Opioids can seriously disturb gastrointestinal function. Opioid receptors are found throughout the enteric nervous system in the nervous plexus of the bowel, in the sacral plexus, along the biliary tree, and in ureters and blad- der. Opioids stimulate tonic contraction of smooth muscle at all of these sites, while reducing normal propulsive activity. This can be a source of signiﬁcant morbidity: Inhibition of normal intestinal secretions and peri- stalsis can lead to increased water absorption and constipation. Very lit- tle tolerance develops to this effect, so patients taking opioids chronically can develop severe ongoing constipation. This is a very common problem in cancer patients. The inhibitory effect of opioids on peristalsis is medi- ated by the enteric nerve pathway and by the blockade of presynaptic re- lease of acetylcholine (De Luca and Coupar 1996). Besides inhibiting peri- stalsis, opioids contract intestinal muscles and induce tonic spasms in the intestine. These effects may involve depression of nitric oxide release from inhibitory enteric neurons or direct activation of smooth muscle cells that express opioid receptors (Townsend et al. 2004). Opioid-induced bowel dys- function can be prevented by selectively targeting intestinal opioid receptors with orally administered opioid receptor antagonists (Holzner 2004). A new μ-receptor selective antagonist with a peripherally restricted site of action was developed recently (Schmidt 2001). This compound (alvimopan) is charac- terized by low systemic absorption and it prevents morphine-induced delays in oral-cecal transit time without antagonizing centrally mediated opioid ef- fects. Alvimopan was found to improve the management of postoperative ileus in patients who underwent abdominal surgery and received opioids for acute postoperative pain (Taguchi et al. 2001). Opioid stimulation of smooth muscles along the gall bladder and cystic duct and opioid-induced contrac- tion of the sphincter of Oddi may increase intrabiliary pressure and lead to episodes of biliary colic and false positive cholangiograms. These effects can be completely reversed by naloxone. In addition, opioids can cause uri- nary retention by decreasing bladder detrusor tone and increasing tone in the urinary sphincter. They also decrease awareness of bladder distension and inhibit the reﬂex urge to void. This complication is more common in males and more likely to occur when opioids are given by epidural or intrathecal injection.
Like many other low molecular weight basic drugs, morphine, codeine, and meperidine can cause displacement of histamine from tissue mast cells, result-
ing in several undesirable effects, such as hypotension, urticaria, pruritus, and tachycardia (Barke and Hough 1993). This is a nonimmunological response that is most often seen as local itching, redness, or hives near the site of i.v. injection. Although functional opiate receptors may exist on mast cells and may be capable of modulating IgE-mediated histamine release, there is no evidence that these receptors account for opiate-induced histamine release. Fentanyl and its congeners do not typically release histamine. Patients who have experienced hives and itching will frequently report that they are aller- gic to the drug, although true allergy to opioids is extremely rare. Itching may be produced by other mechanisms as well. Opioid receptor-dependent processes activate inhibitory circuits in the CNS and regulate the extent of intensity and quality of perceived itch (Greaves and Wall 1996). Opioids fre- quently cause itching and warmth over the neck and face, especially over the malar area. Epidural opioids can produce troublesome generalized itch- ing (Chaney 1995; Ballantyne et al. 1989). These dysesthesias appear to be opioid-speciﬁc effects since they can be reversed by naloxone and are pro- duced by opioids like fentanyl, which do not release histamine (Kjellberg and Tramer 2001).
Chronic Opioid Application
As discussed in Sect. 2.4.2, repeated or prolonged exposure to opioids can result in apparent tolerance, a phenomenon that can be due to opioid recep- tor alterations or to progressively increasing nociceptive stimulation. Cross- tolerance to other agonists can occur, but this cross-tolerance is often incom- plete. Tolerance usually develops most rapidly to opioid depressant effects like analgesia and respiratory depression and very slowly to stimulant effects like constipation or miosis. There is a striking difference between the pro- found degree of tolerance to the analgesic effect of opioids observed in animal models and the relative stability of opioid dose-response relationships in pa- tients with ongoing pain. Dose escalation is common in long-term opioid treatment for the management of cancer pain, but tumor growth could be the reason for this increase. Many clinical studies indicate that opioid tolerance is of minor relevance and develops less frequently in patients experiencing pain (Adriaensen et al. 2003). A survey of over 2,000 cancer patients showed that less than 50% had increased their daily morphine dose over 1 year of treatment (Zech et al. 1995). These differences between clinical and labora- tory investigations caution against generalization from the laboratory to the clinic.