Metoclopramide is not an analgesic: reflection on a premature scientific conclusion

To the Editor: Wood (1) and Ozucelik et al. (2) unambiguously state that relief of pain during nasogastric tube intubation following metoclopramide infusion is a surprising feature because metoclopramide does not have any analgesic or antinociceptive effect. This assumption is incorrect. Moreover, Ozucelik et al. (2) expound an unlikely rather convoluted ‘synergistic’ mechanism to explain the analgesic effect of metoclopramide clearly seen in their study. Metoclopramide has definitive antinociceptive activity that has been seen in a wide variety of clinical circumstances; i.v. metoclopramide usually potentiates the analgesic effects of opioids in postoperative patients (3–5). Metoclopramide predictably stimulates release of biologically active arginine vasopressin (AVP) in normal volunteers who are recumbent, dehydrated or under steady-state water diuresis (6,7). AVP, in turn, promotes vasomotor control, antinociception and behaviour control and can abort as well as prevent migraine attacks (8,9). AVP and corticotropin-releasing hormone potentiate each other's action to exert a critical physiological role in adrenocorticotropic hormone and β-endorphin release from anterior pituitary cells; β-endorphin appears to have potent morphine-like analgesic properties (10,11). The analgesic effect of metoclopramide can be attributed to the combined influence of the stimulated release of AVP and endogenous opioids. Antimigraine action of metoclopramide (9,12,13) is also very probably based on a prominent antinociceptive effect coupled to vasomotor and behaviour control mechanisms. Currently, metoclopramide is being widely used as an analgesic, either alone or as an adjuvant; the analgesic effect seems to be a class effect as domperidone and cisapride have also shown experimental antinociceptive effect (14). In medical research, the approach of the investigator may itself be one of the critical variables affecting the interpretation (15). While accepting any investigative premise or assumption in clinical studies, to remain unbiased it is important to keep questioning its validity. Ozucelik et al. (2) recorded an analgesic effect of metoclopramide during nasogastric tube insertion but maintained the opinion that the pharmacological agent has no direct antinociceptive effect. A premature philosophic commitment can dull critical thinking that, in turn, might lead to disbelief of even one's own data.