INTRODUCTION
Cancer-related pain affects approximately 9 million people worldwide (Vanegas et al., 1998). As cancer progresses, an increasing fraction of patients require treatment with potent opioids, which may be administered via several routes. Opioid medication is frequently used in pain and palliative care patients with malignancy to manage symptoms such as pain and dyspnea. However, morphine and related opioids are associated with various side effects: constipation, nausea, vomiting, pruritis, urinary retention, and so forth. Constipation is a particularly problematic and common side effect of opioid pharmacology. Constipation affects 40%–50% of patients with metastatic malignancy receiving long-term opioids medications (Grond et al., 1994). Unlike other adverse effects of opioid therapy, which tend to resolve with continued therapy, tolerance to opioid-induced constipation (OIC) rarely develops.
The consequences of OIC are not only distressing but are often severe enough to be a dose-limiting side effect that can interfere with adequate pain control. In most cases the problem is managed with stool softeners and laxatives. However, in some patients, especially those requiring increasing doses, conventional management of constipation is insufficient and a significant number of patients receiving long-term opioid treatment would rather endure their pain than the severe, incapacitating constipation that opioids incur (Vanegas et al., 1998). Thus, OIC has a significant negative impact on quality of life in the population of chronic pain and palliative care patients as well as patients with advanced medical illness who are terminal patients.
The treatment of OIC is therefore crucial for optimal pain management. The class of opioid antagonists holds considerable promise in their applications for palliative care, especially in the management of OIC. All opioid antagonists currently approved in the United States for prescription use readily cross the blood–brain barrier. Systemic opioid antagonists such as naloxone, nalmefene, and naltrexone are all pure opioid antagonists that produce laxation in constipated individuals maintained with opioid agonists. These agents may exert their effect on local opioid receptors within the myenteric plexus of the gastrointestinal tract. Competitive antagonists of opioid receptors exert their effects inside and outside of the central nervous system. After systemic administration, they reverse both centrally and peripherally mediated opioid effects that may induce opioid withdrawal symptoms (Choi & Billings, 2002).
Opioid antagonists that do not readily cross the blood–brain barrier such as Alvimopan and Methylnaltrexone are currently under investigation for the treatment of OIC. Alvimopan is a selective opioid antagonist with extremely limited oral absorption and it has been shown to reverse OIC without antagonizing the analgesic effects of opioids (Taguchi et al., 2001). Methylnaltrexone (MNTX) is a peripheral opioid receptor antagonist that offers the potential to reverse the undesirable side effects of opioids without reversing analgesia or potentiating withdrawal. This review focuses on the undertreatment of OIC in palliative care and the use of peripheral opioid-receptor antagonists in reversing the adverse effects of opioids on the gastrointestinal (GI) system.
OPIOID-INDUCED BOWEL DYSFUNCTION
The cause of opioid-induced constipation is unclear. Morphine has been reported to act at supraspinal, spinal, and peripheral opioid receptors to inhibit GI transit (Greenwood-Van Meerveld et al., 2004). Results from previous studies suggest that morphine may act within the central nervous system to alter autonomic outflow to the gut (Kurz & Sessler, 2003). In addition, the three types of opiate receptors—mu, delta, and kappa—have been found throughout the GI system. Mu receptors predominate on the neurons of the submucosal plexus. Kappa receptors are present throughout the neurons of the myenteric plexus. Both mu and kappa receptors are present in the neurons of the myenteric plexus of the stomach and proximal colon. Smooth muscle cells in the circular muscle layers of the intestine contain delta receptors (Kurz & Sessler, 2003; Greenwood-Van Meerveld et al., 2004).
Normal bowel function requires the coordination of motility, mucosal transport, and defecation reflexes (Cohen et al., 1979). Other physiologic issues factor into the schema of constipation in the medically ill, stemming from the effect of medications, metabolic derangement, and dehydration. However, many factors are responsible for opioid-induced constipation. Delay in gastric emptying and pylorospasm attribute to the peripheral action (Yuan et al., 1998). The major factor seems to be a decrease in intestinal motility which contributes to increased colonic transit time. Nonpropulsive motility of both ileum and colon increase transit time and cause distention and bowel dysfunction (Kurz & Sessler, 2003).
OIC is not only distressing but is often severe enough to be a dose-limiting side effect that can interfere with adequate pain control. In most cases the problem is managed with stool softeners and laxatives, which are often insufficient. A significant number of patients receiving long-term opioid treatment would rather endure their pain than the severe, incapacitating constipation (Vanegas et al., 1998). Thus the undertreatment of opioid-induced bowel dysfunction leads to ineffective pain control in patients being treated for advanced cancer or other chronic medical illnesses requiring opioid analgesics for the treatment of refractory pain.
OPIOID-RECEPTOR ANTAGONISTS
Tertiary opioid receptor antagonists such as naloxone, naltrexone, and nalmefene are relatively lipid soluble and readily cross the blood–brain barrier (Choi & Billings, 2002). However, they have not demonstrated selectivity. These antagonists block both the pain relief of opioids as well as their side effects. Oral naloxone has shown to be effective in restoring laxation during opioid therapy. However, it has a narrow therapeutic index and clinical vigilance is necessary to avoid opioid withdrawal and reversal of analgesia (Liu & Wittbrodt, 2002). In addition, although the bioavailability of oral naloxone is approximately 2% because of extensive first pass metabolism, a dose-dependent increase in plasma levels of unmetabolized naloxone occurs (Sykes, 1996). Thus, systemically absorbed naloxone enters the CNS and may lead to signs of withdrawal or reduction in analgesia at doses less than those needed to produce laxation. Nalmefene and naltrexone are similar in structure to naloxone, but have a prolonged duration of action due to long elimination half-life. Limited investigations on the efficacy of nalmefene and naltrexone are available. However, these studies fail to show usefulness in antagonizing opioid constipation (Cheskin et al., 1995).
Methylnaltrexone is a quaternary N-methyl derivative of the opioid receptor antagonist naltrexone. This addition of the methyl group decreases lipophilicity of the compound and therefore reduces its ability to cross the blood–brain barrier (Brown & Goldberg, 1985). Thus, MNTX does not penetrate the CNS and does not antagonize the analgesic effects of opioids or precipitate withdrawal. MNTX has been investigated in both experimental models and humans and seems to selectively block peripherally mediated opioid side effects such as constipation without affecting pain relief.
Alvimopan is a peripherally restricted trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine mu opioid receptor antagonist. It is a large, totally synthetic molecule that acts specifically at opioid receptors. It has a high affinity for mu opioid receptors and no significant affinity for the delta and kappa opioid receptors (Zimmerman et al., 1994). Alvimopan is potent and orally active, and once it is absorbed the drug has a limited ability to cross the blood–brain barrier. Large doses of Alvimopan thus have the ability to act peripherally and antagonize the GI effects of opioids without inhibiting their beneficial analgesic effects (Taguchi et al., 2001).
DEVELOPMENT OF PERIPHERAL OPIOID-RECEPTOR ANTAGONISTS
Preclinical Trials
MNTX has been administered under a variety of protocols. Animal studies have been conducted to define toxicity of the compound, determine the activity of peripheral versus central opioid receptors, and to explore potential clinical uses of MNTX. Toxicity studies showed a relatively high median lethal dose (LD50 > 100 mg/kg in rats; Yuan & Foss, 2000a). Studies on the metabolism of MNTX have demonstrated species-dependent differences in demethylation to naltrexone. Rats and mice demethylate the compound over time as shown by the exhalation of 14CO2 after administration of [14C-methyl] naltrexone methyl bromide (Yuan, 2004). However, dogs and humans did not significantly demethylate the compound using the same protocol (Ponti, 2002). MNTX seems to have a predominately peripheral action with little systemic absorption. Only 5%–7% of MNTX was found in brain after IP injection of 10 mg/kg into rats. In dogs and monkeys, MNTX 10–50 mg/kg did not penetrate the brain (Yuan & Foss, 2000a). Animal experiments were able to evaluate the efficacy of MNTX on GI motility. Methylnaltrexone reversed morphine-induced inhibition of contraction in both guinea pig ileum and human small intestine, indicating the ability of MNTX to act directly on the bowel (Yuan et al., 1995).
In addition, further studies demonstrated MNTX effect in blocking morphine-induced peripherally mediated emesis in dogs (Foss et al., 1993). Also, a peripheral mechanism of cough suppression was demonstrated in guinea pigs (Foss et al., 1996). Morphine at 8 mg/kg suppressed cough and methylnaltrexone returned the cough response to control levels in a dose–dependent fashion without affecting analgesia. Also, MNTX combined with morphine blocked cisplatin- and apomorphine-induced emesis (Foss et al., 1998).
Clinical Trials in Healthy Volunteers
Studies in healthy volunteers indicated that MNTX was well tolerated and has a therapeutic potential to decrease peripheral side effects of opioids while preserving analgesia and displayed the efficacy of MNTX in reversing bowel dysfunction induced by a single dose of morphine. MNTX was well tolerated up to 0.32 mg/kg IV. Dose-limiting adverse effect was transient orthostatic hypotension (Yuan et al., 1996; Foss et al., 1997). MNTX seems readily bioavailable after intravenous or subcutaneous administration. Plasma levels following MNTX 0.1 or 0.3 mg/kg subcutaneous were proportional to dose. Pharmacokinetics showed time to maximum concentrations was approximately 20 min. The plasma half-life after parenteral administration has been reported from 1.5 to 3 h (Yuan et al., 2002). Bioavailability of oral drug is often erratic and incomplete. Gut absorption of oral MNTX seems particularly limited and values of area under the plasma concentration curve showed greater variability among individual subjects (Foss, 2001). Enterically coated MNTX at 3.2 and 6.4 mg/kg has been evaluated. There was no correlation of plasma levels with clinical effects, which may demonstrate that the compound has direct effect on the luminal surface of the intestine (Yuan et al., 2000a). Elimination of parenterally administered MNTX showed 52% and 47% of unchanged compound in urine after 6 h following 0.1 and 0.3 mg/kg S.C., respectively (Yuan et al., 2002). A significant fraction appears to be eliminated in the feces. The metabolism of the compound does not seem to play a major role in its elimination. A small percentage of the compound may undergo possible gluconronidation with subsequent biliary, renal, and fecal elimination.
Efficacy Studies in Healthy Volunteers
The ability of MNTX to antagonize opioid-induced inhibitory effects has been demonstrated in a number of studies. In a double blind, randomized, placebo-controlled trial, morphine was observed to increase oral–cecal transit time. Single dose injection of MNTX with morphine at doses of 0.42 mg/kg and 19.2 mg/kg IV effectively prevented morphine-induced delay in oral–cecal transit using a lactulose hydrogen breath test. These studies also demonstrated that MNTX did not reverse morphine-induced analgesia (Yuan et al., 1996). Compared to intravenous injection, subcutaneous administration can be a more convenient route of delivery. In another study, 0.1 mg/kg and 0.3 mg/kg S.C. MNTX reduced the morphine-induced delay in transit time (Yuan et al., 2002).
Oral MNTX was also observed to prevent delay in oral–cecal transit time after administration of IV morphine and single doses of methylnaltrexone at doses up to 19.2 mg/kg P.O. (Yuan et al., 2000a). MNTX at lower doses (3.2 mg/kg) P.O. given in enteric-coated formulations completely prevented morphine-induced delay in oral–cecal transit. The coating prevented degradation or release in the stomach, thereby allowing release in the small and large intestines and exerting a more direct effect on the intestines. Plasma concentrations after enteric-coated MNTX were substantially lower compared to after administration of uncoated compound (Yuan et al., 2000a). This suggests that the enteric-coated form may exert pharmacological actions on the gut more efficiently that the uncoated form.
Efficacy Studies in Chronic Methadone Recipients
Receptor physiology may be altered in opioid-tolerant individuals such as subjects receiving methadone maintenance therapy and patients with cancer receiving long-term opioid pain medications. The clinical utility of MNTX for treating bowel dysfunction resulting from chronic opioid use was therefore studied in subjects in a methadone maintenance program. A pilot study of four methadone-maintained subjects with constipation (methadone dose 38–90 mg/d) demonstrated immediate laxation during and after intravenous MNTX (0.05–0.45 mg/kg IV) and reduced oral–cecal transit time. One subject experienced severe abdominal cramping, but showed no signs of systemic withdrawal (Yuan et al., 1999). Subsequent double-blind, randomized, placebo studies with 0.09–0.10 mg/kg IV and 0.3–3 mg/kg P.O. of MNTX induced laxation and reduced oral–cecal transit time. Most subjects reported mild to moderate abdominal cramping. No opioid withdrawal was observed in either group (Yuan et al., 2000b). Results demonstrated that MNTX effectively reduced chronic methadone-induced constipation and delay in gut transit time (Yuan & Foss, 2000b). Thus, we anticipate that cancer patients receiving chronic opioids may have sensitivity to MNTX and that MNTX may have clinical utility in managing opioid-induced constipation in chronic pain patients.
Efficacy in Medically Ill Chronic Opioid Users
In a study of a limited number of patients with advanced medical illness, 33 patients with a life expectancy of less than 6 months, opioid-induced constipation with no bowel movement for 2 days, and on stable doses of opiates and laxatives were randomized to one of four unit doses of MNTX (1, 5, 12.5, and 20 mg S.C.) to be administered every other day prior to a 3-week open label period. Nearly all laxation occurred within 4 h and doses ≥5 mg induced laxation within 60% of the patients within 1 h. There were no changes in pain scores or evidence of opioid withdrawal (Boyd & Israel, 2004).
A larger double-blind, placebo-controlled study of subcutaneous MNTX for opioid-induced constipation in patients with advanced medical illness was initiated to demonstrate efficacy and safety. In 154 terminally ill patients enrolled from 16 hospice sites, with no laxation in 48 h on stable opioids for pain were randomized to placebo, MNTX 0.15 mg/kg, or MNTX 0.3 mg/kg. Twenty-four hours after a single dose, patients were eligible for open label MNTX on an as-needed basis for the next 4 weeks. S.C. MNTX induced laxation within 4 h in the majority of patients. The most common side effects were abdominal cramps and flatulence, and there were no reports of systemic opioid withdrawal (Thomas et al., 2005).
CONCLUSION
Constipation can have a negative impact on quality of life, especially in patients with a life-threatening illness such as cancer patients. Current treatment for OIC usually involves stool softeners and laxatives, which are insufficient for the severe opioid-induced bowel disfunction. OIC is the most problematic and dose-limiting side effect of opioids, and its undertreatment prevents optimal pain management. Systemically administered opioid antagonists have a role in reversing opioid toxicity as well as countering side effects. Thus far, the results with methylnaltrexone seem promising. MNTX seems to be well tolerated with limited or transient side effects. MNTX has been shown to improve oral–cecal transit times in opioid-treated patients, induce laxation in chronic opioid users, and neither reverses the analgesic effects of morphine nor causes withdrawal symptoms.
However, larger clinical trials are still necessary to support its use as a standard for treatment of opioid-induced constipation. Optimal administration of both route and dose still need to be established. In addition, as a peripheral opioid receptor, methylnaltrexone may help elucidate the mechanisms of action of peripheral opioid effects in humans. It also remains to be seen if methylnaltrexone may help ameliorate other opioid side effects such as urinary retention. Although this compound is still investigational, it is reasonable to expect this drug will become commercially available, allowing for more aggressive use of opioid analgesics with fewer side effects.
