Opioid Antagonists

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Journal of Pain and Symptom Management

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Review Article

Opioid Antagonists: A Review of Their Role in Palliative Care, Focusing on Use in Opioid-Related Constipation Youn Seon Choi, MD, PhD and J. Andrew Billings, MD College of Medicine (Y.S.C.), Korea University, Seoul, Korea; and Palliative Care Service ( J.A.B.), Massachusetts General Hospital, and the Center for Palliative Care ( J.A.B.), Harvard Medical School, Boston, Massachusetts, USA

Abstract Opioid antagonists have well-established indications in the reversal of life-threatening opioid toxicity, but also hold considerable promise for other applications in palliative care practice, particularly management of opioid-related constipation. We briefly review current understanding of opioid receptors, focusing on their complex role in gastrointestinal physiology. We summarize the pharmacology, conventional indications, and clinical usage of three major groups of opioid antagonists, including a promising new peripherally acting agent, methylnaltrexone, which is not commercially available. We suggest an approach to administering opioid antagonists for reduction of life-threatening opioid toxicity in patients with pain. The literature on opioid-induced constipation and its treatment with opioid-antagonists is reviewed in detail. Finally, other potential uses of opioid antagonists in palliative care are described, especially strategies for reducing such opioid side effects as nausea and pruritus and for improving analgesia or reducing tolerance by concomitantly administrating both an opioid agonist and low dosages of an antagonist. J Pain Symptom Manage 2002;24:71–90. © U.S. Cancer Pain Relief Committee, 2002. Key Words Narcotic antagonists, naloxone, naltrexone, nalmephene, opioid-related disorders, constipation, gastrointestinal motility, nausea/vomiting, pruritus, respiratory depression, substace-related disorders

Introduction The purpose of this article is to review the use of opioid antagonists in palliative care, particularly for managing opioid-related constipation, but also for partial or complete reversal of opioid toxicity or adverse reactions such as overse-

Address reprint requests to: J. Andrew Billings, MD, MGH Palliative Care Service, FND 600, 55 Fruit Street, Boston, MA 02114, USA. Accepted for publication: November 16, 2001. © U.S. Cancer Pain Relief Committee, 2002 Published by Elsevier, New York, New York

dation, respiratory depression, nausea/vomiting, and pruritus.1,2 We summarize current understanding of the complex mechanism of action of opioids on the gut and explore the ameliorating action of various opioid antagonists. Finally, we discuss a few less familiar and less fully established applications of these agents in end-of-life care. To prepare this review, we performed a Medline search on opioids and constipation, and evaluated all articles in English published in the years 1990–2000. We identified further relevant articles from the reference section of these articles. 0885-3924/02/$–see front matter PII S0885-3924(02)00424-4

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Opioid-Induced Constipation in End-of-Life Care In the United States, approximately 500,000 patients die of cancer annually. Opioid pain medications are used in the terminal phase of care for more than 50% of these patients.3 Constipation, a common adverse effect of opioids,4 affects 40– 50% of patients with metastatic malignancy who receive pain medication.3,5 Indeed, some patients receiving long-term opioid treatment for pain would rather endure their pain than the severe, incapacitating constipation that opioids may cause. Constipation may result in abdominal pain, bloating, nausea and vomiting, and urinary retention.6 In patients with advanced cancer, constipation may be the result of many factors, including reduced food intake, immobility, general debility, and the side effects of non-opioid medications. In a prospective study of 498 hospice inpatients with advanced cancer, laxatives were required by 87% of patients taking oral “strong” opioids, 74% of those on “weak” opioids, and 64% of those not receiving opioid analgesia.7 Opioids, therefore, accounted for about a quarter of the constipation found in terminally ill cancer patients. Moreover, the dose of required laxative is likely to be significantly higher when an opioid is being taken. Most patients with constipation related to opioids will require laxatives.8 Numerous laxatives can be used to overcome the constipation,9,10 but none has been found to yield favorable results in all patients. Several studies have attempted to evaluate the novel intervention of oral opioid antagonist therapy to reverse opioid-induced constipation8,11–13 and idiopathic constipation.14

Pharmacology of Opioid Receptors Sites and Types of Opioid Receptors Opioids, the prototype of which is morphine, are potent analgesic and addictive drugs that act through opioid receptors.15 In contrast to the long-held view that opioid antinociception is mediated exclusively within the central nervous system, peripheral opioid receptors have been discovered and shown to mediate analgesic effects when activated by locally applied opioid agonists. Three major classes of opioid receptors have been identified: , , and 16 (see Table 1). A number of subclasses of the principal categories of receptors have been postulated, based

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upon their differential pharmacology: 1 and 2;17 1 and 218 and 1–4.17 The characteristics of these receptor subtypes continue to evolve. The existence of another receptor type, the  receptor, has been postulated, but is still debated. The  receptor is no longer considered an opioid receptor per se, because non-opioid substances also bind at the site, producing effects similar to those of opioids. Early studies produced evidence for opioid binding in the dorsal root ganglion and on central terminals of primary afferent neurons.19 More recently, opioid receptors have been demonstrated on peripheral sensory nerve terminals in rats20,21 and humans.22 Pharmacologic experiments indicate that the characteristics of these receptors are very similar to those in the brain.21 The advent of opioid receptor cloning23 has made it possible to generate specific antisera to identify , , and  receptors in the dorsal root ganglia and on smalldiameter primary afferent nerve fibers.24,25

Gastrointestinal Effects of Opioids Mediated by Opioid Receptors Opioids are widely recognized as excellent antidiarrheal agents. They reduce gastrointestinal (GI) propulsion, resulting in slower movement of intestinal contents and, indirectly, more efficient absorption of water and electrolytes.26 They also appear to inhibit intestinal fluid secretion. They can produce constipation at low dosages.

Central versus Peripheral Receptor Sites Stewart et al.27 showed that intrathecal administration of very low doses of morphine resulted in intestinal anti-propulsive effects. Although subdiaphragmatic vagotomy abolished these effects, subcutaneous morphine still inhibited intestinal transit in the vagotomized animals. This observation indicated a peripheral action of morphine on opioid receptors. Other preclinical studies also suggest both central and peripheral actions.29 Specifically, morphine has been reported to act at supraspinal,30 spinal,31 and peripheral32,33 opioid receptors to inhibit gastrointestinal transit. Thus, opioid effects on the gastrointestinal tract are mediated through  receptors in both the central nervous system (CNS), which includes the brain and spinal cord, and the peripheral nervous system (PNS),

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Table 1 Pharmacologic Profiles of Opioid Receptors17,155,203,204 Name M (1)

Mu (2)

Delta (1, 2)

Kappa (1–4)

Principal Actions Analgesia: supraspinal spinal peripherala Euphoria Low addiction potential Bradycardia Hypothermia Urinary retention Analgesia: spinal Respiratory depression Significant addiction risk Constipation Analgesia: supraspinal, spinal (2) Respiratory depression Significant addiction risk Constipation (minimal risk) Analgesia: supraspinal (3) spinal (1) peripheral Constipation Sedation Dysphoria Low addiction potential Diuresis (1)

Isolated Organ Bioassay

Agonist

Antagonist

Guinea pig ileum

Morphine Sufentanil Meperidine DAMGO

Naloxone Naltrexone -FNA Naloxonazine (1)

Mouse vas deferens

DPDPE (1) DADLE1 Deltorphine (2) DSLET (2)

Naloxone Naltrexone BNTX (1) Naltrindole Naltriben (2)

Rabbit vas deferens

Butorphanol Bremazocine Spiradoline U-50,488 (1)

Naloxone Naltrexone Nor-BNI

knee joint and foot pad.153 DAMGO  [D-Ala2, N-Phe4, Gly-ol5]-enkephalin; DPDPE  [D-Pen2,5]-enkephalin; DSLET  [D-Ser2, Leu5, Thr6]-enkephalin; BNTX  7-benzylidenenaltrexone; -FNA  -funaltrexamine; DADLE  [D-Ala2, D-Leu5]-enkephalin; U-50,488  trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide; Nor-BNI  nor-binaltorphimine. aInflamed

including peripheral nerves, the autonomic nervous system, and the sensory nervous system. Structurally and functionally, the CNS and PNS are interconnected. Indeed, cell bodies of the peripheral nerves can be located in the brain or spinal cord. Furthermore, the CNS and PNS share similarities in their anatomic organization and neurochemistry, even though there are distinct features that are more typical of one or the other component. Clear distinctions and separations among these subdivisions of the nervous system are not always possible, and different components often show functional overlap.28

Differing Actions Among Opioids Various opioids and their metabolites may have differing actions on opioid receptors16 (Table 2). For instance, some agents may have more  or  receptor affinity, and thus might be expected to have different actions on the GI tract. Opioids of the agonist/antagonist type cause less inhibition of gastrointestinal activity in animal studies than do pure agonists,15 though data are insufficient at present to determine whether this effect also applies to humans. Studies in ro-

dents34 and humans35 indicate that a major metabolite of morphine, morphine-6-glucuronide, is more potent than the parent compound in inhibiting gastrointestinal transport, and thus contributes to the drug’s side effects. Despite these suggestions that opioids might have differential effects on the gut, while producing similar beneficial effects, no evidence of this phenomenon has been demonstrated clinically. Little convincing data currently are available to indicate that particular opioids or particular routes of administration of opioids at equianalgesic dosages result in different anti-transit side effects, though a recent partially controlled comparison of transdermal fentanyl and long-acting morphine suggested that the transdermal agent, which has systemic, but presumably less direct, action on the gut, produced less constipation.36

Central Opioid Receptor Involvement in Gastrointestinal Motility A central mechanism of opioid-induced constipation was postulated because administration of morphine-like drugs directly into central nervous system delayed gastrointestinal transit. Intracere-

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Table 2 Summary of the Actions of Prototypical Agonists, Antagonists, and Agonists–Antagonists at Opioid Receptors204 Receptor Type Drugs Morphine Fentanyl Pentazocine Butorphanol Nalbuphine Buprenorphine Naloxone Naltrexone Nalorphinea U 50,488

 P P — P — — —



NA NA — —

1

3





— — —

NA NA — —

The ratio of symbols at various receptors is intended to denote selectivity:  agonist; —  antagonist; P  partial agonist; NA  data unavailable or inadequate. a Produces dysphoric or psychotomimetic effects at relatively high doses that are poorly antagonized by naloxone.

broventricular injection of morphine in the rat inhibits gastrointestinal propulsion,37 and this effect is reversed by intracerebroventricular injection of opioid antagonists38 and vagotomy.27 Thörn et al.39 showed that intrathecal morphine reduced gastroduodenal motility and that intramuscular morphine (4 mg) gave additional effects. These results might suggest that the gastroduodenal effects of epidural morphine are caused by both central and systemic effects of the drug. However, clinical observations of the side effects of epidurally administered opioids in humans reveal that constipation is rare, while pruritus and urinary retention are common.40 Thus it seems likely that the effect of systemic opioids on intestinal motility and transit in humans is not mediated predominantly by spinal opioid receptors.41 Central opioid receptors appear to be associated with specific effects at different regions of the CNS. Thus, compounds affecting the gut at spinal cord sites do not always produce similar effects when the drug is given into the brain. Brain -receptors are linked to both analgesia and intestinal motility, while -receptors are associated with analgesia but not gastrointestinal effects.42 The spinal opioid receptors involved in anti-transit effects appear to be both  and .

Opioid Inhibition of Intestinal Motility: Peripheral Mechanisms Opioid peptides and their receptors are found throughout the gastrointestinal system,

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with particularly high concentrations in the gastric antrum and proximal duodenum.43 Our current focus on opioid-induced constipation may lead us to underappreciate the role of these drugs on gastric emptying or opioidrelated nausea. Studies cited below also suggest that delays in gastric emptying may have significant effects on drug absorption. The three types of opioid receptors— , , and —have been recognized in the digestive tract and found to resemble those in the brain.44 Neurons of the myenteric plexus mainly contain  and to a lesser extent  receptors.24 The submucous plexus contains primarily  receptors, which are found as well on smooth muscle cells in the circular muscle layers of the intestine. Cells of longitudinal muscle layers are devoid of opioid-receptors.45,46 This cellular distribution of receptors suggests different mechanisms of action by opioids through neuronal and direct cellular pathways. Morphine and similar substances affect pyloric and gastric contraction in a variety of species, and these responses are reversed by naloxone.47 Such actions can be correlated with enkephalinergic innervation in these regions, which is probably under vagal control.47 Central and peripheral mechanisms delay gastric emptying, but central inhibition seems to be associated with higher dosages of opioids.48–51 Studies in mice51 indicate that peripheral -receptors inhibit transit independently of central -receptors, and are activated at subanalgesic doses. - and -receptors do not play an important role in these effects, though species variations occur.41 Moreover, systemically administered morphine achieves much higher tissue levels in the intestine compared to the CNS, correlating with observations that lower dosages of opioids are required to produce constipation than analgesia. For now, it seems unlikely that our appreciation of the peripheral versus central anti-transit sites of action of morphine or of differential effects of particular opioids on particular receptors will allow us clinically to separate the GI side effects from the beneficial analgesic effects of the drug.

Normal Bowel Function and the Role of Opioids in Constipation Normal bowel function requires the coordination of motility, mucosal transport, and defecation reflexes:52

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Motility depends on the central nervous system, activity in the peripheral autonomic nervous system (both parasympathetic and sympathetic), and the function of a variety of gastrointestinal hormones.53,54 Muscarinic, adrenergic, and dopamine receptors, and their subtypes at various sites, may contribute to motility.55 Three types of motility have been distinguished: segmental nonpropulsive; short-segment propulsive; and long-segment propulsive (mass movements). Segmental movements of the colon churn and mix the contents, and propulsive movements, or peristalsis, drive the contents forward. Mucosal transport of electrolytes and fluids is a complex and incompletely understood process. Opioids inhibit intestinal secretion evoked by prostaglandins, carbachol, vasoactive intestinal polypeptide (VIP), cyclic adenosine 5 - monophosphate (cAMP), cholera toxin, and Escherichia coli toxin. This antisecretory effect again involves enteric neurons that innervate enterocytes, and appears to be mediated by -receptors in the submucosal plexus. Enterocytes may possess opioid receptors, but this hypothesis is controversial; receptors have not been found on enterocytes themselves.56 An overall increase in fluid and electrolyte absorption from opioids is more pronounced in the small intestine than in the colon.57 Increased absorption of fluids could potentially cause constipation, although it is more likely that absorption proceeds normally in most patients and that desiccation of bowel contents is due to prolonged transit time rather than mucosal processes.58 Interference in defecation reflexes also can cause constipation. This may have particular impact in patients with structural lesions of the pelvis.59,60 Although the factors responsible for opioidinduced constipation may include the delay of gastric emptying and pylorospasm61–65 attributable to peripheral actions,66 the major factor is the decrease in intestinal motility associated with increased colonic transit time.26,64 Opioids increase non-propulsive motility of both ileum and colon,67–70 thereby increasing transit time and causing distention. These actions are mediated through intramural elements of the bowel,71 leading to increases in phasic contractile activity and contractile tone in intestinal circular muscle.65,67,71,72 This is manifested as continuous non-propulsive segmentation.64,68

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Naloxone alone accelerates transit, suggesting that it inhibits the action of endogenous opioids involved in colonic motility.73 Opioids also act on endocrine-paracrine cells, affecting gastric and pancreatic secretion, though the clinical significance of these actions is unclear.64 Finally, morphine and enkephalin may act centrally on the CNS to reduce the urge to defecate in spite of the accumulation of feces in the large bowels.74 Intestinal activity is increased by  and , but not , agonists.55 The actions of opioids on the gut are either “indirect” (i.e., the result of neural interaction through the inhibition of acetylcholine or VIP) or “direct” (due to contraction of smooth muscle).55,75–77 This stimulatory action is probably mediated by release of 5-hydroxytryptamine, which activates the gut through cholinergic and noncholinergic pathways and leads to prolonged transit time. The inhibition of acetylcholine release by opioids from the myenteric plexus is well known for guinea pig intestine, but seems to play no major part in non-rodents.44,57,78 In addition to this indirect neural pathway, the exclusive location of opioid receptors on smooth muscle cells of the circular layer seems to be responsible for an increase of activity of circular but not of the longitudinal muscles, and thus contributes to nonpropulsive segmental contractions and prolonged transit time in the small and large intestine.78,79

Opioid Antagonists in Constipation Opioid Antagonists That Act Both Centrally and Peripherally The pharmacokinetics of opioid antagonists and directions for their conventional administration are summarized in Tables 3 and 4. Nalorphine (Lethidrone, not available in the U.S.) and naloxone (Narcan) were made by substitution of an allyl group for a methyl on the nitrogen of morphine and oxymorphine, respectively. Tertiary opioid-receptor antagonists, such as naloxone, naltrexone (ReVia), and nalmefene (Revex), are fairly lipid-soluble, cross the blood-brain barrier easily, and can block both the beneficial pain-relieving effect and adverse effects of opioids. Naloxone (Narcan). Naloxone is a competitive antagonist of opioid receptors inside and out-

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Table 3 Pharmacokinetics of Opioid Antagonists Commercially Available in the United States (Studies in Adults)104,205,206 Name Naloxone (Narcan) Onset of effect Duration of action Distribution Metabolism Half-life Elimination Naltrexone HCl (ReVia) Onset of effect Duration of action Absorption Distribution Metabolism Half-life Elimination Nalmefene HCl (Revex) Onset of effect Duration of action Absorption Distribution Metabolism Half-life Elimination

Description Endotracheal, IM, SC: within 2–5 minutes; IV: within 2 minutes 20–60 minutes; shorter than that of most opioids, so repeated doses are often needed Vdss: ≈ 180–210, crosses the placenta Primarily by glucuronidation in the liver 1–1.5 hours In urine metabolites Time to peak serum concentration: within 60 minutes 50 mg oral: 24 hours, 100 mg: 48 hours, 150 mg: 72 hours Oral: almost complete Vdss: 19 l/kg; distributed widely throughout the body but considerable interindividual variation exists Protein binding: 21% Undergoes extensive first-pass metabolism to several metabolites including 6-beta-naltrexol 4 hours; 6-beta-naltrexol: 13 hours Prinicpally in urine as metabolites and unchanged drug Time to peak serum concentration: 1 mg IM: 2 hours, 1 mg SC: 1.5 hours, 50 mg oral: 1 2.5 hours Reversal of opioid toxicity is dose related: 1 mg IV: 4 hr, 2 mg IV: 8 hr, a single 50 mg oral dose: 48 72 hours Bioavailability: IM: 100%, SC: 100%, Oral: 4050% Vdss: 8.61/kg Protein binding: 45% Metabolized primarily via glucuronidation Nalmefene glucuronide (inactive): major metabolite 8.510.8 hours Renal: less than 8%, Feces: 17%, Bile: small

Vdss  volume of distribution at steady state; the larger the value, the more likely the effects are terminated by redistribution than by clearance, and the more likely accumulation will take place on repeated (continuous) administration.

side the central nervous system. After systemic administration, it reverses both centrally and peripherally mediated opioid effects. It may induce opioid withdrawal symptoms with adverse reactions in the cardiovascular system (hypertension, hypotension, tachycardia, ventricular arrhythmias, cardiac arrest), central nervous system (irritability, anxiety, restlessness, diaphoresis, tremulousness, seizures), gastrointestinal system (nausea, vomiting, diarrhea), and respiratory system (dyspnea, pulmonary edema, runny nose, sneezing).13,80,81 As a result of extensive hepatic metabolism (first-pass glucuronidation), orally administered naloxone has a systemic bioavailability of less than 3%.82 Albeck et al.83 found the peak plasma level of unmetabolized naloxone after a 30 mg oral dose was only 3.6 ng/ml, compared with 80 ng/ml after the same dose given intravenously. The small amount absorbed systemically may be sufficient to produce withdrawal in some physically dependent patients, depending on dosage.84 Because very little oral naloxone appears in the systemic circulation, however, its action from enteral administration is probably related to antagonism of opioid receptors in the gut.

Studies Using Naloxone for Constipation. Experiments first carried out in rats showed that morphine-induced constipation was reduced by oral naloxone without impairment of antinociception.85 In a crossover, double-blind study of 6 normal volunteers, the subcutaneous administration of naloxone at doses of 0.8 mg every 6 hours accelerated transit in the transverse colon and rectosigmoid colon significantly, but had no effect on the number of bowel movements for 48 hours.73 Thus, naloxone alone accelerated transit in humans, suggesting that it inhibits the action of endogenous opioids involved in colonic motility. No other studies address the value of oral naloxone for constipation in patients not receiving opioids. A variety of small studies have looked at the usage of oral naloxone in reversing opioid-related constipation in humans.11–13,86,87 Culpepper-Morgan et al. reported improved bowel function in two of three opioid-dependent patients after 8–12 mg of oral naloxone, while a third patient developed systemic withdrawal symptoms without laxation at dosages of 14 and 16 mg or two doses of 12 mg separated by three hours.13 Recently, Latasch et al. studied

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Table 4 Usual Administration Regimens for Opioid Antagonists Name Naloxone (Narcan) Indications Usual dosage

Naltrexone (ReVia) Indications Usual dosage

Nalmefene (ReVex) Indications Usual dosage

Regimen Reverse CNS and respiratory depression in suspected narcotic overdose For diagnosis of suspected opioid tolerance or acute opioid overdosage Dosage Forms: Injection, as hydrochloride; 0.4 mg/ml (1 ml, 10 mL), IM, IV (preferred), intratracheal, SC. Opioid Overdose-Known or Suspected: I.V.: 0.4–2 mg every 2–3 minutes as needed, if no response is observed after 10 mg, question the diagnosis. IM or SC administration may be necessary if the IV route is not available. Postoperative Respiratory Depression: In increments of 0.1–0.2 mg intravenously at 23 minute intervals to the desired degree of reversal (i.e. adequate ventilation and alertness without significant pain or discomfort) Repeat doses may be required within 1 2 hour intervals depending upon the opioid amount, type (i.e., short or long acting) and time interval since last administration. Supplemental intramuscular doses have been shown to produce a longer lasting effect. Adjunct to the maintenance of an opioid-free state in detoxified individual. Dosage forms: Tablet, as hydrochloride: 50 mg. Do not give until patient is opioid-free for 710 days as determined by urine analysis: Oral: 25 mg; if no withdrawal signs within 1 hour give another 25 mg; maintenance regimen is flexible, variable and individualized (50 mg/day to 100150 mg 3 times/week). Oral nalmefene has undergone preliminary investigation in several conditions, including interstitial cystitis, and may be a useful alternative to naltrexone for the management of opioid addiction. Dosage form: Solution for injection; 100 g/ml (1 ml) for postoperative use, 1 mg/1ml (2 ml) for opioid overdose; IM, IV (preferred), SC, oral. Opioid overdose: 0.5 mg/70 kg IV. If needed, give second dose of 1 mg/70 kg, 2 5 minutes later. Max cumulative dose 1.5 mg/70 kg; if suspicion of opioid dependency, initial dose of 0.1 mg/70 kg is recommended. If there is no evidence of withdrawal symptoms within 2 minutes, the usual dosage may be used; 0.5 or 1 mg IV bolus injection is also effective. Postoperative respiratory depression: 0.25 g/kg IV, repeat at 2  5 min intervals prn. Max cumulative dose 1 g/kg.

15 patients with opioid-induced constipation.12 For 12 patients, bowel evacuation occurred 1–4 hours after taking oral naloxone in milligrams equivalent to their four-hourly morphine dosage, a regimen suggested by animal experiments.85 Three patients had no laxative effects even after repeated doses; their medical history revealed neurological disturbances that may have been responsible for the constipation. Eleven of the 15 patients reported an average loss of 10–15% of analgesia after oral naloxone, as measured by visual analogue scales. Increasing the morphine dose by about 15% restored the previous level of analgesia without reappearance of constipation. Eight of the 12 patients having a laxative effect experienced abdominal cramps, and therefore the total dose of naloxone was reduced on day 2 to 2–15% of that originally planned; this dose still produced a laxative effect. Four of the 15 patients had a withdrawal syndrome. A single dose of morphine equivalent to their four-hour morphine intake abolished the symptoms. Oral naloxone’s therapeutic index may be narrow, as re-

versal of the gut effects with naloxone occurs at doses near the reversal of analgesia.86 In contrast, Robinson et al.87 could not demonstrate a laxative effect of oral naloxone in doses ranging between 0.4 and 4 mg. The maximum single dose of naloxone used in this study was between 0.5% and 10% of daily morphine dose. None of these studies had a controlled design, nor did they define inclusion or outcome criteria precisely, or employ statistical analysis of results. In a placebo-controlled, dose-ranging study reported as a letter to the Lancet, the anticonstipation effect of oral naloxone was evaluated in constipated hospice patients receiving morphine or diamorphine by mouth.86 Oral naloxone, given at a dose of at least 10% that of concurrent opioid analgesia, reversed constipation without reversing analgesia. Dosing. In some reports,12,86–88 the naloxone dose was based on the pre-existing morphine dose and expressed as a percentage of daily morphine. This dosage regimen is based on the assumption that the effectiveness of an opi-

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oid antagonist depends on the concentration of the opioid agonist.88 Experience in antagonizing opioid effects after short-term administration, such as occurs after opioid anesthesia, seems to confirm this assumption. However, this approach may not be appropriate after long-term opioid intake. In a study with narcotic-dependent subjects, larger dosages of naloxone were required to produce an abstinence syndrome in subjects receiving opioids for brief periods (e.g., 4 days or less) than for those receiving opioids for a few weeks or more, leading to the conclusion that the response to opioid antagonists was proportional to the degree of opioid tolerance or dependence, not necessarily to opioid levels.89 Furthermore, when naloxone is administered enterally, it is not known whether its first-pass hepatic metabolism is related to the concentration of the agonist. Therefore, the risk of systemic withdrawal may increase if the same percentage relationship is used in patients with low and high prevailing opioid doses.11 For managing constipation due to opioid use, authors recommend dosages starting as low as 0.8 mg twice daily, with a maximum of 5 mg a day, titrated up to 12 mg a day, watching for toxicity and loss of analgesic effect.13,88,90,91 Particular caution is indicated for physically dependent patients.84 Doses less than 10% of the daily morphine dosage may be ineffective, whereas most patients respond to a naloxone equivalent of 20% of the total daily morphine dosage,88 and dosages from 0.5–60% of the morphine dosage have been used.11,12 Nalmefene (Revex) and Naltrexone (ReVia). Nalmefene and naltrexone are similar in structure to naloxone, but have a prolonged duration of action due to a long elimination half-life92,93 (Table 3). Antagonistic effects occur by competitive displacement of opioid molecules at receptors, as well as the blocking of opioid access to the receptor sites.94 Nalmefene, like naloxone and naltrexone, has high affinity for , , and  receptors. It binds more competitively with these receptors than naltrexone95–97 and thus is 4 times as potent acutely as naloxone in antagonizing effects at the  receptor, and more potent than naloxone in antagonizing effects at the  receptors.98–100 The serum half-life of nalmefene is 10.3 to 12.9 hours, compared with 63 minutes for naloxone.101,102

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Healthy volunteers given intravenous doses of nalmefene up to 24 mg (15 times the recommended dose) experienced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory abnormalities.103,104 Oral nalmefene is well tolerated in single oral doses of up to 300 mg in healthy volunteers.105 Lerner et al reported 4 cases of psychological dependence to naltrexone,106 The drug can cause dose-related elevations in serum transaminase levels, particularly when used chronically with doses up to 300 mg/day, but these laboratory abnormalities resolve with discontinuation of the drug.107,108 Prolonged use of doses of 50–300 mg daily caused no overt hepatotoxicity in 10 patients.109 Limited investigations on the efficacy of oral nalmefene in humans are available, and the duration of opioid blockade after oral doses is not well characterized. Selective antagonism of opioid gastrointestinal side effects by oral nalmefene has been attempted, but has been limited by the propensity for this compound to reverse analgesia or to induce withdrawal.67 Both 50 and 100 mg of oral nalmefene blocked the physiological and subjective effects produced by 10 and 20 mg of intravenous morphine for at least 48 hours.92 An oral trial of a reportedly gut-selective, systemically inactive nalmefene metabolite, nalmefene glucuronide, failed to show usefulness in antagonizing opioid constipation.110,111

Peripherally Acting Opioid Antagonists By adding an alkyl substituent on the nitrogen atom of a tertiary opioid antagonist, quaternary opioid antagonists were designed with relatively greater polarity and less lipid solubility than the parent compound, thus preventing them from readily traversing the blood–brain barrier.112,113 Ideally, these agents might block peripheral gastrointestinal effects of the opioids while not affecting the central effects, such as analgesia.61,62,114 No quaternary antagonists are available commercially at this time. Methylnaltrexone (N-methylnaltrexone bromide; Mallinckrodt Specialty Chemicals, St Louis, MO) was the first quaternary ammonium opioid receptor antagonist with a limited ability to cross the blood–brain barrier.112,115,116 In contrast to naloxone, it fails to promote withdrawal in morphine-dependent animals.117,118 It does not reverse analgesic effects of morphine

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in rats119 or humans, even if higher plasma levels are attained,62 and has been shown to have direct action on isolated human intestine muscle strips.41 Demethylation of methylnaltrexone, with subsequent central nervous system penetration of naltrexone, has not occurred in humans.115 Methylnaltrexone appears to be well tolerated in healthy humans. Transient, self-limited, orthostatic hypotension occurred at intravenous doses of 0.64–1.25 mg/kg in normal adults, but no subjective complaints were registered and there were no other changes in physical examination or laboratory studies.61 The elimination half-life was 117.5 minutes (53.2 minutes). Enteric coating of methylnaltrexone prevents degradation or release of the drug in the stomach but releases the drug in the small and large intestine. After administration of this drug preparation, less than 0.1% of the unchanged compound was detected in urine from 0 to 6 hours.120 After uncoated drug administration, the unchanged compound detected was less than 1%.121 In studies of intravenous administration, the amount of the unchanged drug excreted during the same period of time was approximately 50%.62 A series of studies using intravenous or oral methylnaltrexone in normal subjects or methadone maintenance patients shows that this agent prevents opioid effects on gastric emptying, nausea, and oral–cecal transit time, while not affecting opioid analgesic action,62,66,120–122 regardless of plasma concentrations of the drug.121 In a double-blind, randomized, placebo-controlled trial in 22 subjects in a methadone maintenance program who had opioidrelated constipation, good laxation responses were noted after intravenous methylnaltrexone, and no opioid withdrawal or significant adverse effects were seen with doses up to 0.365 mg/kg.114 Abdominal cramping without evidence of systemic withdrawal has been seen with lower and higher dosages,123 indicating that individuals receiving long-term methadone treatment are very sensitive to intravenous methylnaltrexone compared with healthy, opioidnaive subjects. Cancer patients receiving longterm opioid treatment also may have increased sensitivity to methylnaltrexone.114,123 The enteric-coated formulation further extends this compound’s action on the gut.120

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The investigational agent ADL 8-2698 (Adolor Corporation, Malverin, PA) is a peripherally selective  opioid antagonist with minimal systemic absorption and limited penetration into the CNS after oral administration. In randomized, placebo-controlled, clinical trials, ADL 8-2698 4 mg orally has been shown to increase gastrointestinal motility and stool weight significantly, without antagonizing analgesia or pupillary constriction following administration of intravenous morphine in 14 healthy volunteers.124,125

Using Opioid Antagonists for Life-Threatening Opioid Toxicity Table 4 summarizes how opioid antagonists may be employed to reverse life-threatening opioid toxicity or overdosages. Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate an acute withdrawal syndrome. Clinicians also should be aware that the usual indicated dosage for reversal of opioid effects may precipitate severe pain in a typical palliative care patient. Many patients can recover from excess opioids by simply withholding or reducing further opioid administration, and may be aroused by verbal stimulation. When attempting to reduce systemic opioid toxicity in patients with chronic pain in whom toxicity is not immediately life-threatening, lower antagonist dosages should be utilized and carefully titrated. Thus, for a terminally ill patient with excess respiratory depression or sedation, rather than administering naloxone 1 ampule (0.4 mg) IV, as is commonly given in the emergency room to reverse an opioid overdose, a quarter of an ampule (0.1 mg) or less might be given IV every 5 minutes until a desired effect is achieved without emergence of severe pain. Antagonists may be used along with spinal administration of opioids. Intermittent intramuscular injection of 0.4 mg naloxone reverses respiratory depression following epidural morphine.126 The effects of continuous intravenous naloxone infusion at lower doses (5 g/ kg/hr) and higher doses (10 g/kg/hr) on analgesia and respiratory depression in postoperative patients have been studied after epidural morphine and fentanyl.127 Either dose of

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naloxone prevented respiratory depression following 4 mg epidural morphine, but the larger dose decreased the duration of analgesia by over 25%, and more frequent injections of epidural morphine were required to give effective analgesia, compared with no effect on analgesia in low-dose naloxone infusion. To reverse the respiratory depression associated with 200 g epidural fentanyl, high-dose naloxone infusion was necessary; this dose also significantly decreased the quality of analgesia.127 In order to protect against respiratory depression after intrathecal injection of morphine, yet also not impair analgesia, Johnson recommended naloxone infusion 1 g/kg/hr given during the first 12 hours postoperatively and 0.25 g/ kg/hr during the next 12 hours.128 Respiratory depression due to methadone and heroin overdose has also been treated successfully by 2.5 g/kg/hr naloxone infusion.129 For prevention or treatment of opioid-related side effects associated with epidural morphine or fentanyl130–133 or intravenous fentanyl.134 both nalbuphine and naloxone can effectively decrease the incidence of respiratory depression, nausea, vomiting, and pruritus. When nalbuphine is used to reverse opioid-related side effects, it produces fewer cardiovascular responses and less reversal of analgesia than naloxone in humans and dogs.130,135 Nalmefene hydrochloride was recently approved by the U.S. Food and Drug Administration for the reversal of opioid overdoses.136 Gal showed that a single 50 mg nalmefene oral dose completely blocked the respiratory depression, analgesia, and subjective effects (e.g., drowsiness and nausea) of 2 g/kg of intravenous fentanyl for up to 48 hours.137 Intravenous nalmefene (0.4 mg/70 kg) was more effective than naloxone (1.6 mg/70 kg) in antagonizing respiratory depression induced by morphine99,138 and in reversing meperidine-induced sedation.139 When doses of nalmefene and naloxone were compared, nalmefene was reportedly equipotent on a mg per kg basis to naloxone, but had a prolonged ability to reverse respiratory depression induced by fentanyl.56 Although high doses of nalmefene have been used safely,104,140 administration of nalmefene 75 g IV to reverse postoperative respiratory depression has been reported to cause acute pulmonary edema.141 The initial recommended dose to reverse postoperative opioid-

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related respiratory depression is 0.1 g/kg, with a maximum of 1 g/kg.142 Use of higher doses is likely to increase the incidence and severity of side effects. The ventilatory response to hypoxia arises from the peripheral chemoreceptors located in the carotid and aortic bodies, and these responses are mediated via the respiratory centers in the brainstem.143 Methylnaltrexone may not reach the centrally located breathing centers responsible for opioid-induced respiratory depression.144 Thus, methylnaltrexone is not effective in reversing morphine-mediated depression of respiration.144

Other Uses of Opioid Antagonists A variety of exciting new applications of opioid antagonists have been suggested, including their concurrent use with opioids to reduce nausea and vomiting, pruritus, respiratory depression, and other adverse reactions to opioids. Opioid antagonists may also play a role in treating nausea and vomiting or pruritus in patients not receiving exogenous opioids, perhaps reflecting the role of endogenous opioids in some clinical syndromes.

Nausea and Vomiting The primary mechanism of opioid-induced nausea apparently results from the drugs’ action on the area postrema chemoreceptor trigger zone in the medulla.145 For instance, in chronically instrumented dogs, intracerebroventricular administration of morphine results in gastric relaxation, increased retrograde pressure activity in the duodenum and finally, vomiting.146 However, direct gastrointestinal effects of opioids may also contribute to nausea and vomiting,66,147 just as they contribute to constipation, and thus oral antagonists with relatively little systemic effects may improve opioid-related nausea and vomiting without impairing systemic analgesic effects. Gan et al. randomized 60 postoperative patients who were receiving patient-controlled morphine analgesia to receive a continuous infusion of either low-dose naloxone (0.25 g/ kg/hr), high-dose naloxone (1 g/kg/hr) or placebo (0.9% saline).2 The naloxone regimens were equally effective in reducing the incidence of nausea, vomiting, and pruritus, compared with placebo, without difference in

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the pain rating scores among the groups. There also was no respiratory depression ( 8 breaths/min) and no difference in sedation scores, antiemetic use, respiratory rate, and hemodynamic parameters among the groups. In Joshi et al.’s study of patients receiving intravenous patient-controlled morphine analgesia, the prophylactic administration of nalmefene by infusion (15 g or 25 g, compared to placebo) significantly reduced the need for antiemetic (33% vs. 63%) and antipruritic (5% vs. 23%) medications during a 24-hour study period.1 Although the total consumption of morphine during the 24-hour study period was similar in the three groups, patients who received nalmefene retrospectively characterized their pain as less severe in the previous 24 hours. Similarly, methylnaltrexone reduced morphine-induced emesis in dogs,148 and the intravenous morphine-induced nausea score produced in healthy volunteers.66 In a doubleblind, randomized, placebo-controlled study, oral methylnaltrexone at 19.2 mg/kg significantly reduced four subjective effects (nausea, pruritus, feeling “stimulated,” and flushing) after intravenous morphine injection (0.05 mg/kg).149 Foss et al. reported that methylnaltrexone (0.25 mg/kg) combined with morphine (1 mg/kg) reduces apomorphine-induced emesis and blocks cisplatin-induced emesis.147 However, in a postoperative double-blind placebo controlled study, 20 mg methylnaltrexone did not prevent nor significantly reduce the incidence and severity of postoperative nausea and vomiting following a balanced anesthetic technique in gynecological procedures.150

Pruritus Pruritus occurs frequently when opioids are administered by the spinal route, presumably due to centrally mediated activation of  receptors.130,151–154 It occurs in less than 10% of patients who receive epidural opioids, but nearly half of patients who receive intrathecal opioids.155 Most patients treated for malignant or chronic pain with epidural or intrathecal opioids reportedly do not experience pruritus after the first or second day, presumably because of rapid development of tolerance.156,157 Pruritus occurs even less frequently after systemic routes of administration.158 The mechanism of pruritus from systemic administration

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is not clearly understood, though morphine and most of its congeners, as well as meperidine and several other opioids (but not fentanyl or its derivatives) release histamine from mast cells, thus causing flushing, hypotension, and bronchospasm.159,160 The pruritus associated with spinal (intrathecal, epidural) administration of opioids is primarily a CNS-mediated autonomic response; histamine release is inconsistently evident in patients suffering from severe pruritus secondary to opioid administration.161 Low-dose intravenous infusion of naloxone (0.25 mg/kg/hr) can be used to treat pruritus without reversing analgesia in persons receiving patient-controlled intravenous morphine,2 as may orally administered methylnaltrexone.2,149 This finding suggests a peripherally mediated action that may be unrelated to histamine release. Other opioid antagonists, such as naltrexone and nalmefene, and also agonist-antagonist opioids, such as butorphanol (Stadol) and nalbuphine (Nubain), have all been used successfully to treat opioid-related pruritus.162,163 A distinction can be made between preventing opioid-related pruritus and treating established symptoms. In a quantitative systematic review of randomized trials for the prevention of pruritus, primarily in postoperative patients receiving intrathecal or epidural opioids, studies of most -receptor antagonists (intravenous naloxone at 0.25–2.4 g/kg/hr; oral naltrexone at 9 mg and perhaps 6 mg but not 3 mg; and intravenous or epidural nalbuphine), along with droperidol, were judged effective agents. Prophylactic propofol, epidural or intrathecal epinephrine, epidural clonidine, epidural prednisone, intravenous ondansetron, or intramuscular hydroxyzine were not considered to be of proven benefit. Valid data on the efficacy of any agents for established pruritus was judged to be lacking.164 Opioid antagonists have been reported to be of benefit in several pruritic conditions where patients are not receiving opioids. For instance, endogenous opioid agonists appear to contribute to the pruritus of cholestasis.165–169 A single blind study of 8 patients with primary biliary cirrhosis showed improvement with a 24-hour naloxone (0.2 g/kg/min) infusion; scratching activity during naloxone infusion was reduced an average of 50% (range, 29– 96%) compared to a placebo saline infusion.170

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Higher dosages of naloxone may be indicated for non-responders to this regimen. These results were confirmed in a double-blind, randomized, controlled study of 29 patients with pruritus from cholestatic liver disease.171 Similarly encouraging responses have been shown with nalmefene,172–175 though these studies are limited by their small sample size and short follow-up periods. A decrease in pruritus, improvement of fatigue, and a fall in plasma bilirubin have been observed in patients with primary biliary cirrhosis after administration of oral nalmefene.172 The dosage of nalmefene was gradually increased over 7–10 days from 5 mg twice daily to 20–40 mg three times daily. However, upon starting the drug, all patients experienced severe symptoms similar to an opioid withdrawal reaction, such as anorexia, nausea, colicky abdominal pain, sweating, pallor, and a rise in arterial pressure. In another study, 14 patients with resistant pruritus secondary to cholestatic liver disease were treated with oral nalmefene for 2 to 26 months.173 The initial dose was 2 mg twice daily and the dose was increased gradually as necessary. Although 13 of the patients reported some amelioration of pruritus, five found that increasing doses were required to produce any benefit, and tolerances appeared to develop in three.173 Thornton and Losowsky recommend that nalmefene be started in hospital, and that the initial dose be set as low as possible and gradually increased to a therapeutic maintenance dose over 2 to 4 weeks.172 Gradual dose titration from 25 mg/day up to a maximum 50 mg/day may minimize withdrawal reactions.175 Rapid improvement of severe pruritus associated with atopic dermatitis or chronic urticaria was reported after a single oral dose of nalmefene 10 or 20 mg in a double-blind study.176 Adverse effects occurred in 67% of patients and included dizziness or lightheadedness, fatigue, and nausea. No effect of the drug on pruritus in patients with eczema or psoriasis was noted in a controlled study.177 In a double-blind study in 15 hemodialysis patients with severe resistant pruritus related to azotemia, administration of naltrexone 50 mg daily by mouth significantly reduced pruritus scores and plasma histamine levels. This suggests that naltrexone’s action in relieving pruritus for dialysis patients is related to histamine release, but the lack of efficacy of antihistamines in managing azotemic pruritus suggest

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that another mechanism is occurring. The long term safety and benefit of naltrexone for this set of patients is unknown.178

Respiratory Depression

Opioids depress respiration via 2, , , and perhaps 1 opioid receptors in the medulla, and thereby increase PCO2.179,180 They decrease the sensitivity of the medulla to carbon dioxide concentrations and also decrease respiratory rate. It is likely that the blood opioid concentration is more important in predicting respiratory depression than the route of the drug entering the blood.181 Opioid antagonists appear to re-sensitize the respiratory center to increase its sensitivity to carbon dioxide.182 In short-term studies in rats, 1 actions (analgesia, prolactin release) seem to show acute tolerance far more rapidly than 2 actions (respiratory depression, GI effects), suggesting that tolerance to the respiratory depressant effects of the opioids may lag behind tolerance to analgesic effects.156 Many studies have demonstrated the successful use of systemic agonist-antagonist drugs such as nalbuphine (Nubain) to reduce the risk of spinal opioid-induced adverse effects, such as nausea, vomiting and pruritus,130 urinary retention, and respiratory depression after surgery.134 Bailey et al.134 showed that either naloxone (0.08 mg) or nalbuphine (2.5 mg) intravenously given every 2 min can produce adequate spontaneous ventilation postoperatively after one to four doses in anesthetized patients who received large doses of fentanyl. Both antagonists produced similar changes in heart rate, blood pressure, arterial blood gas tensions, respiratory rate, and tidal volume, but patients given naloxone required analgesics for pain significantly more often than those reversed with nalbuphine.134

Opioid-Sparing Effects Recent preclinical and clinical studies have demonstrated that co-treatment with extremely low doses of opioid receptor antagonists (e.g., naloxone,2 naltrexone,183 and nalmefene1) can reduce side effects of morphine,2 enhance the efficacy and specificity of morphine and related opioid analgesics, and attenuate development of tolerance.183–185 Similarly, co-treatment with agents, such as cholera toxin, blocks

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excitatory but not inhibitory opioid receptor functions in dorsal root ganglion neurons, and appears both to enhance the inhibitory (antinociceptive) potency of morphine and also to attenuate tolerance or dependence during chronic opioid exposure.185 A large double-blinded clinical study utilized co-treatment with a low dose of naloxone plus pentazocine for the treatment of pain following tooth-extraction surgery. The analgesic potency of a 60 mg dose of the  opioid agonist, pentazocine (1 mg/kg) was markedly increased by co-treatment with 0.4 mg intravenous naloxone(6 g/kg) in pain evaluation tests made at 50 min and at 3 hr after dosing.186 This dose of naloxone (0.4 mg) was effective in enhancing pentazocine’s analgesic potency apparently because naloxone has weaker antagonist potency at , in contrast to , inhibitory opioid receptors.186 In Gan et al.’s study of post-hysterectomy patients,2 low-dose naloxone infusion significantly reduced the average cumulative patient-controlled morphine usage from about 60 mg down to 40 mg. The differences between the cumulative morphine use in the naloxone-co-treated versus placebo groups began to occur after only 4–8 hours and became increasingly prominent by 20–24 hours. These data suggest that the patients using morphine alone were becoming progressively tolerant to the analgesic effects of morphine during the 24-hour test period, in contrast to the stable rate of morphine usage by the patients receiving low-dose naloxone cotreatment.2 On the other hand, no opioid-sparing effect and slight attenuation of morphine analgesia were observed in another group of patients infused with 4-fold higher dose of naloxone, as had been reported in previous clinical trials on post-surgery patients using 1 g/kg/hr naloxone co-treatments.128,187 The exact mechanism by which low-dose naloxone co-treatment induces analgesia is not yet defined. Low-dose naloxone may elicit release of endorphins or perhaps displace endorphins from receptor sites not relevant to analgesia, whereas at higher doses it blocks the action of the released or displaced endorphin at the postsynaptic receptor for analgesia.188,189

Other Uses of Opioid Antagonists Opioid antagonist drugs provide an alternative to methadone for the pharmacologic treat-

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ment of opioid dependence.190,191 By blocking the euphoria produced by opioid agonists, antagonists help deter the use of opioid drugs. Naloxone has not proven useful because of its short duration of action and poor oral bioavailability.192 However, naltrexone is an orally effective opioid antagonist with a long duration of action, and was approved by the Federal Drug Administration in 1983 for the maintenance of opioid abstinence. A 50-mg dose can block the effects of standard doses of exogenously administered opioids (i.e., 25 mg of intravenous heroin) for 24 hours. The recommended dose of naltrexone for opioid abstinence is 50–100 mg daily or 100–150 mg every other day to produce a total weekly dose of approximately 350 mg.190 Naltrexone has been used in a wide spectrum of animal and human studies, and has shown encouraging initial findings for such disorders as amenorrhea, 193,194 retroviral illnesses,195 alcohol dependence,196 erectile dysfunction,197 heroin dependence,198–200 and obesity,107 although no benefit has been demonstrated as an addition to neuroleptics in schizophrenia.201 Use of opioid antagonists has been associated with changes in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones.202 The clinical significance of such changes is not fully understood.

Conclusion Systemically administered opioid antagonists have well recognized roles in reversing opioid CNS toxicity and countering certain side effects, such as pruritus, associated with spinally administered opioids. Palliative care practitioners should be familiar with systemic administration of opioid antagonists at low dosages for rare patients requiring partial or complete reversal of opioid toxicity (typically respiratory depression or severe sedation), and be aware of the need to titrate repeated dosages of an antagonist rather than producing full withdrawal symptoms or failing to maintain adequate reversal. Orally-administered opioid antagonists have an established role now in the management of opioid abstinence, and may be useful in the management of alcohol abuse. They may also have a useful role in palliative care practice for treating or preventing opioid-induced constipation. A va-

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riety of additional usages of opioid deserve attention, including the potential role of these agents in counteracting other gastrointestinal side effects of opioids, the treatment of opioid-related and -unrelated pruritus, and the concurrent use of low dosages of antagonists with standard agonists to reduce toxicity, improve specificity of action, and reduce tolerance. Methylnaltrexone, a new antagonist of peripheral opioid receptors, is not commercially available, but may be clinically useful for the prevention and treatment of opioid-induced side effects, especially constipation, without affecting analgesia, and may allow for more aggressive use of opioid analgesics with fewer adverse effects.

Addendum Since submission of this article, another investigational drug, ADL 8-2698 (Adolor; Exton, PA)—a selective inhibitor of gastrointestinal opioid receptors that is poorly absorbed when given orally and does not readily cross the blood–brain barrier—has been shown to speed the recovery of bowel function and shorten the duration of hospitalization for patients receiving opioids for postoperative pain relief after undergoing partial colectomy or abdominal hysterectomy.207

Acknowledgments Dr. Billings is a Faculty Scholar of the Project on Death in America. This work was supported, in part, by a grant from the Robert Wood Johnson Foundation and by the John D. Stoeckle Center at the Massachusetts General Hospital.

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