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Advances to Block the Adverse Side Effects of Opioid Analgesics on the Gastrointestinal Tract
ENS neurons release not only acetylcholine, substance P, nitric oxide,
Table 1: Clinical Development of Peripherally Acting Mu-opioid
adenosine tri-phosphate (ATP), vasoactive intestinal polypeptide, and
Receptor Antagonists
5-hydroxytryptamine (5-HT), but also opioid peptides (i.e. met-enkephalin,
leu-enkephalin, β-endorphin, dynorphin, and others) as transmitters. Three
Clinical Development Phase
primary opioid receptor types (mu, delta, and kappa) are ubiquitous in the
Indication Agent Phase I Phase II Phase III Under FDA Investigation
OBD/OIC Methylnaltrexone
CNS and the ENS.
3
Opioid analgesic effects are primarily mediated by
Oral X X – –
mu-opioid receptors in the CNS (brain and spinal cord); however, GI-related
IV – – – –
adverse effects are primarily mediated by mu-opioid receptors in the GI
Subcutaneous X X X –
tract.
3
Exogenous opioids (e.g. morphine), administered to mediate
Alvimopan
analgesia or manage chronic pain, can activate the peripheral mu-opioid
Oral X X – –
receptors in the GI tract and may cause GI-related opioid side effects POI Methylnaltrexone
such as disruption of the migrating motor complex and propulsive motor Oral – – – –
activity, inhibition of intestinal ion and fluid secretion, nausea, vomiting, and
IV X X X
R
–
increased GI transit time.
3,22,32
PAM-OR antagonists bind to mu-opioid
Subcutaneous – – – –
receptors in the GI tract without compromising centrally based opioid
Alvimopan
analgesia, thereby mitigating opioid-based GI-adverse events.
11–15,26
Oral X X X X
PAM-OR antagonists have the potential to block GI-related opioid adverse
FDA = US Food and Drug Administration; OBD = opioid-induced bowel dysfunction; OIC = opioid-induced
constipation; IV = intravenous; POI = post-operative ileus;
R
= recruiting.
effects without inhibiting the beneficial action of exogenous opioids
administered to treat or control pain.
11–15
users. Thus far, data indicate that patients who received oral
Clinical Pharmacology methylnaltrexone (1 or 3mg/kg; n=10) had BMs within 12 and five hours of
Alvimopan binds with a higher affinity (alvimopan: K
i
= 0.4nM; dosing, respectively.
41
methylnaltrexone: K
i
= 26–110nM) and has a slower dissociation rate
(alvimopan: t
1/2
= 30–44 minutes; methylnaltrexone: t
1/2
= 0.46 minutes) Results of phase II trials of alvimopan for the treatment of OBD in patients
from the mu-opioid receptor in vitro compared with methylnaltrexone.
33
receiving opioid therapy for chronic pain or methadone for opioid addiction
The half-life of intravenous (IV) or subcutaneous methylnaltrexone ranges were reviewed by Schmidt.
42
In these trials, a single dose of oral alvimopan
from 2.5 to 3 hours, and the time to maximum concentration (T
max
) of (0.5, 1.5, or 3mg) significantly increased stool weight (p<0.05) and the
oral methylnaltrexone is 116 minutes.
25,27,34
T
max
of oral alvimopan is proportion of patients with a BM within 12 hours (p<0.001) compared with
two hours.
35,36
The volume of distribution is similar for both PAM-OR placebo.
42
In another phase II OBD trial in patients with chronic opioid therapy
antagonists (methylnaltrexone: 1.8–2.6l/kg; alvimopan, 0.24–2.0l/kg).
25,36
for non-malignant pain or opioid dependence, alvimopan (0.5mg or 1mg)
Methylnaltrexone can be metabolized to a centrally active precursor in also significantly increased the proportion of patients having at least one BM
rodents; however, this does not appear to occur following metabolism of within eight hours of dosing on each day of a 21-day cycle compared with
methylnaltrexone in humans.
37
An active primary amide hydrolysis metabolite placebo (alvimopan: 43–54%; placebo: 29%; p<0.001).
43
In a subsequent
of alvimopan is produced by GI microflora, but is not required for efficacy in phase IIb dose-finding study, patients (n=522) experiencing OBD and receiving
the management of POI.
35
The majority of methylnaltrexone is excreted in the opioid treatment for chronic non-cancer pain were treated with alvimopan
urine (40–60% within 24 hours of IV administration),
25,37
and the elimination (0.5mg twice daily, 1mg once daily, or 1mg twice daily) or placebo for six
of alvimopan occurs through biliary (65%) and renal (35%) excretion.
38
weeks.
44
Alvimopan (all dose regimens) significantly increased spontaneous
BM frequency and relieved constipation-related symptoms of straining,
Clinical Development incomplete evacuation, and dry, hard stools.
44
Patients also reported
Currently, three formulations of methylnaltrexone are being studied in improvements in symptoms such as abdominal pain and bloating.
44
clinical trials. Subcutaneous and oral methylnaltrexone are under
investigation for OIC in patients with advanced medical illness or chronic Based on the results of this dose-finding study, two phase III studies of
pain. Recruitment for phase III trials of IV methylnaltrexone for the approximately 1,000 patients with chronic non-cancer pain receiving the
management of POI after bowel resection (BR) is currently under way. 0.5mg twice-daily dosing regimen were recently completed. Results of a
Oral alvimopan is currently under investigation by the FDA for the phase IIb trial in patients with cancer-related pain are also expected to be
management of POI after BR, and phase III trials of oral alvimopan for published soon.
the management of OBD were recently reported (see Table 1).
Peripherally Acting Mu-opioid Receptor Antagonists for the
Peripherally Acting Mu-opioid Receptor Antagonists for the Management of Post-operative Ileus
Management of Opioid-induced Bowel Dysfunction and IV methylnaltrexone has been studied in a phase II pilot trial for the
Opioid-induced Constipation management of post-operative bowel dysfunction after segmental
In phase III OBD trials, subcutaneous methylnaltrexone (0.15 or 0.3mg/kg) colectomy.
12
Although complete results of this trial have yet to be published,
significantly increased the proportion of patients with advanced illness who methylnaltrexone (0.3mg/kg) accelerated time to first BM by 20 hours
had a BM within four hours compared with placebo (50–62% compared compared with placebo.
12
Recruitment of patients for phase III trials of IV
with 13–16% for placebo; p<0.0001).
39,40
Phase II OBD trials are currently methylnaltrexone for the management of POI after laparotomy for
ongoing to investigate the effects of oral methylnaltrexone in chronic opioid segmental colectomy is under way.
US GASTROENTEROLOGY REVIEW 2007 95
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