Morphine constipation

Morphine and its salts are very valuable analgesic drugs but are highly addictive. In addition to suppression of pain, morphine causes constipation, decreases pupillary size and depresses respiration. Only the (-l-)-stereoisoraer is biologically active. They appear to produce their effects on the brain by activating neuronal mechanisms normally activated by... 

Morphine has certain undesirable side effects. Among these are respiratory depression, nausea, and vomiting, depression of the cough reflex, cardiovascular depression and hypotension, smooth muscle contraction (constipation), and histamine release (93). Morphine s onset of action, duration, and low therapeutic indices have prompted a search for a more effective opiate iv anesthetic. Extreme simplification of the complex morphine molecule has resulted in anilido —piperidines, the fentanyl class of extremely potent opiate iv anesthetics (118,119). 

A not uncommon side effect observed with morphine and some of the other narcotic analgesics is constipation due to decreased motility of the gastrointestinal tract. It proved possible to so modify pethidine as to retain the side effect at the expense of analgesic activity. Relief of diarrhea, it will be realized, is a far from trivial indication. Alkylation of the anion from diphenylacetonitrile (95) with ethylene dibromide gives the intermediate, 96. Alkylation of normeperidine (81) with that halide... 

There are a number of side-effects of opiates that are due to their actions on opiate receptors outside the central nervous system. Opiates constrict the pupils by acting on the oculomotor nucleus and cause constipation by activating a maintained contraction of the smooth muscle of the gut which reduces motility. This diminished propulsion coupled with opiates reducing secretion in the gut underlie the anti-diarrhoeal effect. Opiates contract sphincters throughout the gastrointestinal tract. Although these effects are predominantly peripheral in origin there are central contributions as well. Morphine can also release histamine from mast cells and this can produce irritation and broncho-spasm in extreme cases. Opiates have minimal cardiovascular effects at therapeutic doses. 

The history of this class of analgesics might have stopped there were it not for the manifold ancillary activities shown by that molecule. Although still one of the most widely used agents for treatment of severe pain, morphine is a drug that must be used with caution. Side effects include respiratory depression, induction of constipation, and sometimes marked sedation. The one property that most severely limits use of this drug is its propensity to induce physical dependence in patients subjected to more than casual exposure. 

It will be recalled that a common side effect of morphine is the induction of constipation. This property of the drug has often been exploited in the design of preparations used to control diarrhea. 

Opium and its derivatives have been employed for centuries for the treatment of pain. Morphine was first synthesized in 1805 and has proven to be one of the most effective analgesic agents available [1], Morphine and its analogs are particularly useful because they diminish pain sensation while maintaining consciousness. However, opiates induce severe side-effects including respiratory depression, nausea, bradycardia and constipation and long-term use of opiates can cause addiction [2]. 

Morphine can cause constipation, spasms of the sphincter of Oddi, urinary retention, and pruritus (secondary to histamine release) (see Table 54-4). In head trauma patients who are not ventilated, morphine-induced respiratory depression can increase intracranial pressure and cloud the neurologic examination results. 

Figure 1 Effects of tegaserod in a constipation model in conscious dogs. Tegaserod normalizes stool frequency, stool quantity and softens stool consistency. Mean SEM (n — 8) p < 0.05 versus Vehicle ftp < 0.05 versus Morphine. From Weber et al., Gastroenterology (2003), 124 A1806 (Please see Color Plate Section in the back of this book).

Meperidine (Figure 7.4) was introduced in the 1930s as an alternative to morphine for relieving pain. Its advantage over morphine was that its duration of action was shorter and it had fewer unwanted side effects such as sedation and constipation. 

It is now widely accepted that there are at least three opioid receptor sub-types, mu kappa and delta. During the last decade increasing evidence has accumulated to support the hypothesis that a selective kappa opioid agonist will be a powerful analgesic without the clinically limiting side-effects that characterise morphine (e.g., respiratory depression, constipation, addiction)... 

Consequently the opioid drugs (e.g. codeine, morphine), which are normally used to control pain, can cause constipation. 

Bisacodyl is a stimulant laxative that does not take long to act and is therefore useful in acute constipation. The bulk-forming laxative ispaghula husk takes longer to act when compared with bisacodyl but is useful for long-term administration. Lactulose, which is an osmotic laxative, has a lag time of about 48 hours before onset of action. Loperamide and kaolin and morphine mixture are antidiarrhoeals used in acute diarrhoea. 

Peripheral effects concern the motility and tonus of gastrointestinai smooth muscie segmentation is enhanced, but propulsive peristalsis is inhibited. The tonus of sphincter muscles is raised markedly. In this fashion, morphine elicits the picture of spastic constipation. The antidiarrheic effect is used therapeutically (ioperamide, p. 

When the oral route is unavailable opioids may be administered by continuous infusion (pump) and when appropriate under control by the patient - advantage constant therapeutic plasma level disadvantage indwelling catheter. When constipation becomes intolerable morphin can be applied near the spinal cord permitting strong analgesic effect at much lower total dosage. 

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