Pain and Chronic Pancreatitis - Clinical End Experimental Studies
Condition: Chronic Pancreatitis
MeSH terms: Pancreatitis; Pancreatitis, Chronic
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Pregabalin; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Pregabalin 300 mg - 600 mg BID; Regime as described for pregabalin
Other intervention name(s): Lyrica; Inactive comparator (placebo)
Intervention MeSH terms: Pregabalin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Pain; Neuropathic pain