Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Drugs
Published in: Drugs 7/2003

01-04-2003 | Review Article

Opioid-Induced Bowel Dysfunction

Pathophysiology and Potential New Therapies

Authors: Andrea Kurz, Dr Daniel I. Sessler

Published in: Drugs | Issue 7/2003

Login to get access

Abstract

Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction. Postoperative ileus, although attributable to surgical procedures, is often exacerbated by opioid use during and following surgery. Postoperative ileus is marked by increased inhibitory neural input, heightened inflammatory responses, decreased propulsive movements and increased fluid absorption in the gastrointestinal tract. The use of opioids for chronic pain is characterised by a constellation of symptoms including hard dry stools, straining, incomplete evacuation, bloating, abdominal distension and increased gastroesophageal reflux.
The current management of opioid-induced bowel dysfunction among patients receiving opioid analgesics consists primarily of nonspecific ameliorative measures. Intensive investigations into the mode of action of opioids have characterised three opioid receptor classes — μ, δ and κ — that mediate the myriad of peripheral and central actions of opioids. Activation of μ-opioid receptors in the gastrointestinal tract is responsible for inhibition of gut motility, whereas receptors in the central nervous system mediate the analgesic actions of opioids. Blocking peripheral opioid receptors in the gut is therefore a logical therapeutic target for managing opioid-induced bowel dysfunction.
Available opioid antagonists such as naloxone are of limited use because they are readily absorbed, cross the blood-brain barrier, and act at central opioid receptors to reverse analgesia and elicit opioid withdrawal. Methylnaltrexone and alvimopan are recently developed opioid antagonists with activity that is restricted to peripheral receptors. Both have recently shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs in non-surgical patients receiving opioids for chronic pain. In addition, recent clinical studies with alvimopan suggest that it may normalise bowel function without blocking opioid analgesia in abdominal laparotomy patients with opioid-related postoperative ileus.
Literature
1.
Friedman JD, Dello Bueno FA. Opioid antagonists in the treatment of opioid-induced constipation and pruritus. Ann Pharmacother 2001; 35: 85–91PubMedCrossRef
2.
3.
Ogilvy AJ, Smith G. The gastrointestinal tract after anaesthesia. Eur J Anaesthesiol 1995; 12: 35–42
4.
Resnick J, Greenwald DA, Brandt LJ. Delayed gastric emptying and postoperative ileus after non-gastric abdominal surgery: part I. Am J Gastroenterol 1997; 92: 751–62PubMed
5.
Bungard TJ, Kale-Pradhan PB. Prokinetic agents for the treatment of postoperative ileus in adults: a review of the literature. Pharmacotherapy 1999; 19: 416–23PubMedCrossRef
6.
Resnick J, Greenwald DA, Brandt LJ. Delayed gastric emptying and postoperative ileus after non-gastric abdominal surgery: part II. Am J Gastroenterol 1997; 92: 934–40PubMed
7.
Ferraz AAB, Cowles VE, Condon RE, et al. Nonopioid analgesics shorten the duration of postoperative ileus. Am Surg 1995; 12: 1079–83
8.
Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 2001; 182 (5A Suppl.): 11S–8SPubMedCrossRef
9.
Fallon MT, Hanks GW. Morphine, constipation, and performance status in advanced cancer patients. Palliat Med 1999; 13: 159–60PubMedCrossRef
10.
Klepstad P, Borchgrevink PC, Kaasa S. Effects on cancer patients’ health-related quality of life after the start of morphine therapy. J Pain Symptom Manage 2000; 20: 19–26PubMedCrossRef
11.
Vanegas G, Ripamonti C, Sbanotto A, et al. Side effects of morphine administration in cancer patients. Cancer Nurs 1998; 21: 289–97PubMedCrossRef
12.
Vainio A, Auvinen A. Prevalence of symptoms among patients with advanced cancer: an international collaborative study: Symptom Prevalence Group. J Pain Symptom Manage 1996; 12: 3–10PubMedCrossRef
13.
World Health Organization. Cancer pain relief. Geneva: WHO Office of Publications, 1986
14.
Meuser T, Pietruck C, Radbruch L, et al. Symptoms during cancer pain treatment following WHO guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 2001; 93: 247–57PubMedCrossRef
15.
Schug SA, Zech D, Dorr U. Cancer pain management according to WHO analgesic guidelines. J Pain Symptom Manage 1990: 5: 27–32PubMedCrossRef
16.
Grond S, Zech D, Diefenbach C, et al. Prevalence and pattern of symptoms in patients with cancer pain: a prospective evaluation of 1635 cancer patients referred to a pain clinic. J Pain Symptom Manage 1994; 9: 372–82PubMedCrossRef
17.
Mancini I, Bruera E. Constipation in advanced cancer patients. Support Care Cancer 1998; 6: 356–64PubMedCrossRef
18.
General principles of gastrointestinal function: motility, nervous control, and blood circulation. In:Guyton AC, Hall JE. Textbook of medical physiology. 10th ed. Philadelphia (PA): WB Saunders, 2000: 793–801
19.
Zenilman ME. Origin and control of gastrointestinal motility. Surg Clin North Am 1993; 73: 1081–9PubMed
20.
Sarna SK. Colonic motor activity. Surg Clin North Am 1993; 73: 1201–19PubMed
21.
Pasternak GW. Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 1993; 16: 1–18PubMedCrossRef
22.
Kromer W. Endogenous opioids, the enteric nervous system, and gut motility. Dig Dis 1990; 8: 361–73PubMedCrossRef
23.
Austrup ML, Korean G. Analgesic agents for the postoperative period: opioids. Surg Clin North Am 1999; 79: 253–73PubMedCrossRef
24.
Mizoguchi H, Tseng LF, Suzuki T, et al. Differential mechanism of G-protein activation induced by endogenous muopioid peptides, endomorphin and beta-endorphin. Jpn J Pharmacol 2002; 89: 229–34PubMedCrossRef
25.
Zuckerman LA, Ferrante FM. Nonopioid and opioid analgesics. In: Ashburn MA, Rice LJ, editors. The management of pain. New York: Churchill Livingston, 1998: 111–40
26.
Tseng LF. Evidence for epsilon-opioid receptor-mediated beta-endorphin-induced analgesia. Trends Pharmacol Sci 2001; 22: 623–30PubMedCrossRef
27.
Chien CC, Pasternak GW. Selective antagonism of opioid analgesia by a sigma system. J Pharmacol Exp Ther 1994; 271: 1583–90PubMed
28.
Couture S, Debonnel G. Some of the effects of the selective sigma ligand (+)pentazocine are mediated via a naloxonesensitive receptor. Synapse 2001; 39: 323–31PubMedCrossRef
29.
Roman F, Pascaud X, Chomette G, et al. Autoradiographic localization of sigma opioid receptors in the gastrointestinal tract of the guinea pig. Gastroenterology 1989; 97: 76–82PubMed
30.
31.
Greenwald MK, Stitzer ML, Haberny KA. Human pharmacology of the opioid neuropeptide dynorphin A (1–13). J Pharmacol Exp Ther 1997; 281: 1154–63PubMed
32.
Calo G, Rizzi A, Bigoni R, et al. Pharmacological profile of nociceptin/orphanin FQ receptors. Clin Exp Pharmacol Physiol 2002; 29: 223–8PubMedCrossRef
33.
Krowicki ZK, Kapusta DR, Hornby PJ. Orphanin FQ/nociceptin and [Phe(1)Psi(CH(2)-NH)Gly(2)] nociceptin (1–13)-NH(2) stimulate gastric motor function in anaesthetized rats. Br J Pharmacol 2000; 130: 1639–45PubMedCrossRef
34.
Bagnol D, Mansour A, Akil H, et al. Cellular localization and distribution of the cloned mu and kappa opioid receptors in rat gastrointestinal tract. Neuroscience 1997; 81: 579–91PubMedCrossRef
35.
Zadina JE, Martin-Schild S, Gerall AA, et al. Endomorphins: novel endogenous mu-opiate receptor agonists in regions of high mu-opiate receptor density. Ann N Y Acad Sci 1999; 897: 136–44PubMedCrossRef
36.
Bianchi G, Ferretti P, Recchia M, et al. Morphine tissue levels and reduction of gastrointestinal transit in rats: correlation supports primary action site in the gut. Gastroenterology 1983; 85(4): 852–8PubMed
37.
De Luca A, Coupar IM. Insights into opioid actions in the intestinal tract. Pharmacol Ther 1996; 69: 103–15PubMedCrossRef
38.
Culpepper-Morgan J, Kreek MJ, Holt PR, et al. Oral administered kappa as mu opioid agonists delay gastrointestinal transit time in the guinea pig. Life Sci 1988; 42: 2073–7PubMedCrossRef
39.
Giaroni C, Somaini L, Marino F, et al. Modulation of enteric cholinergic neurons by hetero-and autoreceptors: cooperation among inhibitory inputs. Life Sci 1999; 65: 813–21PubMedCrossRef
40.
Kromer W. Reflex peristalsis in the guinea pig isolated ileum is endogenously controlled by kappa opioid receptors. Naunyn Schmiedebergs Arch Pharmacol 1990; 341: 450–4PubMed
41.
Allescher HD, Storr M, Brechmann C, et al. Modulatory effect of endogenous and exogenous opioids on the excitatory reflex pathway of the rat ileum. Neuropeptides 2000; 34: 62–8PubMedCrossRef
42.
Kaufman PN, Krevsky B, Malmud LS, et al. Role of opioid receptors in the regulation of colonic transit. Gastroenterology 1988; 94: 1351–6PubMed
43.
Ferraz AAB, Cowles VE, Condon RE, et al. Opioid and nonopioid analgesic drug effects on colon contractions in monkeys. Dig Dis Sci 1995; 40: 1417–9PubMedCrossRef
44.
Frantzides CT, Cowles V, Salaymeh B, et al. Morphine effects on humane colonic myoelectric activity in the postoperative period. Am J Surg 1992; 163: 144–9PubMedCrossRef
45.
46.
Camilleri M, Malagelada JR, Stanghellini V, et al. Dose-related effects of synthetic human beta-endorphin and naloxone on fed gastrointestinal motility. Am J Physiol 1986; 251(1 Part 1): G147–54PubMed
47.
Canty SL. Constipation as a side effect of opioids. Oncol Nurs Forum 1994; 21: 739–45PubMed
48.
49.
50.
51.
Smith J, Kelly KA, Weinshilboum RM. Pathophysiology of postoperative ileus. Arch Surg 1977; 112: 203–9PubMedCrossRef
52.
53.
Kalff JC, Schraut WH, Simmons RL, et al. Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus. Ann Surg 1998; 228: 52–63CrossRef
54.
Kalff JC, Bucholz BM, Eskandari MK, et al. Biphasic response to gut manipulation and temporal correlation of cellular infiltrates and muscle dysfunction in rats. Surgery 1999; 126: 498–509PubMedCrossRef
55.
Cali RL, Meade PG, Swanson MS, et al. Effect of morphine and incision length on bowel function after colectomy. Dis Colon Rectum 2000; 43: 163–8PubMedCrossRef
56.
Wattwil M. Postoperative pain relief and gastrointestinal motility. Acta Chir Scand Suppl 1988; 550: 140–5
57.
Brix-Christensen V, Tennesen E, Sanches RG, et al. Endogenous morphine levels increase following cardiac surgery as part of the antiinflammatory response? Int J Cardiol 1997; 62: 191–7PubMedCrossRef
58.
Brix-Christensen V, Goumon Y, Tennesn E, et al. Endogenous morphine is produced in response to cardiopulmonary bypass in neonatal pigs. Acta Anaesthesiol Scand 2000; 45: 1204–8CrossRef
59.
Yoshida S, Ohta J, Yamasaki K, et al. Effect of surgical stress on endogenous morphine and cytokine levels in the plasma alter laparoscopic or open cholecystectomy. Surg Endosc 2000; 14: 137–40PubMed
60.
Schug SA, Zech D, Grond S, et al. A long-term survey of morphine in cancer pain patients. J Pain Symptom Manage 1992; 7: 259–66PubMedCrossRef
61.
Walsh TD. Prevention of opioid side effects. J Pain Symptom Mange 1990; 5: 362–7CrossRef
62.
McMillan SC. Assessing and managing narcotic-induced constipation in adults with cancer. Cancer Control 1999; 6: 198–204PubMed
63.
Glare P, Lickiss JN. Unrecognized constipation in patients with advanced cancer: a recipe for therapeutic disaster. J Pain Symptom Manage 1992; 7: 369–71PubMedCrossRef
64.
Klepstad P, Kaasa S, Skauge M, et al. Pain intensity and side effects during titration of morphine to cancer patients using a fixed schedule dose escalation. Acta Anaesthesiol Scand 2000; 44: 656–64PubMedCrossRef
65.
Palmer CS, Ingham M, Schmier J, et al. Utility assessments of opioid treatment for patients with chronic non-cancer pain [abstract 790]. Presented at the 20th Annual Scientific meeting of the American Pain Society; 2001 Apr 19–22; Phoenix (AZ)
66.
Sykes NP. The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med 1998; 12: 375–82PubMedCrossRef
67.
Yuan CS, Foss JF, O’Connor M, et al. Gut motility and transit changes in patients receiving long-term methadone maintenance. J Clin Pharmacol 1998; 38: 931–5PubMed
68.
Moulin DE, Iezzi A, Amireh R, et al. Randomised trial of oral morphine for chronic non-cancer pain. Lancet 1996; 347: 143–7PubMedCrossRef
69.
Stewart JJ, Weisbrodt NW, Burks TF. Central and peripheral actions of morphine on intestinal transit. J Pharmacol Exp Ther 1978; 205: 547–55PubMed
70.
Manara L, Bianchetti A. The central and peripheral influences of opioids on gastrointestinal propulsion. Annu Rev Pharmacol Toxicol 1985; 25: 249–73PubMedCrossRef
71.
Russell J, Bass P, Goldberg LI, et al. Antagonism of gut but not central effects of morphine with quaternary narcotic antagonists. Eur J Pharmacol 1982; 78: 255–61PubMedCrossRef
72.
Shook JE, Pelton JT, Hruby VJ, et al. Peptide opioid antagonist separates peripheral and central opioid antitransit effects. J Pharmacol Exp Ther 1987; 243: 492–500PubMed
73.
Manara L, Bianchi G, Ferretti P, et al. Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites. J Pharmacol Exp Ther 1986; 237: 945–9PubMed
74.
Cheatham ML, Chapman WC, Sawyers JL. A meta-analysis of selective versus routine nasogastric decompression after elective surgery. Ann Surg 1995; 221: 469–76PubMedCrossRef
75.
Sagar PM, Kruegener G, MacFie J. Nasogastric intubation and elective abdominal surgery. Br J Surg 1992; 79: 1127–31PubMedCrossRef
76.
77.
Milsom JW, Bohm B, Hammerhofer KA, et al. A prospective randomised trial comparing laparoscopic versus conventional techniques in colorectal cancer surgery: a preliminary report. J Am Coll Surg 1998; 187: 45–54CrossRef
78.
Bonacini M, Quiason S, Reynolds M, et al. Effect of intravenous erythromycin on postoperative ileus. Am J Gastroenterol 1993; 88: 208–11PubMed
79.
Jorgensen H, Wetterslev J, Moiniche S, et al. Epidural local anesthetics versus opioid-based analgesic regimens on postoperative gastrointestinal paralysis, PONV and pain after abdominal surgery. Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration: issue 1. Oxford: Update Software, 2002
80.
Steinbrook RA. Epidural anesthesia and gastrointestinal motility. Anesth Analg 1998; 86: 837–44PubMed
81.
de Leon-Casasola OA, Karablella D, Lema MJ. Bowel function recovery after radical hysterectomies: thoracic epidural bupivacaine-morphine versus intravenous patient-controlled analgesia with morphine: a pilot study. J Clin Anesth 1996; 8: 87–92PubMedCrossRef
82.
Rawal N. Epidural and spinal agents for postoperative analgesia. Surg Clin North Am 1999; 79: 313–44PubMedCrossRef
83.
Wong HY, Carpenter RL, Kopacz DJ, et al. A randomized, double-blind evaluation of ketorolac tromethamine for postoperative analgesia in ambulatory surgery patients. Anesthesiology 1993; 78: 6–14PubMedCrossRef
84.
Basse L, Madsen JL, Kehlet H. Normal gastrointestinal transit after colonic resection using epidural analgesia, enforced oral nutrition and laxative. Br J Surg 2001; 88: 1498–500PubMedCrossRef
85.
Bradshaw BGG, Liu SS, Thirlby RC. Standardized perioperative care protocols and reduced length of stay after colon surgery. J Am Coll Surg 1998; 186: 501–6PubMedCrossRef
86.
Moiniche S, Bulow S, Hesselfeldt P, et al. Convalescence and hospital stay after colonic surgery with balanced analgesia, early oral feeding, and enforced mobilization. Eur J Surg 1995;161: 283–8PubMed
87.
O’Mahony S, Coyle N, Payne R. Current management of opioid-related side effects. Oncology 2001; 15: 61–73PubMed
88.
89.
Herndon CM, Jackson KC, Hallin PA. Management of opioid-induced gastrointestinal effects in patients receiving palliative care. Pharmacotherapy 2002; 22: 240–50PubMedCrossRef
90.
Donner B, Zenz M, Strumpf M, et al. Long-term treatment of cancer pain with transdermal fentanyl. J Pain Symptom Manage 1998; 15: 168–75PubMedCrossRef
91.
Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. J Pain Symptom Manage 1997; 13: 254–61PubMedCrossRef
92.
Allan L, Hays H, Jensen NH, et al. Randomized crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ 2001; 322: 1–7CrossRef
93.
94.
95.
Culpepper-Morgan JA, Inturrisssi CE, Portenoy RK, et al. Treatment of opioid-induced constipation with oral naloxone: a pilot study. Clin Pharmacol Ther 1992; 52: 90–5PubMedCrossRef
96.
Sykes NP. An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med 1996; 10: 135–44PubMedCrossRef
97.
Meissner W, Schmidt U, Hartmann M, et al. Oral naloxone reverses opioid-associated constipation. Pain 2000; 84: 105–9PubMedCrossRef
98.
Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage 2002; 23: 48–53PubMedCrossRef
99.
Cheskin LJ, Chami TN, Johnson RE, et al. Assessment of nalmefene glucuronide as a selective gut opioid antagonist.Drug Alcohol Depend 1995; 39: 151–4PubMedCrossRef
100.
Brown DR, Goldberg LI. The use of quaternary narcotic antagonists in opiate research. Neuropharmacology 1985; 24: 181–91PubMedCrossRef
101.
Bianchi G, Fiocchi R, Tavani A, et al. Quaternary narcotic antagonists’ relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity. Life Sci 1982; 30: 1875–83PubMedCrossRef
102.
Foss J. A review of the potential role of methyl naltrexone in opioid bowel dysfunction. Am J Surg 2001; 182 (5A Suppl.): 19S–26SPubMedCrossRef
103.
Kotake AN, Kuwahara SK, Burton E, et al. Variations in demethylation of N-methylnaltrexone in mice, rats, dogs, and humans. Xenobiotica 1989; 19: 1247–54PubMedCrossRef
104.
Valentino RJ, Katz JL, Medzihradsky E, et al. Receptor binding, antagonist, and withdrawal precipitating properties of opiate antagonists. Life Sci 1983; 32: 2887–96PubMedCrossRef
105.
Gmerek DE, Cowan A, Woods JH. Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats. J Pharmacol Exp Ther 1986; 236: 8–13PubMed
106.
Yuan CS, Foss JF, Moss J. Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea pig ileum and human intestine. Eur J Pharmacol 1995; 276: 107–11PubMedCrossRef
107.
Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther 1996; 59: 469–75PubMedCrossRef
108.
Yuan CS, Foss JF, Osinski J, et al. The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time. Clin Pharmacol Ther 1997; 61: 467–75PubMedCrossRef
109.
Yuan CS, Foss JF, O’Connor M, et al. Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time. Clin Pharmacol Ther 2000; 67: 398–404PubMedCrossRef
110.
Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone for reversal of constipation due to chronic methadone use. JAMA 2000; 283: 367–72PubMedCrossRef
111.
Yuan CS, Foss JF. Oral methylnaltrexone for opioid-induced constipation [letter]. JAMA 2000; 284: 1383–4PubMedCrossRef
112.
Zimmerman DM, Gidda JS, Cantrell BE, et al. LY246736 dihydrate: μ opioid receptor antagonist. Drugs Future 1994; 19: 1078–83
113.
Zimmerman DM, Gidda JS, Canterell BE, et al. Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydro xyphenyl) piperidine opioid antagonist for the treatment of gastrointestinal motility disorders. J Med Chem 1994; 37: 2262–5PubMedCrossRef
114.
Schmidt WK. Alvimopan* (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg 2001; 182 (5A Suppl.): 27S–38SPubMedCrossRef
115.
Liu SS, Hodgson PS, Carpenter RL, et al. ADL 8-2698, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia. Pharmacol Ther 2000; 68: 66–71
116.
Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001; 345: 935–40PubMedCrossRef
Metadata
Title
Opioid-Induced Bowel Dysfunction
Pathophysiology and Potential New Therapies
Authors
Andrea Kurz
Dr Daniel I. Sessler
Publication date
01-04-2003
Publisher
Springer International Publishing
Published in
Drugs / Issue 7/2003
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.2165/00003495-200363070-00003

Other articles of this Issue 7/2003

Drugs 7/2003 Go to the issue

Adis Drug Evaluation

Peginterferon-α-2a (40kD) Plus Ribavirin

Adis Drug Evaluation

Lovastatin Extended Release

Adis Drug Profile

DTPa-HBV-IPV/Hib Vaccine (Infanrix hexa™)

Therapy In Practice

Pharmacological Treatment of Patients with Peripheral Arterial Disease

Adis Drug Profile

DTPa-HBV-IPV/Hib Vaccine (Infanrix hexa™)

Leading Article

Clinical Potential of Insulin Therapy in Critically Ill Patients