Gut, 1965, 6, 57

Effect of morphine, prostigmine, pethidine, andprobanthine on the human colon in diverticulosis

studied by intraluminal pressure recordingand cineradiography

NEIL STAMFORD PAINTER, S. C. TRUELOVE, G. M. ARDRAN, AND M. TUCKEY

From the Nuffield Department of Clinical Medicine and the Nuffield Institute for MedicalResearch, University of Oxford, Oxford

EDITORIAL SYNOPSIS A previous study has shown that morphine causes the generation of highintrasigmoid pressures. In diverticulosis of the colon, this effect is exaggerated in those segmentsactually bearing diverticula. There is therefore a prima facie case for questioning the wisdom ofgiving morphine to patients with diverticulosis. In the present investigation, cineradiography wasused in conjunction with intraluminal pressure recording to study the behaviour of colonicdiverticula after the administration of morphine and other drugs. High intrasigmoid pressuresevoked by morphine are shown to be accompanied by distension of neighbouring diverticula,sometimes to an extrelne degree. Although the necks of the diverticula may shut under the influenceof morphine, they do not remain closed but open intermittently and allow colonic contents to besquirted into the diverticula. It appears possible that the use of morphine in acute diverticulitismay predispose to rupture of inflamed diverticula. These effects of morphine can be abolishedby an intravenous injection of the anticholinergic agent, probanthine. The analgesic drug,pethidine (demerol), does not have the undesirable effects of morphine and it is suggested thatthis drug is to be preferred to morphine for the relief of pain in acute diverticulitis.

The administration of morphine to patients withdiverticulosis results in the generation of an excessivenumber of waves of high intraluminal pressure in thepart of the sigmoid colon that bears diverticula; bycontrast, the unaffected parts of the sigmoid producepressure patterns essentially similar to those of thenormal sigmoid colon (Painter and Truelove, 1964a).A similar but not identical response of the diseasedsigmoid is evoked by prostigmine (neostigminemethylsulphate) (Painter and Truelove, 1964b).Both these drugs cause the sigmoid colon to segment,and this segmentation appears to have an intimateconnexion with the capacity of the colon to generatelocalized intraluminal pressures (Painter, Truelove,Ardran, and Tuckey, 1964). An injection of pro-banthine (propantheline bromide) abolishes thehigh pressures that are evoked by morphine andprostigmine (Painter and Truelove, 1964c). Theanalgesic agent pethidine (demerol) differs frommorphine in causing a diminution of both the numberand the dimensions of the intraluminal waves ofpressure (Painter and Truelove, 1964c).

57

The effect of morphine raises a question which isof immediate practical importance. High intra-sigmoid pressures are potentially dangerous inacute diverticulitis as they might cause inflameddiverticula to rupture. However, it could be arguedthat morphine might cause the colonic musculatureto contract in such a way as to occlude the necks ofthe diverticula and thus isolate the diverticula fromthe force of the intracolonic pressures. We havetherefore employed cineradiography in combinationwith intraluminal pressure recording to study thebehaviour of the colon in diverticulosis when it isbeing influenced by morphine or by other drugs.

METHOD

The method of investigation and the apparatus usedhave already been described (Painter, 1962). Thenumber of subjects studied is given in Table I.

RESULTS

Figure 1 consists of a pressure tracing together with

Neil Stamford Painter, S. C. Truelove, G. M. Ardran, and M. Tuckey

TABLE INUMBER OF PATIENTS STUDIED WITH COMBINED CINE-

RADIOGRAPHY AND INTRALUMINAL PRESSURERFCORDING

Drug Administered Number ofPatients

Normal Diverticulosis

MorphinePethidineProstigmineProbanthineTotal

7

5417

1959437

frames from the corresponding cinefilm. Theexposure of each frame of this film is indicated at thetop of the pressure tracing by a series of notches;every tenth notch is numbered. The frames were

Frame 25

exposed at the rate of one per second. The subjectwas a woman of 58 with a single diverticulum in thesigmoid colon which had already been filmed underbasal conditions (Painter et al., 1964). The presentfilm was taken after she had been given morphine.The tip of a recording lead (lead 2) can be seen in theimmediate vicinity of the diverticulum at the top ofthe print near the number 2. Much of the bariumhas collected in the upper sigmoid leaving the bowelnear the diverticulum less full of barium. Thisdistribution of the barium is the result of a contrac-tion of the sigmoid with partial occlusion of thecolonic lumen in the vicinity of the diverticulum.During this film, lead 2, which was adjacent to thediverticulum, recorded two waves of pressure which

Frame 38 Frame 42

FIG. 1. The efJect of morphine on the colon in divertica-losis (for details see text). D = Diverticulosis, L = Lead 2,R = Rectum, S = Sigmoid.

Frame 10

58

Effect of morphine, prostigmine, pethidine, and probanthine on the humaln colon

reached heights of 20 mm. Hg and 30 mm. Hgrespectively. As the neck of the diverticulum re-mained open during the entire film, it is obviousthat the diverticulum must have been subject, atleast in part, to the force of the intraluminal pressuresthat followed morphine.Lead 2 recorded the pressure of 20 mm. Hg when

the bowel immediately above the diverticulum wasnarrowed (frame 10). This pressure was not registeredby lead 1, presumably because it was isolated fromthis zone of high pressure by the segmentation of thebowel. The tip of lead 1 cannot be seen in the film,being located in the mass of barium in the uppersigmoid. The diverticulum was less well-filled andthe bowel above it less narrowed when the pressurefell to the basal level (frame 25), but it becamebetter filled in frames 38 and 42 during a wave ofpressure of 30 mm. Hg. These frames also showthe narrowing of the bowel above the tip of lead 2that accompanied the rise in pressure whichsqueezed barium into the diverticulum, causing it tohave a more definite outline. The barium within thediverticulum produced a bifid shadow as it encircleda faecolith.

This film demonstrates that a diverticulum may besubject to the intrasigmoid pressures that developafter morphine. This particular diverticulum wasnot markedly distended by these pressures butsometimes morphine causes dramatic changes indiverticula.

1

Figure 2 shows the sigmoid of a woman of 70.The sigmoid was so serpentine that the outline of itsloops overlapped in the film and for this reasononly the top recording lead could be passed beyondthe recto-sigmoid junction into the lower sigmoid.Thus the intraluminal pressures near the twodiverticula that are seen in the right lower quadrantof the prints could not be measured and so thepressure tracing is not reproduced. However,pressures of up to 20 mm. Hg were recorded fromthe bowel below the diverticula after the intravenousinjection of morphine. This injection was completedby the 21st frame.The necks connecting these two diverticula to the

lumen of the colon are clearly seen in frame 20. Theintravenous morphine sulphate took effect rapidlyand the bowel began to narrow in the next 10seconds. Simultaneously the diverticula enlarged(frame 30) and their necks narrowed until at timesthey were shut completely (frame 50). The bowelfrom which they arose contracted so that its lumenwas almost occluded (frame 60). When this film wasprojected, the movements of the colon were seen tobe greatly increased and the diverticula appearedto be blown up like balloons. Although the necks ofthe diverticula were completely closed at times(frame 95), they opened intermittently (frame 99)and allowed barium to be pumped into the diverti-cula.

This effect of morphine was not one that only

FIG. 2. Theeffect ofmorphine oncolonicdiverticula

1Il- 0so (for details_ - _ see text).

I

Fram60rie 959

59

Erm60S11(( Fra;ltlc 93')

Neil Stamford Painter, S. C. Truelove, G. M. Ardran, and M. Tuckey

FIG. 3. The effect ofprobanthine on colonic diverticula that are under the influence of morphine (for details see text).

occurred immediately after its injection by theintravenous route as we have also observed it afterintramuscular administration. Neither is it a short-lived response as a later film of the same subjectwill show (Fig. 3). This film was taken 40 minutesafter the injection of morphine while 30 mg. ofprobanthine was being given intravenously. Thediverticula were still distended (frame 1) beforethe probanthine took effect. The injection of thisdrug was completed by the eleventh frame. Thecolon was still active during these 11 frames but,during the remaining 130 frames, the motor activityof the bowel ceased, while the pressure tracing fromthe lower sigmoid became flat. The colon appearedto dilate as it became immobile (compare frames20 and 139), and as the sigmoid relaxed, the necks ofthe diverticula opened (frames 20 to 30). Thediverticula then diminished in size as their contentsdrained into the bowel (frame 139).

Prostigmine has an effect on the intraluminalpressures similar to that of morphine. Cineradio-graphy reveals that prostigmine causes the inter-haustral folds to contract in much the same manneras does morphine so that the colon has the seg-mented appearance which is usual when it isgenerating high localized intraluminal pressures.This effect of prostigmine is seen in health as wellas in diverticulosis. Like morphine, prostigminecauses colonic diverticula to be subjected to highpressures (Painter et al., 1964), but while this effect isof practical importance in the case of morphine, asfar as prostigmine is concerned this effect is only oftheoretical interest at the present time.

Pethidine does not cause the sigmoid to producean increased number of pressure waves either inhealth or in diverticulosis; in fact the number anddimensions of these waves are slightly diminished.It appears that the drug achieves this effect bydepressing the excitability of the sigmoid so that itdoes not segment in response to stimuli that other-

wise cause it to do so. Figure 4 shows the reactionof the sigmoid colon of a woman of 64 with diverti-culosis to an injection of barium into its lumen.Three polythene tubes were located in the sigmoidand their tips can be seen in frame 5. Leads 1 and 2recorded pressure while a third lead, the 'feeder'tube or lead F, was placed between them to facilitatethe injection of barium into the sigmoid withoutinterrupting pressure recording by the other twoleads. Twenty ml. of barium was injected via lead Fbetween the second and twelfth frames. This bariumpassed up the sigmoid. The bowel around lead Iresponded by segmenting and generating a wave ofpressure that reached a height of 19 mm. Hg(frames 13 and 18). Diverticula appeared near lead 1as this pressure built-up and can be seen on theright-hand side of the bowel. A second injection ofbarium was made between the 26th and 33rd frames;most of this flowed back to the rectum, beingapparently unable to pass upwards as the uppersigmoid was now narrowed by the segmentationthat had occurred (frames 23, 30, and 40). The bowelreacted to this second injection by again segmenting.

Figure 5 shows the same sigmoid after pethidine;the tips of the recording leads can be recognizedthrough the shadow cast by the barium remainingfrom the injections described above (frame 3).Twenty ml. of barium was injected via lead Fbetween the third and tenth frames and it was seento pass along the sigmoid like water flowing througha drain (frames 5, 10, and 65). The barium passedthrough the open lumen of the sigmoid withoutbeing hindered by the configuration of the colonicwall for the lumen did not narrow and no con-traction rings formed. In short, the colon did notsegment. As we have come to expect, this lack ofsegmentation was accompanied by an absence ofhigh intraluminal pressure. The diverticula nowappeared as squat projections with widely opennecks and are quite unlike their appearances seen

60

Effect of morphine, prostigmine, pethidine, and probanthine on the human colon

*P35]...........I

Frame 13

Frame 23 Frame 30

Frame 1I

Frame 40

FIG. 4. The effect ofan injection of barium into the colon in diverticulosis (for details see text).

in the previous figure. Clearly pethidine had

affected the sigmoid colon so that it hardly re-sponded to a stimulus that had previously excited it.The appearances of the colon and the diverticulaafter pethidine have some of the features that areseen after the administration of probanthine.

DISCUSSION

Cineradiography has shown conclusively thatcolonic diverticula are exposed to the force of theintraluminal pressures evoked by morphine. Onceit is realized that administration of this drug isfollowed by the generation of intraluminal pressuresthat may exceed 90 mm. Hg in those segments of the

sigmoid colon that bear diverticula, the wisdom ofgiving it to patients with acute diverticulitis must bequestioned.

In the early stages of diverticulosis, morphinecauses the colon to segment and thus facilitate thegeneration of localized high intrasigmoid pressureswhile diverticula remain in communication with thelumen of the bowel. This stage of affairs favours thefurther herniation of the mucosa or the actualrupture of the diverticula, especially if they areinflamed. In some patients, the necks of the diverti-cula may be intermittently narrowed or completelyclosed after the administration of morphine. Thedegree of protection thus afforded to the diverticulais problematical. Whether the constricted necks act

Frame:

--]i..!

61

Neil Stamford Painter, S. C. Truelove, G. M. Ardran, and M. Tuckey

........{\.{ Z' > ''a~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....:,i\:8.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.. i: .......'. '..

Frame 3 Frame 5 Frame 10 Franme 65

FIG. 5. The effect of an injection of barium into the lumen of the colon in diverticulosis after the administration ofpethidine (for details see text).

as valves so that tension builds up within thediverticula, or whether the smaller channels betweenthem and the bowel lessen the force of the intra-luminal pressure that reaches the herniations, isuncertain. However, this much is certain; theocclusion of the necks after morphine is intermittentand they open at intervals sufficiently to allowcolonic contents to be squirted into the ill-supportedsacs of mucous membrane so that they are inflatedlike balloons, sometimes to an alarming extent.

In diverticulosis of long standing, the bowel maybe so damaged by recurrent diverticulitis that partsof the muscle coat are unable to contract throughbeing transformed into rigid fibrous tissue. Diverti-cula arising from such a sigmoid are not affordedany protection as their necks are widely open aftermorphine while high intraluminal pressures areoccurring in their vicinity.These observations suggest that morphine may be

responsible for some of the perforations that occurwhen acute diverticulitis is treated expectantly. Oneof us (N.S.P.) has operated on 23 cases of perforateddiverticulitis; three of these had no evidence ofperforation on admission to hospital. All threepatients were given morphine before perforationoccurred; in two of them perforation did not occuruntil they had been in hospital for 48 hours. In

retrospect, we wonder whether the drug wasresponsible for these catastrophes.

Furthermore, although the colon may be immobileat times after morphine, when bouts of activity dooccur, its contractions are increased by the drug.It is obvious that this response cannot be beneficialin the inflamed colon of acute diverticulitis norcan it be desirable in other inflammatory diseases ofthe pelvis. What effect the post-operative use ofmorphine has on anastomoses situated in thesigmoid remains to be discovered. Restorativeresections of the rectum are followed by someleakage of faeces at the site of anastomosis in up to25% of patients, according to some authorities.While the poor blood supply of this part of the boweldoes not facilitate the healing of these anastomoses,it is also possible that morphine encourages theirdisruption.These adverse side-effects of morphine can be

counteracted by giving probanthine simultaneously.This rests the bowel by paralysing it, prevents thegeneration of high pressures, and allows thediverticula to drain by opening their necks. It mustbe remembered that this drug in the doses we haveused may cause paralytic ileus, so that its dosageand its place in the treatment of acute diverticulitisremain to be evaluated. Fortunately there is no

62

Effect of morphine, prostigmine, pethidine, and probantthine on the human colon 63

need to use the combination of morphine andprobanthine as pethidine is readily available.

Pethidine almost abolishes the generation ofwaves of high pressure in the sigmoid, both inhealth and in diverticulosis. It achieves this bylessening the tendency of the colon to segment inresponse to various stimuli, so that the lumen of thesigmoid remains open for longer periods thannormally. The sigmoid is therefore less able toproduce zones of localized high pressure. Further-more, pethidine has a somewhat similar action toprobanthine in that it allows diverticula to draininto the bowel as their necks remain open after itsadministration.

Prostigmine has an action that is similar to that ofmorphine as far as the intrasigmoid pressures andsegmentation are concerned, both in health and indiverticulosis. Diverticula are also subject to thepressures that it evokes. While this finding is of noclinical importance, it does suggest that other drugswhich cause segmentation may be followed by high

intraluminal pressures that are transmitted to thediverticula. Localized high pressures in the sigmoidcolon, being generated by the same mechanism thatwas originally responsible for the mucosal herniation,are almost certainly transmitted to diverticularegardless of the stimulus or drug that evokes them.

In brief, the use of morphine in acute diverticulitisappears to be contraindicated and pethidine is apreferable analgesic in this disease.

REFERENCES

Painter, N. S. (1962). Diverticulosis of the colon. M.S. Thesis,University of London, 1962.

, and Truelove, S. C. (1964a). The intraluminal pressurepatterns in diverticulosis of the colon. Part II. The effect ofmorphine. Gut, 5, 207-213.

- , -(1964b). The intraluminal pressure patterns in diverticulosisofthe colon. Part III. The effect ofprostigmine. Gut, 5, 365-369.- (1964c). The intraluminal pressure patterns in diverticulosisof the colon. Part IV. The effect of pethidine and probanthine.Gut, 5, 369-373.

- , Ardran, G. M., and Tuckey, M. (1964). Segmentationand localization of intraluminal pressures in the human colon,with special reference to the pathogenesis ofcolonic diverticula.In preparation.