Ignite Creation Date:
2024-05-05 @ 7:50 PM
Last Modification Date:
2024-10-26 @ 9:55 AM
Study NCT ID:
NCT00755573
Status:
COMPLETED
Last Update Posted:
2010-08-20
First Post:
2008-09-18
Brief Title:
Pain and Chronic Pancreatitis - Clinical End Experimental Studies
Sponsor:
Aalborg University Hospital
Organization:
Aalborg University Hospital
Study Overview
Official Title:
A Randomized Double-Blind Placebo-Controlled Parallel Group Clinical and Experimental Pilot Study of Pregabalin in Patients With Chronic Pancreatitis
Status:
COMPLETED
Status Verified Date:
2009-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CPP
Brief Summary:
The aim of the study is to investigate the effect of pregabalin in pain resulting from chronic pancreatitis The effect will be investigated by means of questionnaires concerning the daily experience of pain and the general quality of life Furthermore the patients will be invited to participate in experimental testing with a multimodal pain model The experimental testing will include stimulation of the skin muscle and visceral tissue The results from the experimental part of the study may help us to understand the mechanisms of action of pregabalin in this patient population
Detailed Description:
Background and Rationale
The aetiology of pain in chronic pancreatitis remains to be elucidated Therefore no common guidelines for the management of the pain exist and it is a topic of great discussion The area is further complicated by the fact that only a few clinical trials have been carried out Wilder-Smith et al 1999 The best attempt to establish clear guidelines for the treatment of chronic pancreatitis is American Gastroenterological Association Medical Position Statement Treatment of Pain in Chronic Pancreatitis Warshaw et al 1998 Initial treatment consists of low fat diet and non-narcotic analgesics which can be supplemented by oral pancreatic enzymes and proton pump inhibitors If an acceptable level of pain relief is not obtained with these drugs only opioids remain for the management of pain Opioids have a number of well-known adverse effects including elevation of smooth muscle tone affecting gastrointestinal motility toxicity in the central nervous system and especially induction of addiction Many patients suffering from chronic pancreatitis have a history of alcoholic abuse making opioids with their associated abuse potential less suitable for these patients Alternatives to medical treatment exist in the form of nerve blockade lithotripsy and surgical treatment However results from studies of non-medical treatment modalities are equivocal and medical analgesic therapy must still be considered as the first choice in the management of painful chronic pancreatitis Thus the importance of identifying potential new treatment regimes for the treatment of pain in chronic pancreatitis is clear
In patients with chronic pancreatitis the pancreatic nerves have been found to have a greater diameter and the area innervated by a single nerve is smaller Bockman et al 1988 A neural genesis of pain therefore seems likely The basis of the neurogenic generation of pain may be due to an altered expression of neuropeptides like SP and CGRP The concentration of nerve growth factor NGF and its receptor TrkA is increased in inflammatory areas which may lead to an enhanced transcription of SP and CGRP both of which are transmitters in the pain system Di Sebatiano et al 2003 Interestingly the release of SP is known to be reduced by agents such as pregabalin
Support for a neuropathic component of the pain of chronic pancreatitis is also found in clinical observations where the pain is typically described as largely constant background pain with shooting burning and lancinating episodes that may mimic that seen in peripheral neuropathies Finally evidence for central neuroplastic findings and strong descending inhibition which may reflect the pain mechanisms in neuropathic pain have been found in recent studies Dimcevski et al 2006 and 2007 Thus inflammatory and true visceral pain components appear to play a role in pancreatic pain Hence the potential to extrapolate from clinical trials demonstrating the activity of pregabalin in the treatment of neuropathic pain to the treatment of the possible neuropathic component of chronic pancreatitis is of great interest
Central sensitization is an essential factor in the development of neuropathic pain Baron 2001 Johnson et al 2001 and in animal experiments the NMDA receptor has been shown to be involved in this process Calcium plays a central role as an increased influx of calcium into the neuron is observed when the NMDA receptor is activated The enhanced concentration of intracellular calcium functions as a second messenger for a number of neurotransmitters and calcium thus contributes to the maintenance of the central sensitization Nicholson 2000
Pregabalin exerts a range of effects in pain transmission and although the precise mechanism of action is not completely understood it likely involves the binding of the drug to calcium channels in the central nervous system Ben-Menachem 2004 In animal experiments it has been shown that pregabalin primarily exerts its effect in the dorsal horn where a reduced pain signal is seen Pregabalin is a ligand of the α2-δ subunit of the voltage-gated calcium channel and binding of pregabalin to this site results in reduced calcium influx at the nerve terminals and therefore a reduced release of several excitatory neurotransmitters including glutamate substance P SP calcitonin-gene related peptide CGRP and noradrenaline This may result in inhibition or reduction of the sensitization mentioned above Moreover this may be the basis for the analgesic effect It has been shown in animal experiments that binding of pregabalin to calcium channels is able to counteract central sensitization in the dorsal horn
The evidence for the clinical effect of pregabalin in neuropathic pain is substantial and is documented in a number of randomized clinical trials Dworkin et al 2003 Sabatowski et al 2004 Rosenstock et al 2004 The recommended dose for treating neuropatic pain is between 150 mg to 600 mg daily which is similar to the dose chosen for this study By the opinion of the principal investigator no clinically relevant medical interactions are described for pregabalin when administered for chronic pancratitis patients
Pregabalin is absorbed in the small intestine by a saturable transporter Piyapolrungroj et al 2001 It is well known that pancreatitis patients suffer from malabsorption of fat and therefore frequently suffer from diarrhea This could lead to changes in the mucosal surface in the small intestine and possibly change the absorption of pregabalin Drug absorption has never been investigated in patients suffering from pancreatitis and the simple and linear kinetics of pregabalin makes it possible to study how drug absorption may vary in these patients A poorer absorption of drugs could partly explain why pain from pancreatitis is difficult to relieve
The aetiology of pain in chronic pancreatitis remains to be elucidated Therefore no common guidelines for the management of the pain exist and it is a topic of great discussion The area is further complicated by the fact that only a few clinical trials have been carried out Wilder-Smith et al 1999 The best attempt to establish clear guidelines for the treatment of chronic pancreatitis is American Gastroenterological Association Medical Position Statement Treatment of Pain in Chronic Pancreatitis Warshaw et al 1998 Initial treatment consists of low fat diet and non-narcotic analgesics which can be supplemented by oral pancreatic enzymes and proton pump inhibitors If an acceptable level of pain relief is not obtained with these drugs only opioids remain for the management of pain Opioids have a number of well-known adverse effects including elevation of smooth muscle tone affecting gastrointestinal motility toxicity in the central nervous system and especially induction of addiction Many patients suffering from chronic pancreatitis have a history of alcoholic abuse making opioids with their associated abuse potential less suitable for these patients Alternatives to medical treatment exist in the form of nerve blockade lithotripsy and surgical treatment However results from studies of non-medical treatment modalities are equivocal and medical analgesic therapy must still be considered as the first choice in the management of painful chronic pancreatitis Thus the importance of identifying potential new treatment regimes for the treatment of pain in chronic pancreatitis is clear
In patients with chronic pancreatitis the pancreatic nerves have been found to have a greater diameter and the area innervated by a single nerve is smaller Bockman et al 1988 A neural genesis of pain therefore seems likely The basis of the neurogenic generation of pain may be due to an altered expression of neuropeptides like SP and CGRP The concentration of nerve growth factor NGF and its receptor TrkA is increased in inflammatory areas which may lead to an enhanced transcription of SP and CGRP both of which are transmitters in the pain system Di Sebatiano et al 2003 Interestingly the release of SP is known to be reduced by agents such as pregabalin
Support for a neuropathic component of the pain of chronic pancreatitis is also found in clinical observations where the pain is typically described as largely constant background pain with shooting burning and lancinating episodes that may mimic that seen in peripheral neuropathies Finally evidence for central neuroplastic findings and strong descending inhibition which may reflect the pain mechanisms in neuropathic pain have been found in recent studies Dimcevski et al 2006 and 2007 Thus inflammatory and true visceral pain components appear to play a role in pancreatic pain Hence the potential to extrapolate from clinical trials demonstrating the activity of pregabalin in the treatment of neuropathic pain to the treatment of the possible neuropathic component of chronic pancreatitis is of great interest
Central sensitization is an essential factor in the development of neuropathic pain Baron 2001 Johnson et al 2001 and in animal experiments the NMDA receptor has been shown to be involved in this process Calcium plays a central role as an increased influx of calcium into the neuron is observed when the NMDA receptor is activated The enhanced concentration of intracellular calcium functions as a second messenger for a number of neurotransmitters and calcium thus contributes to the maintenance of the central sensitization Nicholson 2000
Pregabalin exerts a range of effects in pain transmission and although the precise mechanism of action is not completely understood it likely involves the binding of the drug to calcium channels in the central nervous system Ben-Menachem 2004 In animal experiments it has been shown that pregabalin primarily exerts its effect in the dorsal horn where a reduced pain signal is seen Pregabalin is a ligand of the α2-δ subunit of the voltage-gated calcium channel and binding of pregabalin to this site results in reduced calcium influx at the nerve terminals and therefore a reduced release of several excitatory neurotransmitters including glutamate substance P SP calcitonin-gene related peptide CGRP and noradrenaline This may result in inhibition or reduction of the sensitization mentioned above Moreover this may be the basis for the analgesic effect It has been shown in animal experiments that binding of pregabalin to calcium channels is able to counteract central sensitization in the dorsal horn
The evidence for the clinical effect of pregabalin in neuropathic pain is substantial and is documented in a number of randomized clinical trials Dworkin et al 2003 Sabatowski et al 2004 Rosenstock et al 2004 The recommended dose for treating neuropatic pain is between 150 mg to 600 mg daily which is similar to the dose chosen for this study By the opinion of the principal investigator no clinically relevant medical interactions are described for pregabalin when administered for chronic pancratitis patients
Pregabalin is absorbed in the small intestine by a saturable transporter Piyapolrungroj et al 2001 It is well known that pancreatitis patients suffer from malabsorption of fat and therefore frequently suffer from diarrhea This could lead to changes in the mucosal surface in the small intestine and possibly change the absorption of pregabalin Drug absorption has never been investigated in patients suffering from pancreatitis and the simple and linear kinetics of pregabalin makes it possible to study how drug absorption may vary in these patients A poorer absorption of drugs could partly explain why pain from pancreatitis is difficult to relieve
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None