Opioid antitussive effects

Opioids ( opioid systems) are thought to exert their antitussive effects by acting as agonists at p- and K-opioid receptors in the CNS. Activation of these receptors activates various G-proteins and leads to the inhibition of... 

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 efficacious as the L-isomers as antitussives. This lack of stereoselectivity prompted the development of the D-isomers of opioids as antitussives since they are devoid of the dependence liability of h-isomers. Drugs with predominantly antitussive effects are described later in this chapter. Certain of the opioids, such as propoxyphene and meperidine, are relatively devoid of antitussive effects. 

Like morphine, codeine is a naturally occurring opioid found in the poppy plant. Codeine is indicated for the treatment of mild to moderate pain and for its antitussive effects. It is widely used as an opioid antitussive because at antitussive doses it has few side effects and has excellent oral bioavailability. Codeine is metabolized in part to morphine, which is believed to account for its analgesic effect It is one of the most commonly used opioids in combination with nonopioids for the relief of pain. The administration of 30 mg of codeine in combination with aspirin is equivalent in analgesic effect to the administration of 65 mg of codeine. The combination of the drugs has the advantage of reducing the... 

Certain opioids are used mainly for their antitussive effects. Such drugs generally are those with substituents on the phenolic hydroxyl group of the morphine structure. The larger the substituent, the greater the antitussive versus analgesic selectively of the drugs. 

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... 

The opioid analgesics are among the most effective drugs available for the suppression of cough. This effect is often achieved at doses below those necessary to produce analgesia. The receptors involved in the antitussive effect appear to differ from those associated with the other actions of opioids. For example, the antitussive effect is also produced by stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability (see below). 

The physiologic mechanism of cough is complex, and little is known about the specific mechanism of action of the opioid antitussive drugs. It appears likely that both central and peripheral effects play a role. 

In addition to their use as pharmacological tools, selective 8 opioid antagonists may have clinical potential in the treatment of a variety of disorders where endogenous opioids play a modulatory role, e.g. disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, drug addiction and immune function (Spetea et al., 2001). It is also worth mentioning that 8 antagonists have been shown to possess an antitussive effects in rodents, thus indicating another possible clinical application for these compounds (Kamei et al., 1994). 

Kamei, J., Iwamaoto, Y., Suzuki, T., et al. Involvement of 8-,-opioid receptor antagonism in the antitussive effect of S-opioid receptor antagonists, Eur. J. Pharmacol. 1994, 257, 291-294. 

Aside from the demonstrated antinociceptive effect produced by agonist interactions at 8 receptors [174], NTI has been employed to demonstrate that 8 opioid receptors are involved in the antinociceptive effects of cholecys-tokinin octapeptide in mice [183] and in swim stress-induced antinociception in adult rats [184, 185]. NTI was found to produce a marked and long-lasting antitussive effect in mice and rats which was not antagonized by the irreversible n antagonist /i-FNA [186],... 

Opioid agonists also have an antitussive effect attributed to the depression of the cough reflex. Thus some opioids, typically codeine or one of its derivatives, are used for their antitussive activity, predominantly in combination products. The antitussive effect is in part the result of the interaction with opioid receptors at the cough center in the brain (23). The dose required for antitussive activity, however, is lower than that required for analgesia the opioid receptors involved in blocking the cough reflex are less sensitive to naloxone than those responsible for analgesia (23). 

The major pharmacological actions of methadone, mediated by fi- and 6-receptor interactions, are similar to those of other opioids and include analgesia, sedation, respiratory depression, miosis, antitussive effects, and constipation. Methadone is administered as a racemic mixture (R,S- [ ] -methadone), but the analgesic activity is due almost entirely to the R(-)-isomer. When administered intramuscularly, methadone and morphine have equivalent analgesic potency. In contrast to morphine, methadone retains about 50% of its intramuscular analgesic potency when taken orally. ... 

TRK-851 is a clinical candidate for an antitussive drug it has a novel, complex morphinan ring system. The development of TRK-851 was motivated by the finding that NTI, a selective 8 opioid receptor antagonist, showed antitussive effect. In this section we will describe the process of developing TRK-851, including the structure-activity relationship (SAR) studies on NTI derivatives and the difficulties encountered in overcoming a defect in the metabolism of a prototype clinical candidate, TRK-850. 

It was recently recognized that opioid receptor agonists have antitussive effects [31]. Morphine (Fig. 7) is a potent p opioid receptor agonist that exhibits marked antitussive effect, and it has been used for the treatment of severe coughs. Codeine (Fig. 7) is one of the most reliable centrally acting antitussive agents its antitussive... 

Fig. 7 Structures of opioid receptor ligands that have antitussive effects (agonists morphine, codeine, U-50,488H antagonists NTI), 8 opioid agonist DPDPE, and k opioid antagonist nor-BNI...

T able 2 Different opioid Opioid ligand (s) Antitussive effect... 

The effects of k and 8 opioid receptor activation on the cough reflex have been particularly investigated by Kamei and coworkers. They showed that U-50,488H (Fig. 7), a selective k opioid receptor agonist, suppressed the cough reflex induced by capsaicin inhalation in rats. This antitussive effect was blocked by coadministration of the k receptor antagonist, nor-BNI (Fig. 7). This suggested that the k opioid receptor had mediated the antitussive effects (Table 2) [33],... 

Figure 8 shows the mechanism proposed for the antitussive effect of NTI [36]. When the respiratory tract is stimulated by irritants, e.g., xenobiotics, the cough reflex occurs, and the stress of coughing triggers the secretion of endogenous opioid peptides, which may simultaneously stimulate three types of opioid receptors. In a disease state, the stimulation of the 8 opioid receptor could block the p and k opioid receptor-mediated suppression of the cough reflex, which would result in continual coughing (Fig. 8a). When a selective 8 opioid antagonist, e.g., NTI, is administered,...

Fig. 8 Possible mechanism of the antitussive effect caused by 5 opioid receptor antagonists. Solid arrows indicate activated pathways dotted lines indicate inactivated pathways...

The opioid receptor selectivity of TRK-851 was tested in the MVD assay (Table 9). TRK-851 strongly antagonized the agonist activity of DPDPE (8), and it showed over 200 times greater selectivity for the 5 opioid receptor than for p or k receptors. These results strongly suggested that the antitussive effect of TRK-851 was derived from its marked antagonism of 5 opioid receptors [6]. 

Kamei J, Iwamoto Y, Suzuki T, Misawa M, Nagase H, Kasuya Y (1993) Antitussive effects of naltrindole, a selective delta-opioid receptor antagonist, in mice and rats. Eur J Pharmacol 249 161-165... 

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