Pain and Chronic Pancreatitis - Clinical End Experimental Studies

Overview

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.

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Outcomes