Use, Abuse, and Addiction

Opioid Tolerance

Tolerance can be defined as a decreased response to a drug with repeated administration or the requirement for larger doses of a drug to produce the same effect. Tolerance develops to the analgesic, euphorigenic, sedative, and other central nervous system depressant effects of opioids. Tolerance also develops to the lethal effects of opioids. Individuals with opioid addiction can increase their intake to enormous doses, such as 2 g of morphine administered intravenously over a period of 2–3 h with no significant changes in blood pressure or heart rate. To put this in perspective, the lethal dose of morphine in a non-tolerant person is approximately 30 mg parenterally or 120 mg orally (a 20- to 70-times difference).

Opioid tolerance is also characterized by a shortening of the duration of action. The rate of tolerance development is dependent on not only the dose of the drug but also the pattern of use and setting. With doses in the therapeutic range and appropriate intermittent use, obtaining the desired analgesic effect for an indefinite period is possible. When the opioid is taken continuously, significant tolerance develops rapidly. Cross-tolerance between opioids also develops as long as the mechanism of action of the opioids occurs through the same opioid receptor subtype.

Tolerance can be both dramatic and differential. Subjects may become very tolerant to the lethal or respiratory depressant effects of opioids but still continue to show sedation, miosis, and constipation. Constipation can continue for up to 8 months with daily use in many methadone-maintained individuals. Insomnia is observed in 10–20% of patients, and excessive sweating is observed in 50% of patients.

Tolerance can derive from two mechanisms: dispositional and pharmacodynamic. Dispositional tolerance is the decreased response to a drug with repeated administration caused by a reduction of the amount of drug at its pharmacological site of action. Pharmacodynamic tolerance refers to changes in the response to a drug that result from neuroadaptive changes, excluding changes in drug disposition. Although some evidence indicates that drug metabolism may be enhanced in tolerant animals, most opioid tolerance is thought to have a pharmacodynamic basis.

Acute and chronic tolerance and acute and chronic withdrawal also have important associative bases. Drug administration produces disturbances in the body (largely via the brain to cause the drug’s psychotropic effects), and these disturbances can then elicit unconditioned responses that compensate for the perturbation produced by the drug. For example, individuals with opioid addiction are more likely to overdose in a novel context associated with obtaining a drug:

“[One example is] a case report of a patient, suffering with pancreatic cancer, who was receiving about four morphine injections in his home every day for pain relief. The patient stayed in his bedroom (which was dimly lit and contained apparatus necessary for his care), and received his injection in this environment. For some reason, after staying in this bedroom for about a month, the patient left his bed and went to the living room (which was brightly lit and different in many ways from the bedroom/sickroom). He was in considerable pain in the living room, and, as it was time for his next scheduled morphine administration, he was administered his usual dose of the drug. The patient quickly displayed signs of opiate overdose (constricted pupils, shallow breathing), and died a few hours later.”

(Siegel S, Elsworth DW. Pavlovian conditioning and death from apparent overdose of medically prescribed morphine: a case report. Bulletin of the Psychonomic Society, 1986, (24), 278–280.)

The unconditioned stimulus is the drug effect, and the unconditioned responses are responses that compensate for the drug effect. These compensatory responses are ultimately elicited by drug-associated cues in a Pavlovian conditioning process. Such conditioned compensatory responses are often opposite in direction to the unconditioned effects of a drug and can mediate tolerance in the presence of the drug and withdrawal in the absence of the drug. Pavlovian conditioning and learning in general contribute to the development of tolerance.

Conditioned compensatory responses are observed most clearly by presenting the pre-drug cues that have been paired with the effects of the drug in the absence of the drug. Opioids produce conditioned compensatory responses under such conditions, which can be studied in animal models. Rats are assigned to a paired or unpaired condition. For the paired animals, morphine injections are signaled by an audiovisual cue. Unpaired animals are exposed to the same cues and injections but in an unpaired manner. When subsequently tested in the presence of the cue, paired animals are more tolerant than unpaired animals. Conditioned compensatory responses produced in the absence of drugs are also reflected by conditioned withdrawal-like effects.

The role of associative mechanisms in opioid tolerance, withdrawal, and relapse impacts their neurobiological substrates, which has important practical implications for the treatment of opioid addiction. Opioid-tolerant patients or addicted individuals who administer drugs in a different context or via a different route of administration may be at risk of overdose because conditioned compensatory responses will not be triggered.

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