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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.58 no.5 Campinas Sept./Oct. 2008
The role of peripheral opiate antagonists in pain medicine and perioperative care*
El papel de los antagonistas periféricos de los opioides en el tratamiento del dolor y en los cuidados perioperatorios
Pedro Paulo Tanaka,TSA, M.D.I; Jonathan Moss, M.D.II
Associate Professor (Anestesia) Stanford School of Medicine; Professor Adjunto
da Disciplina de Anestesiologia da UFPR; Co-Responsável do CET/SBA do
Hospital de Clínicas da UFPR
IIProfessor e Vice Chairman for Research Dept of Anesthesia and Critical Care Professor of the College; Chair, Institutional Review Board, University of Chicago
OBJECTIVES: Pre-clinical and clinical trials of peripheral opiate antagonists
have shed new light on the effects of exogenous and endogenous opioids.
CONTENTS: This article review preclinical studies and clinical opioid bowel disfunction trials.
CONCLUSIONS: If approved these drugs may offer potential solutions to important clinical problems in pain management.
Key Words: ANALGESICS, Opioids: antagonists; COMPLICATIONS: constipation.
Y OBJETIVOS: Estudios clínicos y preclínicos sobre los antagonistas
periféricos de los opioides aumentaron nuestro conocimiento sobre los
efectos de los opioides exógenos y endógenos.
CONTENIDO: Este artículo nos trae una reflexión de los estudios clínicos y preclínicos sobre la disfunción intestinal secundaria al uso de opioides.
CONCLUSIONES: Si se aprueban, los referidos fármacos pueden representar soluciones importantes para los problemas encontrados en la práctica médica en relación con el tratamiento del dolor.
Opiates have been used for some 4,000 years and have been the subject of intense study since the crystallization of morphine by Serturner in 1805. We have learned a great deal about the mechanism of action of opiates, identified and cloned opioid receptors (µ, κ, δ, nociceptin), and described the distribution of these receptors in the central nervous system and throughout the gastrointestinal (GI) tract 1,2. Despite our understanding of the biology of opiates and pain, few new approaches to patient care have emerged. Although µ opiates are effective perioperatively and in pain management, their adverse effects remain troublesome and often can limit their use (Table 1). Opiates remain a mainstay in pain management and perioperative care despite attempts to develop alternative analgesic therapies.
Pruritis is common, particularly with parenteral and neuraxial opiates. Antitussive effects, which may be therapeutic, also can be problematic in the perioperative setting. Urinary retention, nausea and vomiting, decreased gastric emptying, and constipation often limit opiate dose or use 3-6.
Among the adverse effects of opiates, the most clinically important is the GI effect. Constipation occurs in over half of patients receiving opiates for palliative care 7. It is often refractory to stool softeners and may limit effective pain control 6,8. Patients preferred pain to the severe constipation induced by opiates 9. Moreover, patients do not become tolerant to the constipating effects of opiates.
Opiates are also widely used perioperatively. In addition to opiates that are administered intraoperatively and post-operatively to facilitate pain relief, a growing body of evidence suggests endogenous opioids, triggered by pain and bowel manipulation, may play a significant role in the pathogenesis of perioperative bowel dysfunction. Opioids can exacerbate this dysfunction.
The development of two peripheral opiate antagonists, methylnaltrexone (MNTX) and alvimopan, have allowed scientists and physicians to differentiate between peripheral and central adverse effects of opiates, and explore their potential clinical uses. It is the purpose of this manuscript to review how peripheral opiate antagonists have been used to respond, focusing on their role in pain medicine and perioperative care with particular reference to their role in the gut.
PHARMACOTHERAPY FOR OPIATE ADVERSE EFFECTS
It has been proposed that the µ opiate receptor modulates both the analgesic and gut effects 10 and that endogenous opiates 2,11 can directly influence gut motility. There have been several attempts to utilize tertiary opiate antagonists to reverse the GI effects of opiates. Initial attempts to separate the analgesic from adverse effects of opiates focused on the oral use of low doses of tertiary compounds such as naloxone. Naloxone seemed a good candidate to reverse opiate-induced constipation because only 2% is absorbed into the circulation from first pass metabolism. In several small trials, naloxone and similar tertiary opiate antagonists successfully reversed the constipating effects of opiates. However, because the tertiary opiate antagonists cross the blood-brain barrier, breakthrough pain attributed to an inability to titrate an exact dose has accompanied their usage 12-15. However, one recent study in children demonstrated that low dose naloxone was successfully used to reduce some opioid-induced side effects 16.
Professor Leon Goldberg reasoned that a charged molecule with opiate antagonist properties would not penetrate the blood-brain barrier, thus preserving central analgesia when given with opiates (Figure 1). He developed methylnaltrexone to reverse opioid-induced constipation.
It has long been known that morphine and other opioids slow normal gut function 2. However without peripheral opiates antagonists it was not known whether the effects on opioids on the gut were central or peripheral. In isolated guinea-pig ileum and muscle strip preparations of human small intestine, methylnaltrexone reversed morphine-induced inhibition of contraction, indicating its direct action on the bowel (Figure 2) 17. Methylnaltrexone exhibited similar effects to naloxone on morphine-induced inhibition, although it was significantly less potent. Interestingly, in the human small intestine preparation, methylnaltrexone by itself enhanced the force of muscle contraction by about 30% 17 suggesting an important role endogenous opioid activity in gut tissue.
An early study in healthy human volunteers demonstrated that intravenous MNTX could prevent opioid-induced delay in bowel motility without affecting analgesia (Figure 2 and 3) 18. Oral-cecal transit time and pain intensity scores (from the cold pressor test) were assessed in a randomized, double-blind study in which 12 volunteers were given placebo, placebo plus 0.5 mg.kg-1 morphine, or 0.45 mg.kg-1 MNTX plus 0.5 mg.kg-1 morphine. During the placebo-morphine period, oral-cecal transit time increased significantly from a baseline of 104.6 ± 31.1 minutes to 163.3 ± 39.8 minutes. During the placebo-morphine-MNTX period, oral-cecal transit time did not change significantly in all 12 subjects (106.3 ± 39.8 minutes). Morphine administration significantly reduced the pain intensity ratings both without and with concomitant administration of MNTX, indicating that MNTX did not antagonize the central morphine activity that induced analgesia (see Figure 3). This experiment represented the first human study separating out the central analgesic effects of opiates from their peripheral enteric effect.
In a subsequent study in 14 human volunteers 19, three ascending single oral doses of MNTX (0.64, 6.4, and 19.2 mg.kg-1) were administered to evaluate whether MNTX could be effective when administered orally. Subjects received intravenous morphine (0.05 mg.kg-1) with either placebo or oral MNTX (19.2 mg.kg-1). Oral MNTX prevented the delay in oral-cecal transit time observed with morphine administered alone (Figure 4). Morphine alone increased oral-cecal transit time significantly from 114.6 ± 37.0 minutes at baseline to 158.6 ± 50.2 minutes (p < 0.001). MNTX prevented the delay in 13 of 14 subjects (transit time 110.4 ± 45.0 minutes; not significant vs baseline; p < 0.005 vs morphine alone). The inhibition of the morphine-induced GI effect by oral MNTX was dose dependent. There was no correlation between changes in transit time and the MNTX plasma concentrations over a three-hour period. This suggests that the effects were predominantly the local luminal actions of the compound.
Preliminary studies have also been performed with an enteric-coated formulation of MNTX that prevents gastric absorption and releases drug only in the small and large intestine 20. Enteric-coated MNTX completely prevented the effects of morphine in delaying oral-cecal transit time in healthy volunteers at substantially lower concentrations than did the uncoated drug, providing further evidence of direct and local action of MNTX on the receptors of the gut.
CHRONIC OPIOID USE
While these studies suggest that MNTX has the therapeutic potential to decrease the effects of opioids on GI motility while preserving analgesia, they were performed in healthy subjects receiving a single dose of morphine. Receptor physiology, however, may be altered in opioid-tolerant individuals, such as subjects receiving methadone maintenance therapy and patients with cancer receiving long-term opioid pain medications. Opioid bowel dysfunction (OBD) is a common side effect among patients in methadone maintenance programs and is a major cause for patients dropping out of these programs. Delays in gut transit time and corresponding increases in complaints of constipation are clinically important and have been studied in these subjects 21. The clinical utility of MNTX for treating bowel dysfunction resulting from long-term opioid use was therefore investigated in subjects in a methadone maintenance program, who were in stable health but were receiving long-term opioid therapy.
A double-blind, placebo-controlled, randomized trial was performed in 22 subjects undergoing long-term methadone therapy to examine the use of intravenous MNTX for the treatment of OBD. Methylnaltrexone doses of 0.015, 0.05, 0.1, and 0.2 mg.kg-1 were administered sequentially on both days 1 and 2 of the study until a laxation response was observed 22. The 11 subjects in the placebo-treated group showed no laxation response, whereas 10 of 11 subjects in the MNTX group achieved laxation on day 1, and all 11 participants had an immediate bowel movement on day 2 (Table II). Oral-cecal transit time remained unchanged in the placebo-treated group, whereas in MNTX-treated patients, mean transit time was reduced from 132.3 ± 36.0 minutes at baseline to 54.5 ± 19.3 minutes (Figure 5). Importantly, no opioid withdrawal symptoms were noted after MNTX treatment, and 8 of 11 subjects receiving MNTX expressed satisfaction with the therapy, in contrast to the placebo-treated group in which none of 11 subjects expressed satisfaction and 7 of 11 expressed dissatisfaction.
The mean doses of MNTX that produced laxation were 0.09 mg.kg-1 and 0.1 mg.kg-1 on days 1 and 2, respectively. The absence of withdrawal symptoms in these patients is strong evidence for the lack of central effects of MNTX, in a population potentially exceedingly sensitive to such effects. A similar trial was performed in methadone maintenance patients receiving oral methylnaltrexone, but in this case laxation was measured in hours as opposed to minutes 23.
The route of antagonist administration may be significant. Laxation occurred immediately after IV administration of MNTX but several hours after oral administration. In order to utilize the drug in a fashion that conferred predicatability a subcutaneous route was developed. After subcutaneous administration, changes in oral cecal transit time occurred over a period of about 15 minutes in volunteers 24. Thus, the several routes for administration; oral, intravenous, or subcutaneous, have various onset of action and duration times. While MNTX clearly worked in the setting of addiction, an important issue is whether response could be achieved in the setting of advanced illness where co-morbidity is significant, and doses of opiates may be very high. A multi-institutional phase 2b study of subcutaneous MNTX in 33 palliative care patients with opiate-induced constipation revealed dose-related laxation 70% of the treated patients laxated, most within one hour, without significant side effects or any evidence of withdrawal 25. This was confirmed in two recently reported randomized double-blind placebo- controlled trials of MNTX in palliative care. In the first study (MNTX 301), in which 154 patients with advanced illness received either a single dose of MNTX (0.15 or 0.3 mg.kg-1) or placebo with 4 weeks of open label therapy (Figure 6) 26 sixty-two percent laxated within 4 hours of their first drug injection vs. 13% with placebo (p < 0.0001). Importantly, most patients responded within an hour of treatment. A second phase 3 clinical study (MNTX 302) of subcutaneous administration of MNTX (0.15 mg.kg-1), induced laxation within four hours in 48.4% of severely constipated patients with advanced illness, more than three times the rate of placebo (15.5%), on average over a two-week period with every-other day dosing. Overall, more than 70% of these medically complex patients responded to subcutaneous MNTX, and in these patients the median time to laxation for patients who responded was 30 minutes. No patients had reversal of their analgesia.
On the basis of these two phase 3 studies in advanced illness subcutaneous methylnaltrexone has been submitted for marketing approval to various health regulatory authorities around the world.
While methylnaltexone has been initially developed for use in opioid-induced constipation in advanced illness, another peripheral opiate antagonist, alvimopan, has been extensively evaluated for its use in post-operastive ileus.
There are three lines of evidence for a role of endogenous opioids in post-operative ileus. First, an animal model of post-operative ileus, equine colic, supports the role of endogenous opioids in GI motility 27. Levels of endorphins in this syndrome are elevated 100-fold. A second argument for a role of endogenous opioids in ileus comes from clinical studies of multimodal therapy. In addition to their direct action on the gut to change GI motility and transit, opioids also alter autonomic output to the gut 28-31. A series of elegant clinical studies by Kehlet et al. 32 suggest that multimodal strategies designed to limit perioperative opiate use (such as thoracic epidurals) result in faster recovery of intestinal function and decreased length of hospital stay after abdominal operations. However, while the use of multimodal therapy in clinical studies is well documented, practical implementation may be difficult. Finally, the recent development of one peripheral opiate antagonist, alvimopan, and its use in post-operative ileus suggests the role of endogenous opioids in this syndrome.
Alvimopan, an orally active novel, peripherally acting mu-opioid receptor antagonist appears to accelerate GI recovery after bowel resection (BR) or hysterectomy. In an initial study of 78 patients undergoing BR or hysterectomy, time to feeding and discharge eligibility were markedly improved without changes in PCA requirements or VAS scales 33. Several phase 3 trials trials have been performed in the post-operative setting. A pooled retrospective subset analysis of BR patients in 3 of the alvimopan phase 3 trials has been published 34. Randomized BR patients received alvimopan 6 mg (n = 397), 12 mg (n = 413), or placebo (n = 402) > 2 hours before surgery and twice daily until hospital discharge for < 7 days. The primary endpoint of each trial was time to recovery of GI function. Hospital discharge order (DCO) written, readmission, and morbidities were also assessed. Cox proportional hazard models were used to analyze treatment effects on time-to-event endpoints. Alvimopan (6 or 12 mg) significantly accelerated GI recovery (GI-3; hazard ratio = 1.28 and 1.38, respectively; p < 0.001 for both). Alvimopan significantly accelerated time to DCO written by 16 hours for 6 mg and 18 hours for 12 mg (p < 0.001 for both) from a mean of 147 hours for placebo. Alvimopan-treated patients had reduced post-operative morbidity compared with placebo, and incidence of prolonged hospital stay or readmission was significantly reduced (p < 0.001). Tolerability profiles were similar among groups. Alvimopan significantly accelerated GI recovery in BR patients. As with any drug given orally in the acute perioperative period, dose-response relationships have proven challenging for alvimopan. The 12-mg dose provided more consistent benefits across both sexes and all ages. Post-operative morbidity rates, prolonged hospital stay, and rates of hospital readmission were significantly reduced by alvimopan. One subsequent phase 3 trial in BR patients supports this analysis. A recent meta-analysis of data from patients with colorectal cancer demonstrated significant improvement in post-operative GI function and discharge eligibility 35. (Table III)
Alvimopan has currently received an approvable letter from the U.S. FDA for use in post-operative ileus but additional safety data has been requested.
In addition to the trials of alvimopan with POI, a small phase two trial of iv MNTX in segmental colectomies led to a significant improvement in post-operative bowel recovery and acceleration of discharge eligibility 36. Taken together these trials suggest a role for peripheral opiate antagonists in post-operative ileus.
OTHER POTENTIAL USES OF PERIPHERAL OPIATE ANTAGONISTS
A series of basic and clinical studies suggest a role for peripheral opiate antagonists beyond reversal of opiate induced effects on GI motility. Nausea and vomiting are other well-known adverse effects of opiates that have peripheral and central components. Intraventricularly administered opioids suppress vomiting, even in low doses. However, opioids given intravenously often induce emesis. The explanation for this dichotomy may be that the area of the brain responsible for mediating opioid-induced emesis has a permeable blood-brain barrier. Methylnaltrexone causes a reduction in nausea and vomiting in volunteers, perhaps manifest through neural circuits between the enteric nervous system and the brain 37. Recent analysis of alvimopan data in patients undergoing colectomy demonstrates a significant reduction in post-operative nausea and vomiting 35. (Table 3)
Peripheral mechanisms may be involved in opioid actions on the urinary bladder. A recent double-blind study of methylnaltexone on bladder function demonstrated that urinary retention, an important side effect of opiates, may be partially peripheral in nature 38. In that study, 13 healthy male volunteers received an intravenous (IV) infusion of remifentanil at 0.15 µg.kg-1.min-1, then a single IV dose of study medication: methylnaltrexone 0.3 mg.kg-1, naloxone 0.01 mg.kg-1, or saline. Urodynamics were measured with indwelling bladder and rectal catheters, and pupil size was assessed with infrared pupillometry. Remifentanil decreased detrusor pressure in 21/25 sessions and caused complete urinary retention in 18/25. Voiding was possible in 7/7, 5/12, and 0/6 sessions after naloxone, methylnaltrexone, and saline, respectively (p < 0.0013). Remifentanil caused marked miosis that was reversed by naloxone, but not methylnaltrexone or placebo (p < 0.0001). The pupil data confirm that methylnaltrexone did not reverse central opioid effects. Reversal of urinary retention by methylnaltrexone indicates that peripheral mechanisms may play a role in opioid-induced bladder dysfunction. Dysphoria and pruritus associated with parenteral opiates are also attenuated by MNTX, although it has not been studied whether the pruritus associated with neuraxial opiates can be relieved by MNTX 39. Finally, decreased gastric emptying, an adverse effect from even low doses of morphine, which can be significant in enteral nutrition, can be rapidly reversed by MNTX 37, suggesting a possible role for the drug in facilitating feeding in ICU patients receiving opiates .
In addition to clinical studies of methylnaltexone, several laboratory studies suggest a role of methylnaltrexone in reversing cellular effects of opiates. These studies include modulation of opiate effects on the immunologic system, angiogenesis, and production of a lethality factor by bacteria. These roles of opioids are are particularly pertinent for post-operative patients, cancer patients, and patients with AIDS. Methadone facilitates replication of the CCR5 binding site, the route by which the HIV virus enters cells 40, in monocyte-derived macrophages and glial cells. This replication has been proposed as an explanation for the increased infectivity described in HIV-positive patients receiving opiates. Clinically relevant doses of MNTX block opiate-induced increases in the CCR5 receptor, as well as viral replication and entry in this model system 41, suggesting a potential therapeutic role in the clinical setting of HIV positive patients with AIDS pain or addiction.
Recent in vitro data suggest that morphine in clinically relevant doses promotes angiogenesis, partly by transactivation of VEGF receptors, and that this opiate-induced endothelial cell migration and proliferation can be attenuated by MNTX 42,43. A recent retrospective study demonstrated two-to-four fold differences in the recurrence rate of breast cancer contingent upon whether patients received general or regional anesthesia for their procedures 44. Whether this is due to an effect of the epidural anesthetic, interruption of stress pathways or an effect of the opiates on angiogenesis is unknown. Further, the model system predicted a synergy between chemotherapeutic agents and MNTX beyond the receptor level. A potentiation of MNTX on the anti-angiogenic effects of chemotherapeutic agents 5FU and bevacizumab has been reported in pulmonary endothelial cells 45. Recent in vitro studies have determined that pseudomonas have mu opiate receptors that produce the lethality factors procyanin and PA-1L. These are blocked by MNTX suggesting a role of opiates in bacterial sepsis that may be influenced by antagonists 46.
METHYLNALTREXONE VS ALVIMOPAN
Although their mechanism of action is similar, there are important differences between MNTX and alvimopan, which derive from their routes of administration. MNTX can be administered parenterally or orally; alvimopan is being developed for oral use. Oral administration has the advantage of ease of use in outpatients, but may result in slower onset of action. Oral alvimopan studies in chronic pain patients generally utilize laxation within 8 hours as an endpoint. IV MNTX promotes laxation within minutes, subcutaneous MNTX in less than an hour, and oral MNTX in several hours. A second difference is that oral drugs also may not be as successful in blocking the systemic adverse effects of opiates if there is limited systemic exposure. Thus, while constipation can be attenuated with an oral agent, pruritis or urinary retention will not be relieved unless that drug enters the systemic circulation 47. Finally, the oral route of administration is convenient but may be undesirable in post-operative or other patients who already have decreased GI motility, or those receiving gastric suction. Thus, there are compelling reasons for development of both a parenteral and oral peripheral opiate antagonist for clinical practice.
Change the approval status - alvimopan is now approved in US to facilitate gut recovery after bowel surgery and anastamosis and that MNTX sq is approved in US, EU and Canada for opioid induced constipation in patients with advanced illness in palliative care when response to laxatives has not been sufficient.
Conflict of interest - J. Moss serves as a paid consultant to Progenics Pharmaceuticals, has a financial interest in MNTX as a patent holder through the University of Chicago, and receives stock options from Progenics.
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Submitted em 20
de setembro de 2007 *
Received from CET/SBA do Hospital de Clinicas da Universidade Federal do Parana
(UFPR), Curitiba, PR
Accepted para publicação em 2 de junho de 2008
Submitted em 20
de setembro de 2007
* Received from CET/SBA do Hospital de Clinicas da Universidade Federal do Parana (UFPR), Curitiba, PR