Benzos Relative abuse liability of hypnotics (study)

[kokaino]

The "revolution" in pharmacologic treatment of insomnia began in 1970 with the availability of flurazepam, the first of the benzodiazepine hypnotics. Flurazepam (Dalmane) largely replaced all other hypnotics during the decade of the 1970s. The second revolution began in the early 1980s as shorter half-life hypnotics, triazolam (Halcion) and temazepam (Restoril), became available and began to replace flurazepam.

Hypnotic drugs, including benzodiazepine receptor ligands, barbiturates, antihistamines, and melatonin receptor ligands, are useful in treating insomnia, but clinicians should consider the relative abuse liability of these drugs when prescribing them. Two types of problematic hypnotic self-administration are distinguished. First, recreational abuse occurs when medications are used purposefully for the subjective "high." This type of abuse usually occurs in polydrug abusers, who are most often young and male. Second, chronic quasi-therapeutic abuse is a problematic use of hypnotic drugs in which patients continue long-term use despite medical recommendations to the contrary. Relative abuse liability is defined as an interaction between the relative reinforcing effects (i.e., the capacity to maintain drug self-administration behavior, thereby increasing the likelihood of nonmedical problematic use) and the relative toxicity (i.e., adverse effects having the capacity to harm the individual and/or society). An algorithm is provided that differentiates relative likelihood of abuse and relative toxicity of 19 hypnotic compounds: pentobarbital, methaqualone, diazepam, flunitrazepam, lorazepam, GHB (gamma-hydroxybutyrate, also known as sodium oxybate), temazepam, zaleplon, eszopiclone, triazolam, zopiclone, flurazepam, zolpidem, oxazepam, estazolam, diphenhydramine, quazepam, tra-zodone, and ramelteon. Factors in the analysis include preclinical and clinical assessment of reinforcing effects, preclinical and clinical assessment of withdrawal, actual abuse, acute sedation/memory impairment, and overdose lethality. The analysis shows that both the likelihood of abuse and the toxicity vary from high to none across these compounds. The primary clinical implication of the range of differences in abuse liability is that concern about recreational abuse, inappropriate long-term use, or adverse effects should not deter physicians from prescribing hypnotics when clinically indicated. Pentobarbital rated highest in abuse liability, toxicity, followed by methaqualone, triazolam, temazepam, and GHB were the hypnotics with highest reinforcing and potential for abuse. Toxicity and overdose potential was also highest in the "top tier" group (pentobarbital> methaqualone> GHB> temazepam> triazolam). Lorazepam, flurazepam, flunitrazepam, diazepam showed moderate abuse potential, toxicity and likelihood of overdose was considerably lower compared to temazepam and triazolam, the benzodiazepines that showed highest abuse potential. Although flurazepam showed toxicity levels that are comparable to temazepam and triazolam, but lower abuse potential. Next came zolpidem, oxazepam, estazolam, quazepam, and zopiclone also showed moderate potential for abuse. Toxicity was low, and many of the drugs in this group had relatively slower absorption rates and reinforcing behavior was low for all drugs in this group. Next came eszopiclone, diphenhydramine, trazodone, and ramelteon showed very little to no abuse potential. From highest abuse potential to lowest is pentobarbital>methaqualone>GHB>triazolam>temazepam>diazepam>flunitrazepam>lorazepam>flurazepam>estazolam>quazepam>zolpidem>zopiclone>eszopiclone>ramelteon>diphenhydramine>trazodone.

A 1985 study found that triazolam and temazepam maintained higher rates of self-injection in both human and animal subjects compared to a variety of other benzodiazepines (others examined: diazepam, lorazepam, oxazepam, flurazepam, alprazolam, chlordiazepoxide, clonazepam, nitrazepam, flunitrazepam, bromazepam, and clorazepate). Abuse liability of triazolam and temazepam are less than that of the intermediate duration barbiturates such as pentobarbital. Although there are considerable data indicating similarities of triazolam and temazepam to other benzodiazepines, there is also substantial speculation among clinical investigators and some limited data suggesting that the abuse liability of temazepam and triazolam are greater than that of a variety of other benzodiazepines, and virtually no credible data or speculation that says they're less. Triazolam(9.4)>temazepam(9.2)>diazepam(8.4)>flunitrazepam(8.2)>nitrazepam(8.1)>flurazepam(7.8 )>bromazepam(7.8 )>alprazolam(7.5)>clonazepam(7.5)>clorazepate(5.9)>chlordiazepoxide(5.5)>oxazepam(5.2)

A Norwegian study on the adverse effects of zopiclone showed that zopiclone may have a higher abuse potential than some benzodiazepines. Scandinavian countries banned triazolam and temazepam in the early 90's, when temazepam was ravaging the UK (Scotland in particular) and the Netherlands. Finland, however, still has temazepam marketed for treatment of severe insomnia (comes only in 10mg formulation). Zopiclone is first line treatment in Scandinavia and much of Europe.

In 1994 zopiclone (Imovane), a cyclopyrrolon, was introduced in Norway as a new kind of hypnotic. In 1996 zopiclone had a 26% share of the hypnotic market. This review of relevant literature has revealed a lack of documentation on the adverse effects of zopiclone. The similarities between zopiclone and benzodiazepine hypnotics are more striking than the differences. The bulk of comparative research has been carried out with triazolam, a drug taken off the Norwegian market in 1991. With zopiclone there is less inhibition of psychomotor function the day after intake than with flunitrazepam. Zopiclone causes less subjective "hangover" than nitrazepam, but there is a similar inhibition of psychomotor function the day after intake, and in some cases greater addictive potential.

Some studies and clinical judgment of medical professionals, and epidemiological studies all indicate that diazepam, in particular, has a greater abuse liability than many of the other benzodiazepines. Although, several comparisons versus nitrazepam, temazepam, and alprazolam consistently showed that temazepam and nitrazepam both induced higher reinforcing behavior than diazepam and alprazolam.

.
Abuse, Addiction, Tolerance, and Dependence to Benzodiazepines in Medical and Nonmedical Populations (American Journal ofDrug Alcohol Abuse
1991;17(1):27-37.) This paper looked at many studies that compared benzodiazepines in their tolerance and dependence liabilty. One study showed that tolerance to temazepam, triazolam, and lorazepam was quick and withdrawal symptoms were severe, particularly within the temazepam group. These patients may usefully be transferred to longer-acting drugs such as diazepam or nitrazepam. A useful table of equivalents is given by Higgitt and colleagues. Ashton, for example, recommends substituting 10 mg diazepam by 1 mg lorazepam. For some patients the transfer may be problematic and the drug may have to be substituted in a stepwise manner. Lorazepam and temazepam (both are 3-hydroxy benzodiazepines) seem to produce a particularly severe withdrawal syndrome. Some evidence suggest that lormetazepam and camazepam -both also 3-hydroxy benzodiazepines and analogues of temazepam also produces a severe withdrawal syndrome.