Opioid analgesic effects

Hylden, J. L., Thomas, D. A., Iadarola, M. J., Nahin, R. L., and Dubner, R. (1991). Spinal opioid analgesic effects are enhanced in a model of unilateral inflammation/hyperalgesia Possible involvement of noradrenergic mechanisms. Eur. J. Pharmacol. 194, 135—143. 

Inoue M, Nakayamada H, Tokuyama S, Ueda H (1997) Peripheral non-opioid analgesic effects of kyotorphin in mice. Neurosd Lett 236 60-62... 

Divalent nations appear to be involved in the pain pathway and magnesium sulfate ean potentiate the opioid analgesic effect, possibly by antagonism of A -methyl-D-aspartate receptor ion channels. It has been suggested that as magnesium ions do not easily cross the blood brain bar-... 

The addition of morphine and fentanyl to intrathecal and epidurally administered local anesthetics decreases local anesthetic dose requirements while reducing surgical and post-operative pain intensity. One exception is chloroprocaine, which may antagonize epidural opioid analgesic effects. 

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Morphine and its derivatives continue to be considered the gold standard for alleviating pain. Morphine is metabolized in the liver via N-dealkylation and glu-coronidation at the third (M3G) or sixth position (M6G). Although M3G are the most common metabolites (accounts for 50% of the metabolites produced), they elicit no biological activity when bound to MOR. It is the M6G metabolite (accounts for 10% of the metabohtes produced) that elicits the nociceptive/analgesic effect upon binding to the p opioid receptor (Dahan et al. 2008). M6G is predominately eliminated via renal excretion. 

Influencing the efficacy or potency of chemicals is a strategy used by the pharmaceutical industry as part of the drug discovery process that can be incorporated into designing safer industrial chemicals. Efficacy is the maximal effect, either therapeutic or toxic, that a chemical can achieve. Potency is a measure of the amount of a substance that is needed to attain a given response level. Opioid analgesics are examples of where structural modifications have been used to establish a relationship between structure and activity. ... 

Few studies have explored the efficacy of opioids specifically for OA. The APS recommends against the use of codeine and propoxyphene for OA because of the high incidence of adverse effects and limited analgesic effectiveness. Oxycodone is the most extensively studied of the agents recommended for OA. However, other narcotic analgesics such as morphine, hydromorphone, methadone, and transdermal fentanyl are also effective. 

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 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-... 

Schiller PW, Fundytus ME, Merovitz L, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN, Coderre TJ. The opioid p agonist/6 antagonist DIPP-NH2 i 1 produces a potent analgesic effect, no physical dependence and less tolerance than morphine in rats. J Med Chem 1999 42 3520-3526. 

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