Opioid agonists interact with receptors in the brain and in the spinal cord. The initial binding of opioids in the brain causes the release of the inhibitory neurotrans-mitter serotonin, which in turn induces inhibition of the dorsal horn neurons. Both the brain and the spinal cord are required for the production of a maximal analgesic effect following systemic administration of opioids, although analgesia can be elicited by spinal administra-tion only. In the spinal cord, morphine inhibits the release of most nociceptive peptides. Morphine also affects descending noradrenergic pathways. Norepi-nephrine release in response to opioid administration results in an analgesic effect at the spinal level.
Opioids have profound effects upon the cerebrocor-tical regions that control the somatosensory and dis-criminative aspects of pain. Thus, the opioids suppress the perception of pain by eliminating or altering the emo-tional aspects of pain and inducing euphoria and sleep with higher doses. Patients become inattentive to the painful stimuli, less anxious, and more relaxed. Disruption of normal REM sleep occurs with opioid ad-ministration. In addition, opioids depress polysynaptic responses but can increase monosynaptic responses and lead to convulsant effects in high doses. In patients with chronic pain, the euphoric effect of opioids, mediated by the μ-receptor, is usually blunted. Some patients feel a dysphoric effect upon the administration of opioids, which is most likely mediated by the σ-receptor.
Opioids depress respiration via the μ2-receptor at the level of the medulla and thereby increase PCO2. Opioids reduce respiration, an effect that is fatal in the case of overdose, by a dual action. The opioids decrease both the sensitivity of the medulla to carbon dioxide concentra-tions and the respiratory rate. Cardiovascular function and the response to hypoxia are not compromised. By contrast, tolerance to the respiratory depressant effects of the opioids does not appear to occur, while tolerance to the emetic effects of the opioids occurs upon repeated administration. The area postrema chemoreceptor trig-ger zone of the medulla mediates opioid-induced vom-iting.
Miosis, or the pinpoint pupillary response to the opi-oids, is diagnostic of the use and abuse of the opioids. No tolerance to such an effect is observed. Miosis is due to disinhibition of the Edinger-Westphal nucleus in the cortex resulting in increased pupillary constrictor tone.
The opioids have pronounced effects on the release of hormones from both the pituitary and the hypothala-mus. Stimulation of some of the opioid receptors in hy-pothalamic nuclei decrease the release of dopamine, thus increasing release of prolactin. Opioids bind in the supraoptic nuclei of the hypothalamus and increase the release of antidiuretic hormone (vasopressin).
Morphine and most other opioids produce some degree of constipation by increasing sphincter tone and de-creasing gastric motility. Such an effect is uncomfort-able for patients required to take opioids chronically. Tolerance to the constipative effects of the opioids does not generally occur. In addition, the decrease in gastric motility increases gastric emptying time and reduces absorption of other drugs. The constriction of sphinc-ters, especially the bile duct, may result in increased pain in certain patients with biliary colic or other GI distress. Constriction of the urinary sphincter can lead to painful urine retention in some patients. The effects of opioids on the GI tract are largely mediated by the parasympathetic release of acetylcholine. All of the opi-oid receptors have been shown to mediate such GI ef-fects.
Opioids induce the release of histamine, which leads to the itching sensation associated with use and abuse of opioids. Bronchiolar constriction is possible. Opioids are also immunosuppressive, having effects on the T-helper and T-suppressor cells.
The opioids block cough by a mechanism that is not yet understood. No stereoselectivity of the opioids for blockade of the cough reflex has been shown. Thus, the isomers of opioids, such as dextrorphan, are as effica-cious as the L-isomers as antitussives. This lack of stere-oselectivity prompted the development of the D-isomers of opioids as antitussives since they are devoid of the de-pendence liability of L-isomers
All of the opioid agonists produce some degree of tol-erance and physical dependence. The biochemical mechanisms underlying tolerance and physical depend-ence are unclear. It is known, however, that intracellular mechanisms of tolerance to opioids include increases in calcium levels in the cells, increased production of cAMP, decreased potassium efflux, alterations in the phosphorylation of intracellular and intranuclear pro-teins, and the resultant return to normal levels of re-lease of most neurotransmitters and neuromodulators. Tolerance to the analgesic effects of opioids occurs rap-idly, especially when large doses of the drugs are used at short intervals. However, tolerance to the respiratory depressant and emetic effects of the opioids occurs more slowly. The miotic and constipative effects of the opioids rarely show tolerance.
Tolerance to one opioid usually renders a patient cross-tolerant to other opioids but not to drugs of other classes. Within the opioid class of drugs, certain drugs with high intrinsic activity (e.g., fentanyl) appear to lack cross-tolerance to opioids of lower intrinsic activity (e.g., morphine), an effect thought to be related to the change in receptor number induced by the chronic opi-oid administration. Theoretically, a drug with high in-trinsic activity would need to occupy fewer receptors to exert an effect and would be less affected by changes in receptor number, which occurs upon chronic adminis-tration of drugs with lower intrinsic activity.
The cessation of opioid drug administration leads to an observable abstinence syndrome. In the case of the opioids, signs of withdrawal include chills, fever, sweat-ing, yawning, vomiting, diarrhea, nausea, dizziness, and hypertension. The onset of symptoms occurs 6 to 12 hours after the last drug dose (depending on the kinet-ics of the drug) and continues for several days, with most of the signs of withdrawal ending by 72 hours af-ter the last dose of the drug. However, signs of with-drawal, including restlessness, anxiety, and drug craving, may be detectable for 6 months to 1 year after cessation of drug use.
In general, the effects observed upon withdrawal from a drug are opposite to those observed when the person is taking the drug, and such is the case with the opioids. The degree of dependence is generally reflected by the severity of withdrawal signs. In addition, drugs with long half-lives, such as methadone, produce a grad-ual and prolonged withdrawal. The use of methadone replacement for heroin is based upon the pharmacoki-netics of methadone. The longer onset and duration of action and the oral bioavailability render the drug use-ful for the treatment of opioid addiction by decreasing the rapid highs and lows associated with fast-onset, short-duration drugs such as heroin. Drugs with a short duration of action produce a more rapid onset of with-drawal signs.
A derivative of methadone, L- -acetyl-methadol (LAAM) has been approved for the treatment of opi-oid addiction. In some addicts whose degree of toler-ance is not known, the patient is first given methadone to stabilize the withdrawal signs and is then switched to LAAM. LAAM has an advantage over methadone in that it has a longer duration of action. Dosing is re-quired only three times per week in most addicts to pre-vent withdrawal.
Babies born to opioid-addicted women also exhibit withdrawal signs, but because of the slower metabolism of opioids in the newborn, the withdrawal signs are more protracted. The babies are often treated with the opium preparation paregoric to reduce withdrawal signs.