CHAPTER 32 Drugs of Abuse 581 tolerance and dependence. The withdrawal syndrome may be very severe (except for codeine) and includes intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, and fever. Beyond the withdrawal syndrome, which usually lasts no longer than a few days, individuals who have received opioids as analgesics only rarely develop addiction. In contrast, when taken for recreational purposes, opioids are highly addictive. The relative risk of addiction is 4 out of 5 on a scale of 1 (nonaddictive) to 5 (highly addictive).
The opioid antagonist naloxone reverses the effects of a dose of morphine or heroin within minutes. This may be life-saving in the case of a massive overdose (see Chapters 31 and 58). Naloxone administration also provokes an acute withdrawal (precipitated abstinence) syndrome in a dependent person who has recently taken an opioid.
In the treatment of opioid addiction, a long-acting opioid (eg, methadone, buprenorphine, morphine sulphate) is often substituted for the shorter-acting, more rewarding, opioid (eg, heroin). For substitution therapy, methadone is given orally once daily, facilitating supervised intake. Using a partial agonist (buprenorphine) and the much longer half-life (methadone, morphine sulphate, and buprenorphine) may also have some beneficial effects (eg, weaker drug sensitization, which typically requires intermittent exposures), but it is important to realize that abrupt termination of methadone administration invariably precipitates a withdrawal syndrome; that is, the subject on substitution therapy remains dependent. Levomethadone, a preparation containing only the active enantiomer, has similar kinetics and effects as methadone, but lower side effects, particularly when cardiac repolarization is perturbed (long QT interval in the electrocardiogram). Some countries (eg, Canada, Denmark, Netherlands, United Kingdom, Switzerland) even allow substitution of medical heroin for street heroin. A follow-up of a cohort of addicts who received heroin injections in a controlled setting and had access to counseling indicates that addicts under heroin substitution have an improved health status and are better integrated in society. Abuse of prescription opioids has soared in the USA over the last 10 years, and the National Institute on Drug Abuse (NIDA) estimates that more than 2 million individuals are dependent on these substances, some of whom may become heroin addicts.
Endogenous cannabinoids that act as neurotransmitters include 2-arachidonyl glycerol (2-AG) and anandamide, both of which bind to CB1 receptors. These very lipid-soluble compounds are released at the postsynaptic somatodendritic membrane, and diffuse through the extracellular space to bind at presynaptic CB1 receptors, where they inhibit the release of either glutamate or GABA. Because of such backward signaling, endocannabinoids are called retrograde messengers. In the hippocampus, release of endocannabinoids from pyramidal neurons selectively affects inhibitory transmission and may contribute to the induction of synaptic plasticity during learning and memory formation.