Central nervous system opioid effects

Severe pain should be treated with an opioid such as morphine, hydromorphone, methadone, or fentanyl. Moderate pain can be treated effectively in most cases with a weak opioid such as codeine or hydrocodone, usually in combination with acetaminophen. Meperidine should be avoided owing to its relatively short analgesic effect and its toxic metabolite, normeperidine. Normeperidine may accumulate with repeated dosing and can lead to central nervous system side effects including seizures. 

The opium alkaloids codeine and morphine served as models for the synthesis of naloxone, an important analog used to treat and diagnose opiate addicts, and also led to the discovery of endogenous opioids (enkephalins and endorphins) (see Chapter 47). Similarly, A9-tetrahydro-cannabinol (THC), the component of Cannabis sativa responsible for the central nervous system (CNS) effect, has also been found to reduce nausea associated with cancer chemotherapy (see Chapter 18). 

Acute toxicity induced by pentazocine is primarily associated with central nervous system (CNS) effects that include dizziness, anxiety, hallucinations, mood alterations, and seizures. Respiratory depression, increased PaCOi levels, pulmonary edema, and apnea may occur. Tachycardia, increased systolic and diastolic blood pressure, pinpoint pupils, nausea, vomiting, and abdominal pain have also been reported. In a recently published case series, 40% of acute pentazocine overdose patients did not have the classic opioid toxidrome of CNS and respiratory depression with miosis. 

A. Benzodiazepines will potentiate the central nervous system-depressant effects of opioids, ethanol, and other sedative-hypnotic and depressant drugs. 

Concurrent use of butorphanol with central nervous system depressants (e.g. alcohol, barbiturates, tranquilizers, and antihistamines) may result in increased central nervous system depressant effects. When used concurrently with such drugs, the dose of butorphanol should be the smallest effective dose and the frequency of dosing reduced as much as possible when administered concomitantly with drugs that potentiate the action of opioids. 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Another site of action for opioids is through the regulatory actions of the central nervous system (CNS) on the immune system. Substantial evidence supports the existence of a complex, bidirectional link between the CNS and the immune system (e.g., [65]). Experimental evidence indicates that morphine s immunomodulatory effects involve central opioid receptors. An initial study by Shavit and colleagues [12] found that systemic administration of morphine, but not N-methylmorphine (a form of morphine which does not readily penetrate the blood-brain barrier), produces a naltrexone-reversible suppression of splenic natural killer cell activity in the rat. That same study showed that intracerebroventricular (icv) administration of morphine dose-dependently suppresses... 

Fecho, K. et al., Assessment of the involvement of central nervous system and peripheral opioid receptors in the immunomodulatory effects of acute morphine treatment in rats, J. Pharmacol. Exp. Ther., 276, 626, 1996a. 

Codeine phosphate is still used for diarrhea predominantly based on hypermotility but the longer-acting loperamide is more convenient and has less central nervous system effects. Codeine has an exceptionally low affinity for opioid receptors and its effects are due to the fact that it is converted for approximately 10% to morphine. The active metabolite of morphine, morphine-6-glucuronide, may also accumulate during repeated administration of codeine to patients with impaired renal function. 

The behavioral effects of nicotine have been defined as both stimulant and depressant, effects that are influenced by the present mental status and expectations of the smoker. Smokers may feel alert and relaxed. Nicotine produces myriad effects on the central nervous system (CNS), almost all of which appear to be mediated through nicotinic receptors. Additionally, nicotine influences multiple neuronal systems. One of its most prominent effects is stimulated release of dopamine, particularly in the nucleus accumbens, which is a major component of the reward system. Nicotine also stimulates the release of endogenous opioids and glucocorticoids. 

Mechanism of Action An opioid agonist that binds at opiate receptor sites in central nervous system (CNS). Therapeutic Effect Reduced intensity of pain stimuli incoming from sensory nerve endings, alteringpain perception and emotional response to pain. Pharmacokinetics Rapidly absorbed. Protein binding 40%-50%. Extensively distributed. Metabolized in liver. Excreted in urine. Half-life 11 hr. 

Central nervous system depression is the usual effect of morphine, and sedation and drowsiness are frequently observed with therapeutic doses. When given in the absence of pain morphine may sometimes produce dysphora—an unpleasant sensation of fear and anxiety. The most important stimulatory effects of morphine in man are emesis and miosis. Miosis, due to stimulation of the Edinger-Westphal nucleus of the third nerve, occurs with all opioids. The combination of pinpoint pupils, coma, and respiratory depression are classical signs of morphine overdosage. Stimulation of the solitary nuclei may also be responsible for depression of the cough reflex (antitussive effect). Pharmacokinetics and metabolism... 

As previously noted, opioids have significant constipating effects (see Chapter 31). They increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption. They also decrease mass colonic movements and the gastrocolic reflex. Although all opioids have antidiarrheal effects, central nervous system effects and potential for addiction limit the usefulness of most. 

---