Gastrointestinal System

16 May

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.

Histamine Release

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

Tolerance

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.

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