Interaction of morphine and clonidine on gastrointestinal transit in mice.
BACKGROUND
Combinations of drugs are frequently used to achieve effective analgesia while minimizing side effects. Although the analgesic effects of morphine and clonidine seem to be synergistic, few studies have investigated other effects. Their role in inhibiting gastrointestinal transit was evaluated using different methods of analysis.


METHODS
Percentage inhibition of transit induced by morphine, clonidine, or their combination was measured in mice that had been given an intragastric charcoal meal. Dose-response curves were obtained for each drug individually; for morphine:clonidine at 1:3, 1:1, and 1:0.33 ratios; and for morphine in the presence of 0.0138 mg/kg clonidine. The interaction was evaluated by isobolograms, combination indexes, and fixed-dose analysis.


RESULTS
Each drug and their combinations inhibited transit in a dose-related manner. Combinations of morphine and clonidine produced interaction that depended on the ratio and level of response. The interaction analyzed by isobolograms and combination indexes showed that combinations in 1:1 and 1:3 proportions were synergistic at the median effective doses or less and were antagonistic at larger doses. Fixed-dose analysis using different ratios showed similar results. The effects of the combination (median effective dose at 1:1 ratio) were antagonized by efaroxan but not by naloxone, suggesting a predominant role of alpha-2-mediated effects.


CONCLUSIONS
Investigations into drug interactions should include several levels of response and combinations at different ratios. Isobolographic analysis permits the statistical evaluation of results without making assumptions about mechanisms of action of the drugs or their interactions. In this study, the combination of morphine and clonidine should produce synergy, antagonism, or no interaction depending on the relative doses and the level of effect.
Puig
M M
MM
Department of Anesthesiology, Hospital Universitario del Mar, IMIM, Barcelona, Spain.
Pol
O
O
Warner
W
W
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology*; D003248:Constipation / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005772:Gastrointestinal Transit / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D013565:Sympatholytics / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D007093:Imidazoles; D009292:Narcotic Antagonists; D009294:Narcotics; D013565:Sympatholytics; D009270:Naloxone; D009020:Morphine; C062597:efaroxan; D003000:Clonidine