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

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).