Addiction liability

The search for opioid analgesics which show reduced addiction liability ha.s centered largely on benzomorphan and morphinan derivatives. Some research has, however, been devoted to derivatives of the structurally simpler meperidine series. The preparation of one such compound, picenadol (59), starts with the reaction of N-methyl-4-piperidone with the lithium derivative from m-methoxybromobenzene. Dehydration of the first formed carbinol 51 gives the intermediate 52. Deprotonation by means of butyl lithium gives an anion which can be depicted in the ambident form 53. In the event, treatment of the anion with propyl bromide gives the product 54 from reaction of the benzylic anion. Treatment of that product, which now contains an eneamine function. 

In 1988, the Surgeon General established three criteria for addiction liability.284 These general areas are Psychoactivity, Compulsive Use (Substance Dependence), and Drug-Reinforced Behavior (Reinforcing Effects). 

Azapirones. Though several azapirones have been developed and tested in the laboratory setting, only one, bnspirone (Bnspar), is currently on the market. Buspirone is the first nonsedating, nonbenzodiazepine anxiolytic, other than the antidepressants described earlier. It has no dependence or addictive liability and is not lethal in overdose. Buspirone is also devoid of many of the problems of the benzodiazepines such as sedation, motor impairment, addiction, physical dependence, or withdrawal. Yet, doubts remain in the minds of many practitioners regarding the effectiveness of buspirone. This will be discussed in more detail later in this chapter. 

Dihydromorphinone is 3-4 times more powerful than morphine and dihydrocodeinone is just a little less than morphine in potency. Their pitfall is an addiction liability, as great if not greater than morphine. To produce Hydrogenate morphine or codeine in a warm, strongly acidic solution, in a large excess of palladium or platinum catalyst, as per instructed in the reductions chapter. 

Little recent clinical data on the potent 2-benzylbenzimidazoles developed by Ciba [170] have been reported, probably because of their pronounced side-effects and addiction liabilities, but a number of chemical and pharmacological studies have been made. Activity is retained when the methylene group linking the two ring systems of the most potent 2-benzylbenzimidazole derivative (LVl) (1 000 X morphine in mice) is altered to NH [171] or CH2O [172], but... 

The CNS depressants include barbiturates, nonbarbiturate sedatives, and the benzodiazepines. As the medical use of barbiturates decreased, primarily because of their high addiction liability and the danger of acute lethality, the use of the benzodiazepine anxiolytics increased. The most commonly abused barbiturates are secobarbital, pentobarbital, and amobarbital. Pheno-barbital is not generally abused, because of its slow onset of action. The most commonly abused anxiolytics include diazepam, chlordiazepoxide, midazolam, lo-razepam, and flurazepam. These drugs are readily attainable from illicit sources. 

There are various opioid receptors the three major classes of opioid receptors are mu (p), delta (5) and kappa (k) receptors. The p, receptor is the principal pain-modulating site in the CNS, mediating the action of morphine. There is considerable interest in the K receptor, which mediates a sedating analgesia with decreased addiction liability and respiratory depression and which allows for some structural flexibility. Unfortunately, the K receptor seems to be coupled to the sigma (a) receptor, which is implicated in psychotomimetic and dysphoric side effects. 

Dextromethorphan is a synthetic compound and its dextroisomer is used as antitussive and is as effective as codeine without any addiction liability. 

Melatonin is promoted commercially as a sleep aid by the food supplement industry (see Chapter 64). Ramelteon is a selective MTi and MT2 agonist that is approved for the medical treatment of insomnia. This drug has no addiction liability (it is not a controlled substance), and it appears to be distinctly more efficacious than melatonin (but less efficacious than benzodiazepines) as a hypnotic. It is metabolized by P450 enzymes and should not be used in individuals taking CYP1A2 inhibitors. It has a half-life of... 

The opioid analgesics are among the most effective drugs available for the suppression of cough. This effect is often achieved at doses below those necessary to produce analgesia. The receptors involved in the antitussive effect appear to differ from those associated with the other actions of opioids. For example, the antitussive effect is also produced by stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability (see below). 

Older drugs still available in some countries include phenylpropanolamine, benzphetamine, amphetamine, methamphetamine, phentermine, diethylpropion, mazindol, and phendimetrazine. These drugs are all amphetamine mimics and are central nervous system appetite suppressants they are generally helpful only during the first few weeks of therapy. Their toxicity is significant and includes hypertension (with a risk of cerebral hemorrhage) and addiction liability. 

Antitussives Codeine, 10-20 mg every 4-6 hours, not to exceed 120 mg in 24 hours (with guaifenesin) Guiatuss AC, Mytussin AC, various generic Acts centrally to increase the cough threshold. In doses required for cough suppression, the addiction liability associated with codeine is low. Many codeine-containing antitussive combinations are schedule V narcotics, and OTC sale is restricted in some states. 

In the 1920s a most significant change in analgesic research came about the beginning of the first systematic study of structure-action relationships which endeavored to separate analgesic effectiveness from side-effects and addiction liability. 

Except for the addiction liability of some of the narcotic antitussives, side effects for most of the centrally acting compounds are relatively few and mild at therapeutic doses. Qualitative comparisons of both side effects and pharmacological profiles have been summarized for many of the compounds described above (97). 

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