Pain and Chronic Pancreatitis – Clinical End Experimental Studies

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Brief Title

Pain and Chronic Pancreatitis - Clinical End Experimental Studies

Official Title

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Clinical and Experimental Pilot Study of Pregabalin in Patients With Chronic Pancreatitis

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.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Patient pain diary based on the VAS score and different questionaries

Secondary Outcome

 Questionary addressing quality of life

Condition

Chronic Pancreatitis

Intervention

Pregabalin

Study Arms / Comparison Groups

 Pregabalin
Description:  Pregabalin 300 mg - 600 mg BID

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

64

Start Date

October 2008

Completion Date

May 2010

Primary Completion Date

May 2010

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female patients between the ages of 18 and 75 years with a diagnosis of
             chronic pancreatitis diagnosed using the Mayo Clinic Diagnostic criteria criteria
             ((Layer P, Gastroenterology 1994;107:1481-1487]). Both diabetic and non-diabetic
             patients will be allowed to enter the study.

          2. The patients must suffer from chronic abdominal pain typical for pancreatitis, meet
             the criteria for chronic pain (pain ≥ 3 days per week in at least 3 months) and must
             consider their pain as severe enough for medical treatment.

          3. Personally signed and dated informed consent document indicating that the patient has
             been informed of all pertinent aspects of the trial.

          4. Patients willing and able to comply with the scheduled visits, treatment plan,
             laboratory tests and other trial procedures.

        Exclusion Criteria:

          1. Patients with evidence or history of medical or surgical disease of importance for
             this study as judged by investigator

          2. Presence or history of major depression

          3. Patients with previously diagnosed moderate to severe renal impairment. Patients with
             creatinine values > 2x ULN and/or with a significant change to their normal values
             should be excluded.

          4. Patients with a screening 12-lead ECG demonstrating any of the following: heart rate
             >100 bpm, QRS duration >120 msec, QTc interval >450 msec, PR interval >210 msec, any
             clinically significant rhythm abnormality, any evidence of myocardial ischemia or
             injury.

          5. Patients with any clinically significant laboratory abnormalities that in the opinion
             of the investigator may increase the risk associated with trial participation or may
             interfere with the interpretation of the trial results.

          6. Patients treated with pregabalin (Lyrica®) during the previous 4 months.

          7. Treatment with an investigational drug within 4 months preceding the first dose of
             study medication of importance for this study as judged by investigator.

          8. Female patients who are pregnant or lactating, or intend to become pregnant. Male
             patients who intend to father a child during the course of the study. A pregnancy test
             will be conducted at visit 1 and 3 to ensure that female patients are not pregnant
             during the study period. The investigator will have to ensure that fertile female
             patients use a safe contraception method during the study and for at least 35 hours
             after termination of the study period. The following methods are considered as safe
             contraception methods:

               -  The pill

               -  IUD

               -  Gestagen Injection

               -  Subdermal Implantation (Implanon)

               -  Hormone vaginal ring

               -  Transdermal Plaster

          9. Patients unwilling or unable to comply with the lifestyle guidelines.

         10. Patients must not suffer from generalized painful conditions other than chronic
             pancreatitis; however patients with localized painful disorders will be allowed to
             enter the study

         11. Clinical significant illness within two weeks of participating in this study.

         12. Involved in planning or conducting the study.

         13. Hypersensitivity to pregabalin or any of its components.
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Asbjørn M Drewes, MD, PhD, , 

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT00755573

Organization ID

A0081172/8967



Study Sponsor

Aalborg University Hospital

Collaborators

 Radboud University

Study Sponsor

Asbjørn M Drewes, MD, PhD, Principal Investigator, Dapartment og Gastroenterology, Aalborg Hospital


Verification Date

July 2009