Use, Abuse, and Addiction

Opioid Withdrawal

The characteristic withdrawal syndrome associated with withholding opium derivatives from chronic users was described over a half century ago by C.K. Himmelsbach (1942). The symptoms of withdrawal included yawning, lacrimation (tearing eyes), rhinorrhea (runny nose), perspiration, gooseflesh, tremor, dilated pupils, anorexia, nausea, emesis, diarrhea, restlessness, insomnia, weight loss, dehydration, hyperglycemia, elevations of temperature and blood pressure, and alterations in pulse rate. Although many of these symptoms were recognized at that time as manifestations of disturbances in the function of the autonomic nervous system, a negative emotional state was also acknowledged as accompanying these physical signs of opioid withdrawal (see Box 5.3). A negative emotional or affective state is defined as a dysphoric state accompanied by depressive-like and anxiety-like symptoms that do not fully meet the criteria of a major mental disorder, such as a major depressive episode or generalized anxiety disorder. Individuals with opioid addiction were described as attempting to obtain sufficient drug to “prevent the dysphoria associated with the [opioid] withdrawal syndrome.” (Reichard JD. Can the euphoric, analgetic and physical dependence effects of drugs be separated? I. With reference to euphoria. Federation Proceedings, 1943, (2), 188–191.)

Subsequent descriptions of acute opioid withdrawal included two types of symptoms: purposive symptoms and non-purposive symptoms. Purposive symptoms were defined as symptoms that are goal-oriented (i.e., directed at getting more drug) and included complaints, pleas, demands, and manipulations. Purposive symptoms significantly decreased in a hospital setting where such efforts to obtain more drug had no consequences. In contrast, non-purposive symptoms were defined as those that are not goal-oriented and are relatively independent of the observer, the patient’s will, and the environment. A more modern framework probably would consider purposive symptoms as “craving” or motivational symptoms and non-purposive symptoms as physical or somatic.

The symptoms of opioid withdrawal also change significantly over time since the last administration (Table 5.4). In the early stages of withdrawal from heroin (6–8 h after the last dose), purposive, goal-oriented behavior is prominent and peaks 36–72 h after the last dose. Non-purposive, peripheral autonomic signs appear 8–12 h after the last dose and include yawning and sweating, runny nose, and watery eyes. These mild autonomic signs increase in intensity during the first 24 h and then level off. Additional non-purposive, physical symptoms then appear, peak at 36–48 h, and continue up to 72 h. These symptoms include pupillary dilation, gooseflesh, hot and cold flashes, loss of appetite, muscle cramps, tremor, and insomnia. Other autonomic signs include elevated blood pressure, increased heart rate, increased respiratory rate, increased body temperature, nausea, and vomiting.

Withdrawing individuals complain of feeling chilled, alternating with a flushing sensation and excessive sweating. Waves of gooseflesh (goose bumps) are prominent, resulting in skin that looks like a plucked turkey. Interestingly, this symptom is the basis of the expression “quitting cold turkey.” Accompanying these symptoms are also the subjective symptoms of aches and pains and general misery, mimicking a flu-like state. Muscle spasms, uncontrollable muscle twitching, and kicking movements may be the basis of the expression “kicking the habit.” At 24–36 h, diarrhea and dehydration may occur. The peak of the physical withdrawal syndrome appears to be approximately 48–72 h after the last dose. Without treatment, the physical syndrome completes its course in 7–10 days. However, residual, subclinical signs may persist for many weeks after withdrawal.

The persistent signs of abstinence in detoxified subjects, including hyperthermia, mydriasis (pupillary dilation), increased blood pressure, increased respiratory rate, increased pain and stress sensitivity, and dysphoria can continue for months after opioid withdrawal and have been termed “protracted abstinence.” Protracted abstinence includes signs of drug abstinence that persist after the acute withdrawal syndrome subsides. Metabolic changes have been reported during an even later stage of protracted abstinence, in which the direction of the changes is opposite of the acute signs of abstinence (for example, hypothermia instead of hyperthermia, miosis [pupil constriction] instead of mydriasis, hypotension instead of hypertension, etc.). This protracted abstinence state also has a motivational component, with individuals reporting a “gray” mood state in which few stimuli or activities produce pleasure:

“It’s staying off that is the hard part. It takes a lot of willpower. But seeing smack eats away at your willpower; it makes it very hard. When I stop I just feel vacant with no direction or energy and that lasts for months.”

(Stewart T. The Heroin Users. Pandora, London, 1987, p. 166.)

Table 5.4

Abstinence Signs in Sequential Appearance after Last Dose of Narcotic

na, not applicable.

[Modified with permission from Blachly PH. Management of the opiate abstinence syndrome. American Journal of Psychiatry, 1966, (122), 742–744.]

Other opioid drugs show qualitatively similar opioid withdrawal effects that vary in duration and intensity, depending on pharmacokinetics. Methadone is a well-known, long-acting opioid that is used as a replacement for heroin in users who are attempting to quit. Methadone withdrawal, even after large doses, is slower to develop than heroin withdrawal and is less intense and more prolonged. Few or no withdrawal symptoms are observed for almost two days, and peak withdrawal intensity is reached on about the sixth day. In contrast, the meperidine (Demerol) withdrawal syndrome usually develops quickly, within three hours of the last dose, reaches a peak within 8–12 h, and then decreases. These differences in the time course and intensity of opioid withdrawal with different opioids reflect the general principle that long-acting drugs produce a withdrawal syndrome with a longer onset, longer duration, and less intensity compared to short-acting opioids (Table 5.5).

Table 5.5

Time Course of Withdrawal from Various Narcotic Agents

Purposive symptoms are goal-oriented, highly dependent on the observer and environment, and directed at getting more drugs.

Non-purposive symptoms are not goal-oriented, are relatively independent of the observer and of the patient’s will and the environment.

The purposive phenomena, including complaints, pleas, demands, and manipulations, and symptom mimicking are as varied as the psychodynamics, psychopathology, and imagination of the drug-dependent person. In a hospital setting, these phenomena are considerably less pronounced when the patient becomes aware that this behavior will not affect the decision to give him a drug.

[Taken with permission from Kleber H. Detoxification from narcotics. In: Lowinson JH, Ruiz P (eds.) Substance Abuse: Clinical Problems and Perspectives. Williams and Wilkins, Baltimore, 1981, 317–338.]

Stimuli paired with opioid withdrawal or opioids themselves can have motivational significance by eliciting drug taking or alleviating withdrawal, respectively (Table 5.6). Environmental stimuli can be conditioned both to the acute reinforcing effects of opioids and the withdrawal associated with opioids, and both have been suggested to contribute to craving. These phenomena may contribute to the maintenance and relapse associated with opioid addiction. In humans, stimuli paired with a morphine injection have also been shown to alleviate withdrawal:

Table 5.6

Conditioned Positive and Negative Reinforcement

“Further evidence that the picture of withdrawal symptoms has its basis in an emotional state is the response on the part of one of our addicts at the end of a 36 hour withdrawal period to the hypodermic injection of sterile water. Despite his obvious suffering, he immediately went to sleep and slept for eight hours. Addicts frequently speak about the ‘needle habit,’ in which the single prick of the needle brings about relief. It is not uncommon for one addict to give another a hypodermic injection of sterile water and the recipient to derive a ‘kick’ and become quiet. On the other hand, it has been our experience just as frequently to have the addict know that he was given a hypodermic injection of sterile water and to have him fail to respond to its effect. Paradoxical as it may seem, we believe that the greater the craving of the addict and the severity of the withdrawal symptoms, the better are the chances of substituting a hypodermic injection of sterile water to obtain temporary relief.”

(Light AB, Torrance EG. Opium addiction: VI. The effects of abrupt withdrawal followed by readministration of morphine in human addicts, with special reference to the composition of the blood, the circulation and the metabolism. Archives of Internal Medicine, 1929, (44) 1–16.)

Later studies of this phenomenon described these individuals as “needle freaks.” At least part of the relief and pleasure they experienced from injecting the drug resulted from a conditioned positive response to the heroin injection procedure. In an experimental laboratory setting under double-blind conditions, subjects were administered an opioid antagonist and then allowed to self-administer vehicle or an opioid. All of the self-injections were rated as pleasurable at first. After three to five injections, the subjects reported neutral effects.

In contrast, conditioned withdrawal can be observed in humans, setting up a condition of negative reinforcement (see Table 5.6). A physician described the experience of an individual with opioid addiction upon returning to an environment where he had previously experienced opioid withdrawal:

“For example, one patient who was slowly detoxified after methadone maintenance went to visit relatives in Los Angeles after receiving his last dose. Since he knew that he would be away from the clinic in Philadelphia for three weeks, he saved one take-home bottle of methadone in case he got sick while in California. To his surprise, he felt no sickness while in this new environment and never even thought about the bottle of methadone in his suitcase. He felt healthy over the three-week, drug-free period, but as soon as he arrived in the Philadelphia airport, he began to experience craving. By the time he reached his home, there was yawning and tearing. He immediately took the methadone he had been saving and felt relieved, but the symptoms re-occurred the next day. After three weeks of being symptom-free in Los Angeles, he experienced regular withdrawal in Philadelphia.”

(O’Brien CP, Ehrman RN, Ternes JM. Classical conditioning in human opioid dependence. In: Goldberg SR, Stolerman IP (eds.) Behavioral Analysis of Drug Dependence. Academic Press, Orlando FL, 1986, pp. 329–356.)

Conditioned withdrawal has been experimentally induced in the laboratory. Methadone-maintained volunteers were subjected to repeated episodes of opioid withdrawal induced by a very small dose of the opioid receptor antagonist naloxone associated with a tone and peppermint smell in a specific environment. Naloxone administration alone elicited tearing, rhinorrhea, yawning, decreased skin temperature, increased respiratory rate, and subjective feelings of drug sickness and craving. After repeated pairings of naloxone with the peppermint smell, a simple injection of physiological saline accompanied by the peppermint smell and tone also elicited reliable signs and symptoms of opioid withdrawal that were similar to precipitated withdrawal, although the symptoms were less severe.

Thus, “needle freak” behavior is an excellent example of conditioned positive reinforcement, and “conditioned withdrawal” is an excellent example of conditioned negative reinforcement (see Table 5.6).

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