Other Side Effects Constipation. The most common side effect of long-term narcotic analgesia is constipation plus other gastrointestinal (GI) effects collectively referred to as opioid bowel dysfunction. The frequency of these side effects is very high [40-50% or more in patients receiving opioids (34-36)] and can become the limiting factor in opioid use. These effects are mediated predominantly by jit receptors in the bowel (23).The effects begin with delayed food digestion in the small intestine and decrease in peristaltic waves in the large intestine, resulting in the retention of bowel contents. This is compounded by the enhanced tone of the anal sphincter and the reduction of the reflex relaxation in response to rectal distension. Tolerance does not usually develop to this side effect, and the patient on long-term opioid therapy remains chronically constipated.

Patients are generally started prophylacti-cally on a regimen including a laxative such as bisacodyl or senna that increases bowel motility plus a stool softener like docusate (20, 22). In patients refractory to laxatives, oral naloxone (22) has been successfully used as a therapeutic alternative for constipation without loss of analgesia (37). Because of its central activity, however, higher doses of naloxone can decrease the analgesic effectiveness of the opiate and precipitate opioid withdrawal in some patients (37). Peripherally selective antagonists offer the advantage of reversing the gastrointestinal and other peripheral side effects of narcotic analgesics without the potential for decreasing their central analgesic activity. Two peripherally selective antagonists, the quaternary derivative of naltrexone N-methylnaltrexone bromide (methylnaltrex-one, see Section 5.3.1) and the phenylpipei;i-dine alvimopan (ADL 8-2698, LY246736; see Section 5.7.1), are undergoing clinical trials for opioid-induced constipation (34-36, 38). After both i.v. and oral administration meth-ylnaltrexone reverses the opioid-induced delay in GI transit (34-36) and is effective in individuals receiving chronic opioid treatment (methadone users) as well as in healthy volunteers (34, 36). In clinical trials oral alvimopan reverses the delay in GI transit after the administration of exogenous opioids to both opi-oid naive individuals and patients receiving chronic opioid treatment (both pain patients and individuals taking methadone for opioid addiction) (38, 39); in addition it has been shown to speed the recovery of bowel function after abdominal surgery (40).

The constipating effect of orally administered opiates can be used for the treatment of diarrhea, as with camphorated tincture of opium (Paregoric or Parepectolin, which is a paragoric plus kaolin as an adsorbent and pec tin as a demulcent) (24). Two phenylpiperi-dine derivatives are used solely as antidiar-rheal agents. Diphenoxylate, which is a congener of meperidine, is available only in combination with atropine, which has anti-spasmodic activity in the intestine. At therapeutic doses diphenoxylate does not show any central nervous system (CNS) effects, but at high doses it displays the typical opioid profile including euphoria. The carboxylic acid metabolite, difenoxylic acid (Motofen; Table 7.1) has activity similar to that of the parent (23). Unlike diphenoxylate, the second opioid used for diarrhea, loperamide, does not exhibit pleasurable CNS effects even at large doses (23) ¡loperamide is a substrate for P-glycopro-tein in the blood-brain barrier, which excludes this drug from the CNS (41, 42). Itching. After administration of opioids there may be urticaria at the injection site or generalized itching because of degranulation of mast cells, resulting in histamine release. The itching is a common side effect and often one that results in severe patient distress (23). The histamine release may also be partially responsible for the pruritus and sweating after drug administration as well as flushing resulting from blood vessel dilation of the skin (23). Antihistamines may be used to combat the discomfort (20) or patients can be switched to either fentanyl or oxymorphone which do not tend to cause histamine release. Opioid antagonists such as naloxone are effective in controlling the pruritus and can be used at low doses without loss of pain control (34, 44); the peripherally selective antagonist methylnaltrexone exhibits antipruritic efficacy without the potential to reverse morphine analgesia (45).

2.2.3 Contraindications. Contraindications include hypersensitivity to opioids, head trauma or increased intracranial pressure, severe respiratory depression or compromised respiratory function, and potentially, liver or renal insufficiency (46). Whether morphine or other opioids are used depends on the severity of the contraindication, and the potential benefits must be weighed relative to the risk. Ana-phylactoid reactions have been reported after morphine or codeine administered i.v., although the reactions are rare (23). Morphine may induce or exacerbate asthmatic attacks; hence, fentanyl may be a better choice in asthmatic patients (23).Other relative contraindications to the use of narcotics also exist with respect to the potential for drug abuse (17). Although a history of substance abuse does not definitely preclude the use of opioids, it does necessitate careful vigilance. If the episode of abuse is active or recent, then another pain management strategy may be prudent. Consideration of the social network also requires consideration, especially if the patient lives with a substance abuser or has a home life conducive to enabling abuse.

2.2.4 Drug Interactions. The pharmacological activity of opioids can be affected by a number of other drugs, including amphetamines, antihistamines, antidepressants, and antipsychotics (see Ref. 23). Small doses of amphetamine significantly enhance the analgesic activity and euphoric effects of morphine and may counteract sedation. Diphenhydramine and hydroxyzine are antihistamines that exhibit modest analgesic activity themselves, and hydroxyzine has been shown to enhance the analgesic effects of low doses of narcotic analgesics (47).The depressant effects of some opioids may be exaggerated and prolonged by monoamine oxidase inhibitors, tricyclic anti-depressants, and phenothiazines; the exact mechanism of action is not fully understood, but may involve metabolic or neurotransmit-ter alteration (23). The antidepressants des-ipramine (48) and nefazodone (49) appear to enhance morphine-induced analgesia. The phenothiazine antipsychotics can potentiate the analgesic effect of opioids, but also increase respiratory depression and sedation (23). Interactions with Cytochrome P450 Enzymes. Drug interactions with opioid analgesics can also result from their interaction with cyctochrome P450 (CYP) isozymes, specifically 3A4 and 2D6 (Table 7.5) (50).

The CYP3A4 isozyme is responsible for the metabolism of a large number of endogenous compounds as well as a wide range of drugs (50). Fentanyl, alfentanil, and sufentanil are substrates for CYP3A4, and therefore drugs that inhibit this enzyme, such as erythromycin, HIV protease inhibitors, or cimetidine,

Table 7.5 Cytochrome P450 Isozymes and Opioid Substrates and Inhibitors
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