramadol (M1 metabolite) to the μ-opioid receptor and (2) weak inhibition of norepinephrine and serotonin reuptake. Clinical experience suggests that tramadol appears to have a low potential for abuse or addiction. Results from clinical trials conducted in the United States as well as European postmarketing surveillance studies indicate that tramadol is an effective analgesic that may have a particularly important role in the management of chronic painful conditions.

EPIDEMIC FREE-BASE COCAINE ABUSE: Case Study from the Bahamas

Beginning in 1983, a sharp increase was noted in the number of new admissions for cocaine abuse to the only psychiatric hospital and to the primary outpatient psychiatric clinic in the Bahamas. For the two facilities combined, new admissions for cocaine abuse increased from none in 1982 to 69 in 1983 and to 523 in 1984. Although there was some evidence for a rise in cocaine use during this time, as the drug became cheaper and more available, a primary cause of this medical epidemic seemed to be a switch by pushers from selling cocaine hydrochloride, which has a low addictive potential, to almost exclusive selling of cocaine free base, which has a very high addictive potential and causes medical and psychological problems. Although the use of free cocaine base is rising around the world, this is the first report of a nationwide medical epidemic due almost exclusively to this form of the drug, although similar problems are reported with smoking coca paste in South America.

ChemInform Abstract: ACYLMORPHINANS. A NOVEL CLASS OF POTENT ANALGESIC AGENTS

AbstractDie gemäß Formelschema zugänglichen Verbindungen (II), (IV) und (V) werden auf analgetische Aktivität sowie Opiat‐Rezeptor‐Affinität untersucht.

Subject index

This chapter describes a hallucinogen, Ibogaine as a potential treatment for opiate addiction. Ibogaine is an indole alkaloid derived from the roots of a West African shrub called Tabernanthe iboga. It mentions that Ibogaine can reduce drug cravings, lessen withdrawal symptoms and improve self-control. Presently, the drug is said to be a Schedule I Controlled Substance in the United States, which makes it illegal to manufacture, buy or distribute without DEA (drug enforcement administration) license. The pharmacology of Ibogaine is discussed and its physiological effects and administration. The drug has severe side effects resulting in fatalities and so has low potential for addiction. For treatment of opiate addiction, currently three treatments are medically recognized: Methadone, L-alpha-acetyl-methanol (LAAM) and Buprenorphine, but these treatments do not offer a perfect solution. The use of Ibogaine for treatment of opiate addiction could be implemented which could prove more successful than the other drugs. It states that the inclusion of Ibogaine as a Schedule I is inappropriate, as hallucinogens are rarely addictive and potential for abuse and recreational use is low.