TY - JOUR
AU - Hagemann, Tracy, M.
AB - Abstract Purpose Published reports on placebo-controlled clinical trials and other studies investigating the use of pure opioid antagonists for the prevention and treatment of opioid-induced pruritus (OIP) were evaluated. Summary OIP is a common adverse effect of therapeutic use of opioid medications that can have a major impact on patients’ comfort, quality of life, and willingness to continue opioid therapy. A literature search identified more than a dozen published reports on the use of pure opioid antagonists (naloxone, naltrexone, methylnaltrexone) for the management of OIP in pediatric and adult patients. Of the studies included in this review, most investigated the effects of naloxone administered by various parenteral routes for the prevention of OIP. Some of those studies indicated a significant reduction in the frequency or severity of pruritus with use of naloxone (a low-dose, continuous i.v. infusion of naloxone appeared to be the most effective treatment). A significant diminution of analgesia requiring increased cumulative doses of morphine was also observed in some studies. A number of studies evaluating the use of orally administered naltrexone for the management of OIP yielded generally less favorable results. Evidence from one small study suggested a potential role for orally administered methylnaltrexone in the prevention of OIP. Conclusion Based on the existing data, a low-dose, continuous i.v. infusion of naloxone has the largest body of evidence supporting its use for prevention of OIP in adult and pediatric patients. Dosage, Drug administration, Methylnaltrexone, Morphine, Naloxone, Naltrexone, Opiate antagonists, Opiates, Pediatrics, Pruritus, Quality of life, Toxicity Opioid analgesics are the cornerstone of the treatment of moderate-to-severe pain, but their use is often limited by opioid-related adverse effects, such as sedation, pruritus, nausea, respiratory depression, hypotension, and constipation. Opioid-induced pruritus (OIP) affects 10–50% of patients receiving i.v. opioids and 20–100% of those receiving epidural or intrathecal opioid therapy.1 The frequency of OIP rises with increasing opioid dosages.2 A variety of medications with differing mechanisms of action have been used for the prevention and treatment of OIP, with mixed results; these medications include pure opioid-receptor antagonists, mixed opioid-receptor agonist–antagonists, serotonin 5-HT3 antagonists, dopamine D2-receptor agonists, and antihistamines.1 The mechanism of OIP has not been fully elucidated; several mechanisms have been proposed. Traditionally, because it was believed that OIP occurs secondary to histamine release from mast cells, antihistamines (e.g., diphenhydramine) were used as first-line agents. However, research has shown that central μ-opioid receptors play a significant role in the pathophysiology of OIP.3 Moreover, itching may be mediated by the peripheral effects of opioid peptides.4 In light of those findings, pure opioid antagonists (e.g., naloxone, naltrexone) have been evaluated for the management of OIP. Published studies have evaluated the use of opioid antagonists for OIP prevention; however, there are limited data on the use of opioid antagonists for the treatment of active pruritus. Due to the mechanism of action of pure opioid antagonists, it is prudent to balance the potential benefits of their use as adjunct agents for management of OIP against the potential for reversal of analgesic activity. This article evaluates the current body of literature for evidence on the most effective pure opioid antagonist, route of administration, and dosage for the management of OIP. A search was conducted using MEDLINE (1950–May 2010), EMBASE (1988–May 2010), International Pharmaceutical Abstracts (1970–May 2010), and the Cochrane Library (1996–May 2010) with the keywords naloxone, naltrexone, pruritus, and opioid antagonist. The search was limited to English-language human studies. Reference citations from relevant articles were also reviewed. Naloxone A synthetic derivative of oxymorphone, naloxone antagonizes the pharmacologic effects of opioid analgesics.5 It competitively antagonizes all opioid-receptor sites, including the μ, κ, and δ sites. Naloxone has no opioid effects. The onset of effect is typically within two minutes after i.v. administration and two to five minutes after administration by subcutaneous, intramuscular, and other parenteral routes. Naloxone is poorly absorbed from the gastrointestinal tract and has a relatively short half-life, approximately one hour.5 Naloxone is marketed for use in children and adults for reversal of opioid overdose and for reversal of respiratory depression resulting from therapeutic opioid use.5 The recommended dosage of naloxone hydrochloride for adults for total reversal of opioid overdose is 0.4–2 mg via an i.v. bolus, repeated every two to three minutes to a maximum dosage of 10 mg. For reversal of opioid-induced respiratory depression, the adult dosage is 0.1–0.2 mg administered as an i.v. bolus and repeated every two to three minutes as needed.5,6 The dosage for total reversal in children five years of age and younger is 0.1 mg/kg, to be repeated every two to three minutes as needed; the dosage for children over five years of age is 2 mg, to be repeated every two to three minutes as needed. The dosage used to treat pediatric opioid-induced respiratory depression is 0.001–0.015 mg/kg, to be repeated every two to three minutes as needed. Several routes of administration (and dosages of naloxone) for OIP have been investigated, including intermittent and continuous i.v. infusion, subcutaneous injection, and epidural infusion. Intermittent i.v. administration Saiah et al.7 conducted a prospective, randomized, double-blind comparison trial of naloxone versus propofol for treatment of epidural morphine-induced pruritus in 40 postsurgical patients. All patients received a single 4-mg bolus of epidural morphine sulfate at the completion of the surgery. Patients with severe pruritus (i.e., a score of 4–5 on a 5-point pruritus rating scale, with 1 indicating no pruritus and 5 indicating intractable pruritus and scratching) received propofol 10 mg i.v. (n = 20) or naloxone hydrochloride 2 μg/ kg i.v. (n = 20). If no relief occurred within five minutes of the first dose, a second dose of the same agent was administered; patients who did not experience adequate relief after the second dose (i.e., still had a pruritus rating scale score of >2) were treated with the other study agent. The rate of successful treatment of OIP with the first dose was identical in both treatment groups (55%), as was the overall therapy success rate (80%). Diminished pain control, as evidenced by a 2-point increase in pain rating, was noted in 9 patients (45%) in the naloxone group and no patients in the propofol group. Of note, 6 patients (30%) reported a decrease in pain in the propofol group. Cepeda et al.8 conducted a prospective, randomized, double-blind controlled trial in 166 patients undergoing surgical procedures lasting longer than 3 hours. The study sought to determine the efficacy of combining naloxone with morphine to be delivered intermittently by an i.v. patient self-administration (PSA) device. The patients received PSA morphine plus naloxone (n = 86) or PSA morphine plus placebo (n = 80). Initial PSA settings specified morphine sulfate 0.5 mg plus either naloxone hydrochloride 3 μg or 0.9% sodium chloride (placebo) every 10 minutes, with no basal infusion. The severity of pruritus was assessed, but the method of assessment was not specified. No significant differences were found between treatment groups in the rates of opioid-induced adverse effects, including pruritus (2.3% with naloxone versus 5% with placebo, p = 0.3). This study was powered only to detect a decrease in opioid requirements, not the frequency of adverse effects. A greater proportion of patients in the naloxone group had inadequate analgesia (44.2% versus 25.6% in the placebo group, p = 0.025). Compared with the placebo group, the morphine-plus-naloxone group required an average of 2.9 mg more morphine sulfate (95% confidence interval [CI], 0.7–5.0), reported greater pain intensity (p = 0.04), and were less satisfied with treatment (p = 0.01). The average dose of naloxone hydrochloride used over 24 hours was calculated to be 0.06 μg/kg/hr; however, within the first 2 hours, more rescue doses were required in the naloxone hydrochloride group, increasing the mean dosage during that period to 0.5 μg/kg/hr. Patients reporting lower satisfaction with treatment received higher doses of naloxone than patients with higher satisfaction, with a mean difference of 72 μg in naloxone hydrochloride dosage between groups (95% CI, –61 to –85 μg). Sartain et al.9 performed a double-blind, randomized, controlled study comparing use of intermittent i.v. therapy with morphine plus placebo (n = 46) versus morphine plus naloxone (n = 46) delivered via a PSA device after hysterectomy. Patients were stratified by type of operation (abdominal or vaginal) and randomly assigned to treatment groups. Settings for PSA specified a 1-mg bolus of morphine sulfate plus naloxone hydrochloride 13.3 μg or placebo, with a five-minute PSA lockout and no basal infusion. Pain and adverse effects were assessed at 6 and 24 hours postoperatively. Pruritus was assessed using verbal ratings (none, mild, moderate, severe). This study found no difference between groups in the frequency of pruritus (58.7% with placebo versus 56.5% with naloxone, p = 0.833), pain scores, the amount of morphine used, or the use of supplemental analgesia. The median naloxone hydrochloride dosage over 24 hours was calculated as 0.38 μg/kg/hr. Overall, the two studies of combination i.v. naloxone–morphine therapy given via PSA device indicated no benefit in the prevention of OIP when compared with placebo.8,9 The lack of a significant antipruritic effect in the two studies may have been due to the relatively short half-life of naloxone (55 minutes). Intermittent i.v. administration of naloxone results in greater fluctuation of drug concentrations and a shorter duration of action than are seen with morphine. The study by Saiah et al.7 evaluated treatment of active pruritus after a single dose of epidural morphine with two intermittent doses of naloxone. Only 55% of patients responded to the initial dose, with 80% responding after two doses; however, only a single epidural dose of morphine was used. As noted previously, epidural administration of opioids is typically associated with an increased frequency of pruritus. In regard to analgesia, the studies by Cepeda et al.8 and Saiah et al.7 found a significant reversal in analgesia and increased pain with naloxone, whereas the study by Sartain et al.9 reported no difference. When evaluating the two studies of combination naloxone–morphine therapy administered by a PSA device, it is difficult to directly compare the outcomes because the doses used differed (3 μg versus 13.3 μg of naloxone hydrochloride).8,9 Moreover, the primary outcomes evaluated differed: Cepeda et al. focused on opioid requirements whereas Sartain et al. focused on opioid-related adverse effects. Continuous i.v. administration Kendrick et al.10 conducted a randomized, double-blind study comparing naloxone and nalbuphine, a partial μ-receptor antagonist and κ-receptor agonist, for the prevention of OIP in 51 women undergoing cesarean section. All patients received one dose of morphine via epidural catheter after delivery; the study drugs were delivered via a PSA device. The patients were randomly assigned to three groups: group A (n = 17), which received nalbuphine hydrochloride at a basal rate of 2.5 mg/hr and a PSA dose of nalbuphine hydrochloride of 1 mg every five minutes; group B (n = 16), which received naloxone hydrochloride at a basal rate of 50 μg/hr and a PSA dose of placebo every five minutes; and group C (n = 18), which received naloxone hydrochloride at a basal rate of 50 μg/hr and a PSA dose of naloxone hydrochloride of 40 μg every five minutes. Pain and pruritus were assessed at the beginning of the infusion and every 8 hours thereafter for 24 hours by a 10-cm visual analogue scale (VAS). The only significant difference in pruritus scores among treatment groups occurred from hours 16–24, with group B (naloxone and PSA placebo) having significantly higher pruritus scores (p < 0.05). No differences were noted in pain scores among treatment groups. However, the authors of the study noted that there was a shortened duration of analgesic effects after 16 hours in patients receiving naloxone. For the naloxone groups (groups B and C), the mean ± S.D. hourly dosages of naloxone hydrochloride (basal and PSA) at 24 hours were 50 μg/hr and 74 ± 32 μg/hr, respectively. The maximum dosage of naloxone hydrochloride received by any patient in the study was approximately 3 μg/kg/hr. The authors noted that there is wide interpatient variability in the naloxone dosage required and that PSA may be appropriate for delivery of patient-specific therapy. Wang et al.11 also compared continuous i.v. infusions of naloxone versus nalbuphine for the prevention of epidural morphine-related adverse effects in a randomized, double-blind study of 68 women after total hysterectomy. All women received two 3-mg doses of epidural morphine sulfate 12 hours apart. Patients were randomized into three treatment groups: group 1 (n = 23) received nalbuphine hydrochloride 60 μg/kg/hr, group 2 (n = 22) received naloxone hydrochloride 2 μg/ kg/hr, and group 3 (n = 23) received a placebo. Assessment of pruritus was performed using a 3-point ordinal scale (0 = none, 1 = pruritus but no treatment requested, 2 = pruritus with treatment requested). The frequency of pruritus was significantly greater in the placebo group (group 3) than in groups 1 and 2 (78% versus 13% and 18%, respectively; p < 0.01). No differences were noted in pain scores among groups. It was noted, however, that group 2 had a greater percentage of patients requiring rescue analgesia (54.5% versus 13.0% in group 1 and 17.4% in group 3) and greater total morphine sulfate dosage (1600 mg versus 250 mg in group 1 and 300 mg in group 3). A randomized, double-blind study by Gan et al.12 evaluated the dose-related efficacy of naloxone in reducing opioid-induced adverse drug reactions, including pruritus, in 60 women during the 24 hours after hysterectomy procedures. Patients were randomly assigned to receive one of three treatments: low-dose naloxone hydrochloride at 0.25 μg/ kg/hr (n = 20), high-dose naloxone hydrochloride at 1 μg/kg/hr (n = 20), or placebo (n = 20) in conjunction with i.v. morphine sulfate PSA (40-μg/kg loading dose, 20-μg/kg maintenance dose, and a lockout interval of eight minutes, with no preset maximum dose). The method of assessment of pruritus was not described. There was a significant increase in the frequency of pruritus in the placebo group (55%) relative to the low-dose group (25%) and the high-dose group (20%, p = 0.04). There was no difference in pain scores among the groups; however, it was noted that patients receiving low-dose naloxone therapy required a lower cumulative dose of morphine sulfate (mean ± S.D., 42.3 ± 24.1 mg) than those receiving the placebo (59.1 ± 27.4 mg) or high-dose naloxone therapy (64.7 ± 33.0 mg) (p < 0.05 for both differences). The authors concluded that opioid-related adverse effects occurred at different concentration–response curves; thus, lower doses of naloxone can reverse the adverse effects without affecting pain control. The authors suggested that low-dose naloxone therapy may exert an opioid-sparing effect, noting that the patients in the low-dose naloxone group required a lower cumulative dosage of morphine. Maxwell et al.13 conducted a prospective, double-blind, randomized, controlled clinical trial of low-dose continuous-infusion naloxone therapy for prevention of opioid-induced adverse effects in 46 postoperative patients 6–17 years of age. All patients received a morphine sulfate bolus of 100 μg/kg, followed by a basal infusion at a rate of 20 μg/kg/hr and a demand dose of 20 μg/kg, with an eight-minute lockout interval and a maximum of five doses per hour. Patients were randomly assigned to receive i.v. naloxone hydrochloride at a dose of 0.25 μg/kg/hr (n = 20) or 0.9% sodium chloride (placebo) via continuous infusion (n = 26). Assessment of pruritus was performed using a 3-point ordinal scale (0 = none, 1 = pruritus present but tolerable, 2 = severe, intolerable pruritus). The frequency and severity of pruritus were nearly four times higher in the placebo group than in the naloxone group (77% versus 20%, p < 0.05). However, there were no significant differences between treatment groups in pain scores or cumulative morphine dosage (p < 0.05). A recent prospective pilot study by Koch et al.14 in 16 pediatric patients (8–18 years of age) receiving treatment for sickle cell crisis evaluated the use of continuous i.v. naloxone infusion for the management of OIP associated with the use of continuous i.v. morphine therapy. Patients were initiated on morphine sulfate at a dose of 0.05 μg/kg/hr, with PSA doses of 0.03 μg/kg every 20 minutes. The first 12 patients enrolled received naloxone hydrochloride at a dose of 0.25 μg/kg/hr (the low-dose group), and the next 6 patients enrolled received a dose of 1 μg/kg/hr (the high-dose group), based on an interim analysis showing that pruritus was still prominent with low-dose therapy. Pruritus was assessed using a 10-point VAS. Data on 2 patients were excluded from analysis due to the development of hypertension and excessive somnolence. In the high-dose group, lower pruritus scores were seen on day 1 (p = 0.08), and there was significantly less use of rescue diphenhydramine on day 2 (median, 0.4 mg/kg versus 1.6 mg/kg in the low-dose group; p = 0.04). No differences in analgesia were noted between groups. In the studies described above, the range of dosages of continuous-infusion naloxone hydrochloride therapy varied from 0.25 μg/kg/hr to a maximum of 3 μg/kg/hr. It is difficult to compare these five studies due to differing patient populations, routes of morphine delivery, dosing regimens, methods of assessing pruritus, and comparator agents (placebo, nalbuphine). In the placebo-controlled studies, a decrease in the frequency of OIP was observed; no differences were noted in trials comparing naloxone with nalbuphine. Reversal of analgesia was noted in the study by Wang et al.,11 and shortened duration of analgesia after 16 hours of naloxone therapy via continuous infusion was noted in the study by Kendrick et al.10; this could be due to decreased μ-receptor occupancy by morphine as the effectiveness of a bolus epidural dose diminishes. Additionally, patients receiving higher dosages of naloxone hydrochloride (≥2 μg/kg/hr) tended to report higher pain ratings and required a greater number of opioid rescue doses. Gan et al.12 noted an opioid-sparing effect with a lower dosage of naloxone hydrochloride (0.25 μg/kg/hr) that was not seen in the other studies. Subcutaneous administration The short duration of activity of naloxone when the drug is administered as an i.v. bolus may limit its effectiveness for the management of OIP. Intravenous access may not be feasible for all patients, and alternative routes need to be considered. It has been proposed that naloxone administered subcutaneously might behave as a slow-release preparation, thereby extending the duration of activity; a longer duration of activity could theoretically produce less fluctuation in the drug concentration and thus be more aligned with the duration of action of morphine. Lockington and Fa’aea15 evaluated the use of subcutaneous naloxone for the prevention of opioid-induced pruritus in women undergoing cesarean section with spinal analgesia in a randomized, double-blind, placebo-controlled study. All patients received intrathecal bupivacaine, morphine, and fentanyl and were randomized to receive either 400 μg of naloxone hydrochloride (n = 24) or placebo (n = 23) subcutaneously. Pain and adverse effects were evaluated at 8 and 24 hours after the subcutaneous injection using verbal rating scales. The assessment of pruritus severity was performed using a 4-point verbal rating scale (0 = no itch, 1 = itch with no need to scratch, 2 = itch with need to scratch, 3 = itch with need to scratch requiring treatment). There were no differences in the frequency of pruritus or in pain control between groups. The authors of the study speculated that the lack of benefit with subcutaneous naloxone hydrochloride might have been related to the use of an empirical dose of 400 μg, which might have resulted in underdosing naloxone hydrochloride at dosages below 0.25 μg/kg/hr, based on the average patient weight of 89.3 kg. The authors suggested that a weight-based dosage may be more appropriate. Epidural administration Choi et al.16 conducted a dose-finding study of naloxone in combination with morphine administered via continuous epidural infusion for reduction of morphine-related adverse effects in 80 women undergoing hysterectomy. Patients were randomly assigned to one of four treatment groups: group 1 received morphine sulfate 80 μg/hr only (n = 20), group 2 received morphine sulfate 80 μg/hr plus naloxone hydrochloride 0.083 μg/kg/hr (n = 20), group 3 received morphine sulfate 80 μg/hr plus naloxone hydrochloride 0.125 μg/kg/ hr (n = 20), and group 4 received morphine sulfate 80 μg/hr plus naloxone hydrochloride 0.167 μg/ kg/hr (n = 20). Pain assessment via VAS and screening for adverse effects were performed at 2, 4, 8, 16, 32, and 48 hours after treatment initiation. The severity of pruritus was assessed using a 3-point verbal rating scale (1 = no itching, 2 = tolerable itching, 3 = severe itching, needs medication). The group receiving the highest naloxone dosage (group 4) had significantly lower VAS pain scores at postoperative hours 8, 16, and 32 than group 1 (p < 0.05). Patients in groups 3 and 4 had significantly less pruritus at hours 8, 16, and 32 than those in group 1 (p < 0.05). Okutomi et al.17 conducted a double-blind, randomized, placebo-controlled study of naloxone in combination with fentanyl via continuous epidural infusion in 69 women during labor. All patients received an epidural infusion containing fentanyl, bupivacaine, and epinephrine. Patients were randomized into treatment (n = 34) and placebo (n = 35) groups. The treatment group received naloxone hydrochloride 40 μg/hr concomitantly with the epidural infusion. A visual analogue itching score was used to assess the frequency and severity of pruritus. There were no differences noted in analgesia, but patients who received naloxone had a significantly lower frequency of itching and less severe itching than those receiving placebo (71% versus 26%, p = 0.0005). Jeon et al.18 evaluated the use of naloxone mixed with morphine and delivered via a continuous epidural infusion in a double-blind, randomized, placebo-controlled study in 58 women after cesarean section. All patients received a single 4-mg bolus dose of epidural morphine sulfate. The women then received either morphine sulfate 125 μg/hr in 0.1% bupivacaine hydrochloride (group M, n = 28) or naloxone hydrochloride 25 μg/ hr plus morphine sulfate 125 μg/hr in 0.1% bupivacaine hydrochloride (group N, n = 30). Pain and opioid-related adverse effects were assessed during the first 24 hours using rating scores. The degree of pruritus was assessed with a 5-point verbal scale (1 = no itching, 2 = mild, localized itching, 3 = mild, generalized itching, 4 = moderate itching, 5 = intolerable, severe itching). The frequency of pruritus was significantly greater in group M (82% versus 47% in group N, p = 0.003), with significantly more reports of severe itching in group M (p = 0.001). There were no significant differences between groups in pain scores. The authors commented that although the frequency of OIP was significantly reduced in the naloxone group, OIP was still reported by about 50% of the treatment group; they attributed that finding to the use of a bolus dose of morphine before initiation of the naloxone infusion and suggested that naloxone be given simultaneously with the first injection of morphine. In the three aforementioned studies of epidural delivery of naloxone in combination with an opioid (fentanyl or morphine), the frequency of pruritus was decreased, with no reversal of analgesia noted. In the study by Choi et al.,16 the group receiving the highest naloxone hydrochloride dosage (0.167 μg/kg/hr) had significantly lower VAS pain scores than the group receiving morphine alone. The authors suggested that the observed lower pain scores could have been due to reduced opioid adverse effects, leading to the increased overall comfort of the patient. Naltrexone Naltrexone, an analogue of naloxone, is an orally administered pure opioid antagonist with a longer half-life than naloxone (four hours versus 55 minutes) and twice the potency.19 It competitively displaces opiate molecules at the opioid receptors while blocking opioid receptor sites. Naltrexone is considered to have no agonist effects, but some studies have reported adverse effects such as miosis, dysphoria, and respiratory depression in healthy nonaddicted recipients, suggesting that naltrexone has some degree of partial agonist activity.20 Naltrexone hydrochloride labeling is approved for the treatment of alcohol and opioid addiction in adults5; the recommended initial dose is 25 mg orally, to be followed by a maintenance dose of 50 mg daily. Abboud et al.21 conducted a prospective, double-blind, dose-finding study in 45 healthy postpartum women after cesarean delivery with epidural anesthesia. After surgery, all patients were given 4 mg of morphine sulfate epidurally at the first request for analgesia. The patients were randomly assigned to receive one of three treatments: naltrexone hydrochloride 6 mg (n = 15), naltrexone hydrochloride 9 mg (n = 15), or placebo (n = 15). Pain and pain relief were assessed at baseline and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours. The appearance of adverse effects was noted and recorded at the same time intervals (the method for assessing pruritus was not specifically described). More patients in the group receiving 9 mg naltrexone hydrochloride reported inadequate analgesia compared with those receiving placebo or 6 mg naltrexone hydrochloride (5, 1, and 1 patients, respectively; p < 0.05). Significantly more patients in the placebo group had pruritus compared with those receiving 6 or 9 mg naltrexone hydrochloride (10, 0, and 1 patients, respectively; p < 0.05). A second study conducted by Abboud et al.22 evaluated a lower dose of naltrexone in a double-blind, randomized, placebo-controlled study of 35 women after cesarean delivery with spinal anesthesia. Patients received 6 mg (n = 12) or 3 mg (n = 10) of naltrexone hydrochloride or placebo (n = 13). The intensity of pain and the frequency of pain relief were assessed with a VAS at 4, 8, 12, 16, 20, and 24 hours after administration of intrathecal morphine. There was no specific description of the evaluation of pruritus. The duration of analgesia was shorter for both naltrexone groups (mean ± standard error of the mean, 10.0 ± 2.5 hours and 12.4 ± 2.6 hours with 3- and 6-mg doses, respectively) relative to the placebo group (19.2 ± 4.5 hours). Although the difference did not reach statistical significance, clinically it was significant enough that the study was terminated early due to the shortened duration of analgesia in the treatment groups. Additionally, there were no differences noted in the use of rescue opioid doses among the groups. Pruritus was reported by 92% of patients in the placebo group, 70% of the group receiving naltrexone hydrochloride 3 mg, and 58% of patients receiving naltrexone hydrochloride 6 mg. A significant difference was found only between the placebo group and the group receiving naltrexone hydrochloride 6 mg (p < 0.05), and the latter group had significantly less vomiting and somnolence. These two studies evaluated oral doses of naltrexone hydrochloride of 3, 6, and 9 mg in obstetric patients.21,22 There was evidence of decreased pruritus only in patients receiving the higher doses of naltrexone (6 and 9 mg). The duration of analgesia was shortened in all naltrexone treatment groups but significant only with the 9- and 6-mg doses (mean ± S.D., 19.8 ± 14.7 minutes versus 33.2 ± 17.2 minutes; p < 0.05).21 Methylnaltrexone Methylnaltrexone, a derivative of naltrexone, is more polar and less lipid soluble than its parent compound, resulting in a decreased ability to cross the blood-brain barrier. As a result, methylnaltrexone functions as a peripherally acting opioid antagonist with no effect on central analgesic activity. It targets peripheral opioid-binding sites in tissues such as the gastrointestinal tract. Methylnaltrexone was developed for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care.23 To our knowledge, no published study has specifically evaluated the efficacy of subcutaneous methylnaltrexone in the management of OIP. However, a small study of 10 healthy adult volunteers by Yuan et al.24 demonstrated that oral methylnaltrexone effectively reduced the sensation of “skin itch” after administration of i.v. morphine. The frequency and severity of pruritus were assessed using a 5-point rating scale (0 = not at all, 4 = extremely). This study demonstrated a potential therapeutic benefit of methylnaltrexone in the prevention of peripherally mediated pruritus. However, due to the agent’s limited penetration across the blood-brain barrier, it may be of minimal benefit for management of centrally mediated pruritus. Discussion Pruritus is a well-recognized adverse effect of systemic opioids. While not typically life-threatening, pruritus may have an impact on patient comfort, quality of life, and willingness to continue opioid therapy. A variety of pharmacologic agents may be used to control OIP, but all have limitations. The traditional first-line agents, antihistamines (e.g., diphenhydramine), have well-known sedative effects that could add to the sedative effects of opioids, possibly leading to oversedation and an increased risk of respiratory depression. Unlike antihistamines, opioid antagonists do not cause additional sedation and have been used to reverse respiratory depression. Recently published evidence suggests that the dominant pathway for OIP is μ-receptor mediated rather than histamine-mediated, leading to increased recognition that opioid antagonists may be more appropriate first-line agents for OIP. A number of small published studies have evaluated the use of opioid antagonists such as naloxone7–18 and naltrexone21,22 in the management of OIP. The majority of studies have evaluated the use of various agents for the prevention of OIP rather than the treatment of active OIP. Only one study included in our literature review assessed naloxone as a treatment option7; while the drug was found to be effective in that study, treatment of OIP can still be difficult and there are few other published studies indicating its effectiveness. Additional research on naloxone therapy for OIP is needed. Mixed results were seen in the studies evaluating the use of opioid antagonists for the prevention of OIP. While oral naltrexone provided some benefit in some studies and its use would be more appealing to ambulatory patients, more research is needed to provide conclusive recommendations on the use of this agent. Based on the currently available evidence, a dose of 6 mg naltrexone hydrochloride appears to be appropriate for most patients. It should be noted that naltrexone is commercially available in the United States only as 25-, 50-, and 100-mg tablets; low-dose naltrexone hydrochloride (e.g., 3, 6, or 9 mg) is not available in tablet form. Epidural delivery of naloxone has been found effective against OIP; however, epidural access is not always feasible in all patients. In those patients for whom an epidural opioid is indicated, concomitant administration of epidural naloxone hydrochloride at an initial dose of 0.167–0.3 μg/kg/hr should be considered. The most well-studied regimen of naloxone involved i.v. therapy administered by continuous infusion. A continuous infusion produces less fluctuation of naloxone concentrations than bolus injections and compensates for naloxone’s relatively short half-life. Published studies of naloxone hydrochloride continuous infusion for OIP used a wide range of doses (0.25–3 μg/kg/hr). It appears that a starting dose of 0.25–1 μg/kg/ hr is the most effective without affecting analgesia. A systematic review by Kjellberg and Tramer1 concluded that doses above 2 μg/kg/hr are more likely to lead to reversal of analgesia and thus are not recommended. Despite the limited number of published studies and the small patient samples evaluated in most of the available studies, low-dose naloxone by i.v. continuous infusion may be the most practical agent and route of administration for use in the prevention of OIP in inpatient settings. That approach should be considered in patients requiring high-dose opioids (e.g., those with sickle cell disease, acute trauma, or end-stage cancer), patients receiving epidural opioids, and patients with a history of severe OIP. There is a need for additional research, especially comparisons of agents with different mechanisms of action and evaluations of different agents for the treatment of active OIP. Conclusion Based on the existing data, a low-dose, continuous i.v. infusion of naloxone has the largest body of evidence supporting its use for prevention of OIP in adult and pediatric patients. Footnotes The authors have declared no potential conflicts of interest. The Clinical Consultation section features articles that provide brief advice on how to handle specific drug therapy problems. All articles are based on a systematic review of the literature. The assistance of ASHP’s Section of Clinical Specialists and Scientists in soliciting Clinical Consultation submissions is acknowledged. Unsolicited submissions are also welcome. References 1 Kjellberg F Tramer MR . Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials . Eur J Anaesthesiol . 2001 ; 18 : 346 – 57 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Herman NL Choi KC Affleck PJ et al. . Analgesia, pruritus, and ventilation exhibit a dose-response relationship in parturients receiving intrathecal fentanyl during labor . Anesth Analg . 1999 ; 89 : 378 – 83 . Google Scholar PubMed WorldCat 3 Ko MC Song MS Edwards T et al. . The role of central μ opioid receptors in opioid-induced itch in primates . J Pharmacol Exp Ther . 2004 ; 310 : 169 – 76 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Graves MW Wall PD . Pathophysiology of itching . Lancet . 1996 ; 348 : 938 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Micromedex Healthcare Series DRUGDEX system (Internet database) . Greenwood Village, CO : Thomson Reuters Healthcare . Updated periodically . WorldCat COPAC 6 Lexi-Comp Online . Naloxone . Hudson, OH : Lexi-Comp, Inc .; 2010 Aug 4 . WorldCat COPAC 7 Saiah M Borgeat A Wilder-Smith OH et al. . Epidural-morphine-induced pruritus: propofol versus naloxone . Anesth Analg . 1994 ; 78 : 1110 – 3 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Cepeda MS Africano JM Manrique AM et al. . The combination of low dose naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period . Pain . 2002 ; 96 : 73 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Sartain JB Barry JJ Richardson CA et al. . Effect of combining naloxone and morphine for intravenous patient-controlled analgesia . Anesthesiology . 2003 ; 99 : 148 – 51 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Kendrick WD Woods AM Daly MY et al. . Naloxone versus nalbuphine infusion for prophylaxis of epidural morphine-induced pruritus . Anesth Analg . 1996 ; 82 : 641 – 7 . Google Scholar PubMed WorldCat 11 Wang JJ Ho ST Tzeng JI . Comparison of intravenous nalbuphine infusion versus naloxone in the prevention of epidural morphine-related side effects . Reg Anesth Pain Med . 1998 ; 23 : 479 – 84 . Google Scholar PubMed WorldCat 12 Gan CJ Ginsberg MB Glass PS et al. . Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate . Anesthesiology . 1997 ; 87 : 1075 – 81 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Maxwell LG Kaufmann SC Bitzer S et al. . The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: a double-blind, prospective, randomized, controlled study . Anesth Analg . 2005 ; 100 : 953 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Koch J Manworren R Clark L et al. . Pilot study of continuous co-infusion of morphine and naloxone in children with sickle cell pain crises . Am J Hematol . 2008 ; 83 : 728 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Lockington PF Fa’aea P . Subcutaneous naloxone for the prevention of intrathecal morphine induced pruritus in elective caesarean delivery . Anaesthesia . 2007 ; 62 : 672 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Choi JH Lee J Choi JH et al. . Epidural naloxone reduces pruritus and nausea without affecting analgesia by epidural morphine in bupivacaine . Can J Anaesth . 2000 ; 47 : 33 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Okutomi T Saito M Mochizuki J et al. . Prophylactic epidural naloxone reduces the incidence and severity of neuraxial fentanyl-induced pruritus during labour analgesia in primiparous parturients . Can J Anaesth . 2003 ; 50 : 961 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Jeon Y Hwang J Kang J et al. . Effects of epidural naloxone on pruritus induced by epidural morphine: a randomized controlled trial . Int J Obstet Anesth . 2005 ; 14 : 22 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Blumberg H Dayton HB Wolf PS . Analgesic and narcotic antagonist properties of noroxymorphone derivatives . Toxicol Appl Pharmacol . 1967 ; 10 : 406 . WorldCat 20 Crabtree BL . Review of naltrexone, a long-acting opiate antagonist . Clin Pharm . 1984 ; 3 : 273 – 80 . Google Scholar PubMed WorldCat 21 Abboud TK Afrasiabi A Davidson J et al. . Prophylactic oral naltrexone with intrathecal morphine: effect on adverse reactions and ventilatory responses to carbon dioxide . Anesthesiology . 1990 ; 72 : 233 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Abboud TK Lee K Zhu J et al. . Prophylactic oral naltrexone with intrathecal morphine for cesarean section: effects on adverse reactions and analgesia . Anesth Analg . 1990 ; 71 : 367 – 70 . Google Scholar Crossref Search ADS PubMed WorldCat 23 Relistor (methylnaltrexone bromide) package insert . Philadelphia : Wyeth Pharmaceuticals, Inc .; 2010 . WorldCat COPAC 24 Yuan C Foss J O’Connor M et al. . Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine . Drug Alcohol Depend . 1998 ; 52 : 161 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Copyright © 2011, American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - Use of pure opioid antagonists for management of opioid-induced pruritus
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp100475
DA - 2011-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/use-of-pure-opioid-antagonists-for-management-of-opioid-induced-SDl06lKx9t
SP - 1419
VL - 68
IS - 15
DP - DeepDyve
ER -