Opioid addiction consists of three recognizable phases: (1) intoxication, or “euphoria,” (2) pharmacogenic dependence or drug-seeking behavior (addiction), and (3) the propensity to relapse after a period of abstinence. Some of the symptoms of opioid intoxication have already been considered. In patients with severe pain or pain-anticipatory anxiety, the administration of opioids produces a sense of unusual well-being, a state that has traditionally been referred to as morphine euphoria. It should be emphasized that only a negligible proportion of such persons continue to use opioids habitually after their pain has subsided. The vast majority of potential addicts are not suffering from painful illnesses at the time they initiate opioid use, and the term euphoria is probably not an apt description of the initial effects. These persons, after several repetitions, recognize a “high,” despite the subsequent recurrence of unpleasant, or dysphoric, symptoms (nausea, vomiting, and faintness as the drug effect wanes).
The pharmacologic (in contrast to psychologic) criteria of addiction, as indicated earlier in regards to alcoholism, are tolerance and physical dependence. The latter refers to the symptoms and signs that become manifest when the drug is withdrawn following a period of continued use. These symptoms and signs constitute a specific clinical state, termed the abstinence or withdrawal syndrome (see later). The mechanisms that underlie the development of tolerance and physical dependence are not fully understood. However, it is known that opioids activate an opioid antinociceptive system (enkephalins, dynorphins, endorphins), which are opioid receptors and are located at many different levels of the nervous system (these were referred to earlier and are described in Chap. 7; see also the review of Fields). The desensitization of opioid receptors, probably mainly the mu type, accounts for tolerance through a mechanism of uncoupling of the receptor from the G-protein complex.
The repeated self-administration of the drug is the most important factor in the genesis of dependence aspect of addiction. Regardless of how one characterizes the state of mind that is produced by episodic exposure to the drug, the individual quickly discovers the need to increase the dose in order to obtain the original effects (tolerance). Although the initial effects may not be fully recaptured, the progressively increasing dose of the drug does relieve the discomfort that arises as the effects of each injection wear off. In this way a new pharmacogenically induced need is developed, and the use of opioids becomes self-perpetuating. At the same time a marked degree of tolerance is produced, so that enormous amounts of drugs, for example, 5,000 mg of morphine daily, can eventually be administered without the development of toxic symptoms.
The Opioid Abstinence Syndrome
The intensity of the abstinence or withdrawal syndrome depends on the dose of the drug and the duration of addiction. The onset of abstinence symptoms in relation to the last exposure to the drug, however, is related to the pharmacologic half-life of the agent. With morphine, the majority of individuals receiving 240 mg daily for 30 days or more will show moderately severe abstinence symptoms following withdrawal. Mild signs of opiate abstinence can be precipitated by narcotic antagonists in persons who have taken as little as 15 mg of morphine or an equivalent dose of methadone or heroin for 3 days.