Pain and Chronic Pancreatitis - Clinical End Experimental Studies
Pain and Chronic Pancreatitis - Clinical End Experimental Studies
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.
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.
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.