Oddi sphincter’s function is important in the regulation of postprandial flow of biliopancreatic secretion. The neurohumoral regulation of these small groups of smooth muscles is complex. Corresponding to this complexity, a considerable number of neurons was found in the sphincter region, almost comparable to the subserosal plexus of gallbladder.1 In addition, intrinsic innervation depends mainly on neuronal connections between the duodenal mucosa and the sphincter.2 The main extrinsic innervation is vagal.3 Acetylcholine stimulates the motor activity of the intact sphincter,4,5 the phasic contractions probably contribute in the injection of bile from the sphincter region to the duodenum6 and avoid the reflux of duodenal content to the bile duct. Buscapina (scopolamine butylbromide and hyoscine butylbromide), a nonselective muscarinic antagonist relaxes the sphincter, inhibits the duodenal motility and these effects permit its use as a spasmolytic, even in control of biliary pain.7
Endoscopic sphincterotomy (EST) has become a treatment of choice in the extraction of bile duct stones. EST destroys the major part of the muscles of Oddi sphincter (OS), but this destruction is not always complete: variable degree of residual motor activity has been observed in patients after EST.8-10 We have no data available about eventual changes of innervation of OS after EST.
In this paper we communicate a paradoxical stimulatory response to Buscapina observed in several patients after EST.
The study involved 14 patients (9 females and 5 males, mean age 50.4 ± SEM 4.2 years, range 32-73 years). All patients had a previous cholecystectomy.
Endoscopic manometry of OS was performed after EST in order to control the residual motor activity of the OS. The patients were placed in the left lateral position, and they received 10 mg diazepam intravenous (IV) injection as premedication. The motility of OS was studied by means of a 3-lumen perfused catheter (Wilson-Cook Medical Inc, Winston-Salem, NC, USA) which has 3 lateral orifices circumferentially orientated each 120º, with a distance of 2 mm between them. In addition, the catheter has 10 well visible marks with 2 mm distance between them, which permits evaluation of the profundity of the duct cannulation. The 3 lumens of the manometry catheter were perfused by sterile bidistilled water with a speed of 0.25 mL/minute/lumen, by a pneumohydraulic capillary infusion system (Arndorfer Medical Specialty, Greendale, WI, USA). The intraluminal pressure was registered to external transducers (TP-400T) and connected to a polygraph (Nihon-Kohden Co, Tokyo, Japan). The diameter of sphincterotomy orifice was estimated comparing to the caliber of the manometry catheter: 5.5F = 1.84 mm outer diameter. Pressure in the duodenal lumen was registered and considered as zero. Bile duct cannulation was confirmed by aspiration of yellow bile. Bile duct pressure was registered and the catheter was then slowly withdrawn into the sphincter region, where the residual motor activity was registered, as described previously.11 Independently of the basal manometry results, 20 mg of Buscapina was injected IV and the sphincter pressure continuously registered at least for 5 additional minutes. Pancreatic duct was not cannulated and manometry of pancreatic sphincter segment was not performed in this group of patients. Duodenal peristalsis was estimated visually.
This work was approved by the Committee of Ethics for Clinical Research of Hospital Clínico Universidad de Chile (No. 24/20).
The EST was performed with the aim to treat choledocholithiasis and the manometry was done 1 month to 56 months after the EST (mean ± SEM: 15.9 ± 4.3 months). The papillotomy orifice was estimated between 5 mm to 15 mm (mean ± SEM: 10.4 ± 1.3), no significant stenosis was observed in this group of patients (Table).
Choledocho-duodenal pressure gradient was absent in all patients. The basal pressure of OS was zero in 7 patients and within the normal range, 7 mmHg to 30 mmHg in the other 7. Residual motor activity was found in 11 of our 14 patients, detecting phasic contractions of 20 mmHg to 130 mmHg amplitude and 3/minute to 7/minute frequency. Irregular contractions were observed in 2 cases.
We registered motor activity only with 2 of the 3 registry points in all but 2 of our patients after previous endoscopic papillotomy, as a signal of a short remnant sphincter segment. Buscapina IV injection inhibited the residual motor activity of sphincter in 3 patients, with a clear reduction of phasic contraction amplitude and frequency and minor variation of basal sphincter pressure (Fig. 1). These patients had a basal motor function of OS near to normal, with basal pressure of 7, 25, and 30 mmHg, respectively. In 2 patients with initial basal OS pressure of 0 mmHg and 15 mmHg, Buscapina had no effect at all, the pressure values and contractions did not change after the injection. An unexpected stimulatory effect was observed in 9 patients, with initial basal OS pressure of 5, 10, and 25 mmHg in 3 of them and 0 mmHg in the remaining 6. An increase in basal OS pressure is seen in a patient with a relatively preserved sphincter activity (Fig. 2). Already in this case, very quick phasic contractions appeared in one of the traces. In other 2 patients with almost absent motor activity, a markedly increased basal OS pressure was detected with phasic contractions of high frequency and amplitude (Fig. 3). Minor similar changes were seen in another patient (Fig. 4). Similar phasic contractions of 20-40 mmHg but about 18-22/minute frequency appeared in 6 patients, in some of them also conserving the presence of phasic contractions observed before injecting Buscapina, with a slight increase in their frequency.
Evaluating together our 9 patients who presented a paradoxical stimulatory effect, a significant increase in basal sphincter pressure (Fig. 5A), in frequency (Fig. 5B) of phasic contractions was observed, with no significant changes in their amplitude (Fig. 5C). Duodenal peristalsis was invariably inhibited in all patients.
No relation was found between the response to Buscapina and the estimated size of papillotomy (Fig. 6A), neither the time elapsed since the endoscopic intervention (Fig. 6B). The size of papillotomy orifice did not vary depending on time (Fig. 6C).
EST is part of the endoscopic treatment of choledocholithiasis. It destroys variable fraction of the OS muscles and results in a loss of sphincter function in variable degrees. EST is considered as complete, if the pressure in the bile duct is equal to the duodenal pressure, and it means that the choledocho-duodenal gradient is zero. This criterion was accomplished in all our patients. The importance of preserved or lost OS function in the late outcome of these patients is not clear: Bergmann12 described a permanently lost sphincter function more than 10 years after EST, with basal sphincter pressure 0 mmHg. Others found preserved basal sphincter pressure, while with low normal values.9 Balloon dilation of the papilla instead of EST is supposed to preserve OS function, but no evident relation was demonstrated to the risk of stone recurrence or other late complications.8,10,13,14
These patients have a major probability to suffer abdominal cramps, biliary type pain, thus they receive frequently antispasmodic drugs, amongst them one of the most widely used is Buscapina. Being an anticholinergic agent, Buscapina inhibits the increased intestinal motility, cramps, and relaxes the normal OS.7
The innervation of OS is complex. Stimulation of vagal fibers induces phasic contractions, on the contrary, Buscapina relaxes the normal sphincter. It has been routinely used in endoscopic retrograde cholangiopancreatography, in order to facilitate cannulation of the bile duct, inhibiting the duodenal motility and opening the OS.15,16 It is also frequently and safely administered in other routine endoscopic procedures.17 Paradoxical response of intact OS has been described to secretin in alcoholics18 and to cholecystokinin (CCK) in OS dyskinesia,19 but not to cholinergic agents or their antagonists. Our experiences represent the first observation and it was found only after EST and never with intact papilla. Even after EST, this effect is not the rule: 9 of 14 patients had this unexpected reaction, but we saw a habitual inhibitory effect in 3 and lack of change in 2 patients after Buscapina. No relation was found with the size of EST orifice, with the time elapsed between the EST and the manometry, nor with the age or eventual symptoms of the patient. It seems that the probability of paradoxical response increased as the functional destruction of the sphincter muscles was more important. The innervation of OS is complex and a closely connected duodeno-sphincteric circuit is described, which is mainly cholinergic in different species,1,20,21 but other neurotransmitters also participate in the regulation of motor function. It was demonstrated that neural transmission in this circuit was bidirectional.20 In the paper of Deng et al,22 the proximal duodenum close to the pylorus was transected and reanastomized. Followed this intervention, a slight decrease in basal OS pressure was observed and CCK-octapeptide injection produced a paradoxical stimulatory response, high amplitude phasic contractions instead of sphincter relaxation observed before the transection. Dong et al23 performed duodenectomy and gastro-jejunostomy in dogs and inserted the intact papilla in the “neoduodenum” formed by the jejunum. In these dogs, no inhibitory effect was observed after CCK injection. In any of these experimental settings, once the duodenal continuity was interrupted, CCK did not produce more OS relaxation.
EST destroys not only muscular elements of the OS, but probably interrupts the integrity of duodeno-sphincteric circuit and changes the proportion of stimulatory and inhibitory fibers. One can speculate that Buscapina in these cases blocks the inhibitory vagal fibers, which permits a consecutive dominance of stimulatory, probably non-cholinergic fibers. Endoscopic manometry is an invasive method with risk of complications, for this reason we did not try to search for the antagonist of this stimulatory effect. It is worthwhile to remark, that the paradoxical effect of Buscapina was only observed in the motor function of OS, the powerful inhibition of duodenal peristalsis was unaltered. Thus, the EST interferes exclusively with the innervation of OS but not with that of the duodenum.
In conclusion, we report a paradoxical stimulatory effect of an anticholinergic agent, Buscapina observed in 9 patients treated previously by EST. Apart from destruction of variable fractions of OS muscle, this endoscopic intervention probably interrupts the duodeno-sphincteric circuit of nerve fibers, and alters the proportion of stimulatory and inhibitory components. The partially preserved OS muscles respond with paradoxical contractions in several patients. This effect seems to be related rather with the individual variations of length of OS and its nerve fibers and ganglia than the technical aspects of EST. The clinical importance of this phenomenon is not clear but it seems reasonable to avoid the use of Buscapina in patients after EST for the treatment of abdominal cramps, eventually of biliary origin.
The authors acknowledge the skilled technical assistance of Silvana Riquelme and José Matus (deceased); and Abraham Gajardo Cortez’s assistance in statistical analysis.
This work forms part of project (No. 1950290 FONDECYT).
Zoltán Berger and Ana María Madrid S participated equally in the design and execution of the work, as well as in the recollection and interpretation of data, and redaction and critical revision of manuscript.