Multimodal pain stimulation of the gastrointestinal tract

Table 1 Multimodal comparison of clinical experimental data obtained in the esophagus from healthy volunteers

Group	Mechanical stimuli	Heat stimuli	Cold stimuli	Electrical stimuli	Sensitization with acid
Basic data	Differences between the sensations and referred pain areas was evoked by the stimulus modalities[18]. Reliability demonstrated[19,60]. The sensation to mechanical stimulations was unaffected by relaxation of the smooth muscle[40,61]. Evidence for low and high threshold high threshold	Reliability demonstrated. Stimulus-response functions obtained[18,19,60].	Reliability demonstrated. Stimulus-response functions obtained[18,19,60].	Reliability demonstrated. Stimulus-response unctions obtained[18,19,60].	Allodynia and hyperalgesia evoked[19,26], although not consistent for mechanical stimuli (see text)[26,41]. Increased referred pain and amplitude of the nociceptive reflex indicating central hyperexcitability[19,26,46]. Acid perfusion sensitizes the oesophagus to heat but not cold, indicating sensitization of peripheral TRPV1 receptors[28,46]. Remote hyperalgesia was seen in the rectum after acid perfusion of the esophagus[20]. Hyperreactivity of contractions in esophagus, but tone was unaffected[26,46].
Gender differences	Males were more sensitive to stimulations, but an increased referred pain area was seen in females, reflecting sex differences incentral pain processing[27,46].	No differences in sensation, but the referred area was larger in females[27,46].	As heat stimuli	Males less sensitive to single and repeated stimuli (Staahl et al., unpublished).	In females, the referred pain area increased to heat after acid sensitization, but no changes were seen to mechanical and cold stimulations[46].
Pharmacologic modulation	Oxycodone was better than morphine (and placebo) in attenuating mechanical pain[59].	Oxycodone was better than morphine (and placebo) in attenuating heat pain[59].	Not done	Both morphine and oxycodone attenuated the electrically evoked pain, but there were no differences between the opioids[59].	Not done

Table 2 Multimodal comparison of clinical experimental data obtained in the esophagus from patient with different GI diseases

Patient group	Mechanical stimuli	Heat stimuli	Cold stimuli	Electrical stimuli	Sensitization with acid
Non-cardiac chest pain[41]	No differences to single stimuli, but increased pain to repeated stimuli and increased referred pain area, reflecting central hyperexcitability.	Not done	Not done	Not done	Increased sensation to mechanical stimulations after acid in patients only.
Esophagitis[31]	Patients were hyposensitive but with larger and more widespread referred pain. The distension induced more reactive contraction.	Patients were Hypersensitive probably via increased activation of TRPV1 receptors.	No differences	Not done	Not done
Non-erosive reflux disease (Reddy et al unpublished data)	Patients were hyposensitive to mechanical stimuli. The distensions induced more reactive contractions in the esophagus in the patients and they had larger referred pain areas. Patients with pathological 24-h pH-measurement were more hyposensitive than the patients with normal pH profile.	The patients were hypersensitive to heat with increased referred pain areas to this modality.	No differences between patients and controls	Not done sensitivity score unpublished data)	Patients had a higher sensitivity score to acid perfusion.
Diabetes (Frøkjær et al, unpublished data)	Patients had hyposensitivity to distension, but increased referred pain areas, reflecting peripheral neuropathy and central hyperexcitability. Increased stiffness of the gut wall in diabetes.	As mechanical stimulations	Not done	As mechanical stimulations	Not done
Chronic pancreatitis (Dinmcevski et al, unpublished data)	No differences in sensation. No differentiated effect on morphine and oxycodone in attenuation of mechanical pain.	No differences in sensation Oxycodone attenuated heat pain better than morphine.	Not done	Larger referred pain area in the patients. Opioids were not better than placebo in attenuating electrical pain	Not done unpublished data)