Analgesics endogenous opioids

Nalorphine and levallorphan are examples. For example in patients with postoperative pain the analgesic effects of 10 mg of nalorphine is about the same as 10 mg of morphine. On the other hand naloxone and naltrexone seem to have no agonistic activity and some antagonistic affinity for all types of opioid receptors. Although antagonists could be expected to have effects by altering the actions of endogenous opioid peptides mostly such effects are not discernable. 

A series of peptides, occurring naturally in brain and possessing pharmacological properties similar to those of morphine, have been described. At least three separate families of peptides have opioid properties (Table 24.2), and the different classes of peptides reside in separate distinct neurons. It is likely that the endogenous opioid peptides coexist in neurons with other nonopioid neurotransmitters. The initial hope that these endogenous agents or synthetic derivatives of them would be found to retain the analgesic activity of the opioids but be devoid of respiratory depression and/or addictive properties has now somewhat abated. 

Ketorolac (Toradol) is an NS AID with very mild antiinflammatory and antipyretic activity. It is a potent analgesic for postoperative pain. Its efficacy is equivalent to that of low doses of morphine in the control of pain. For this reason it is often combined with opioids to reduce opioid dose and related side effects while providing adequate pain relief. It is also used to replace the opioids in some patients with opioid sensitivity. The mechanism of action of ketorolac involves the inhibition of COX and decreased formation of prostaglandins. However, some evidence exists that ketorolac may stimulate the release of endogenous opioids as a part of its analgesic activity. 

There are two main hypotheses about the involvement of endogenous opioid systems in the maintenance of self-injurious behaviors (Sandman, 1988 Buitelaar, 1993). The pain hypothesis suggests that in some subjects self-injury does not induce pain because excessive basal activity of opioid systems in the CNS has led to an opioid analgesic state. The addiction hypothesis posits that particularly repetitive and stereotyped forms of self-injury stimulate the production and release of en-dogeneous opioids. Therefore, chronic maintenance of self-injury may be due to addiction to endogenous opioids or to positive reinforcement by a central release of opioids triggered by the self-injurious behavior. Irrespective of which hypothesis one favors, treatment with opiate antagonists seems to be a rational approach. 

Diclofenac, a derivative of phenylacetic acid, is equipotent as an inhibitor of COX-1 and COX-2. In addition to prostaglandin inhibition a central analgesic action of diclofenac mediated by endogenous opioid peptides has been demonstrated. It can be administered orally, intramuscularly or intravenously, and is effective as a postoperative analgesic in a dose of 75-150 mg. The risks of adverse gastrointestinal effects is moderate and diclofenac does not appear to increase blood loss during or after surgery. 

Opioid analgesics stimulate the release of ADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone. These effects suggest that endogenous opioid peptides, through effects in the hypothalamus, regulate these systems (Table 31-1). 

Endogenous opioid peptides. Extensive processing is also involved in formation of analgesic opioid peptides, which are present naturally in the brain (see also Section B). Tire formation of (1-endorphin in the hypothalamus from prepro-opiomelanocortin (Fig. 30-2) has already been mentioned. Prior to the discovery of P-endorphin, the pentapeptides Met-enkephalin and Leu-enkephalin (Table 30-4) were discovered and were found to compete with opiate drugs for receptors in the brain. Tire larger P-endorphin, which contains the Met-enkephalin sequence at its N terminus, is a far more potent opiate antagonist than are the enkephalins. Since the Met-enkephalin sequence within P-endorphin is not flanked by basic residues, it apparently is normally not released. Two other recently discovered brain peptides are endomorphin-1 (YPWF-NH2) and endomorphin-2 (YPFF-NH2). They are also potent agonists for the opioid receptors, especially the p receptor (see Section B,10).,61a,61b... 

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