Is Morphine or Merperidine More Effective in Treating Pain Related to Pancreatitis and Chole-

cystitis?

Abstract

This paper will discus the function of the pancreas and gallbladder, and will also explore the

background of pancreatitis and cholecystitis. It will analyze and critically appraise studies ex-

ploring the question of whether morphine or meperidine is more effective in treating pain related

to pancreatitis and cholecystitis.

Background and Rationale:

Pancreatitis and Cholecystitis are conditions that impair the functioning of the gallblad-

der. The liver produces bile, which is a fluid used to break down fat. The gallbladder stores this

bile. When fat is ingested, the gallbladder releases bile, which travels to the sphincter of Oddi

through the cystic duct and common bile duct. Through the sphincter of Oddi, the bile passes

into the duodenum.

Cholecystitis occurs when there is a blockage in the cystic duct, usually caused by gall-

stones. The gallbladder becomes inflamed and there becomes a back up of bile into the gallblad-

der. (Bloom, 2016). Furthermore, the pancreas’s digestive function involves the secretion of en-

zymes that break down fats, carbohydrates, and proteins. These enzymes, produced by the pan-

creas are released during digestion and travel through the sphincter of Oddi to the duodenum. A

feedback mechanism exists to control pancreatic enzyme activation after metabolism. In pancre-

atitis, the enzymes are activated prematurely, which causes auto-digestion of the pancreas. Fac-

tors involved in maintaining cellular homeostasis are out of balance. It is speculated that Sphinc-

ter of Oddi dysfunction can lead to pancreatitis by causing increased pancreatic duct pressures.

However, pancreatitis in patients without elevated sphincter pressures remains controversial

(Gardner, 2015).

The most common presenting symptom of cholecystitis is upper abdominal pain. The

sharp right upper quadrant pain can radiate to the right shoulder and the pain can worsen when

the client inhales deeply. Furthermore, biliary colic, or the pain that is associated with the gall-

bladder contraction due to gallstones, can occur when the client eats a high-fat meal. Other

symptoms include fever, tachycardia, and rebound tenderness or guarding. Clients who have

pancreatitis have pain located in the middle-upper region on the abdomen that worsens with con-

suming high fat foods, or drinking alcohol. Pancreatitis and Cholecystitis pain control is essential

for quality care. Morphine and meperidine have both been effective in treating the pain related to

both these conditions. There is debate over which of these opioid analgesics is more beneficial

because many believe morphine irritates the sphincter of Oddi more than meperidine does.

Search Methods

Databases that were searched include CINAHL Complete, Cochrane, EBSCOhost, MEDLINE,

PubMed, ScienceDirect, and UpToDate. Google search engine was used to find definitions,

background information, and pathophysiology of pancreatitis and cholecystitis. Key words used

to search included “Merperidine vs. Morphine,” “Sphincter of Oddi Morphine,” “Sphincter of

Oddi Meperidine,” and “Pancreatitis and Cholecystitis pain.” Limits that were used included

English Lanuage, Abstract Available, and Linked Full Text. The total number of citations used is

eight. Inclusion criteria included articles and research studies that compared morphine and

meperidine related to pancreatitis, cholecystitis, or the sphincter of Oddi as related specifically to

the topic. Exclusion criteria consisted of articles that did not have sufficient evidence, sordid not

relate to the topic.

Critical Appraisal of the Evidence:

In the research study titled Nitroester drug’s effects and their antagonistic effects against

morphine on human sphincter of Oddi motility, the effects of nitroester drugs and morphine on

the sphincter of Oddi was evaluated. The study confirmed the increase in biliary pressure related

to morphine and also confirmed nitroester drugs’ ability to antagonize the excitatory effects.

The effects of the nitroester drugs on the sphincter of Oddi were evaluated by

choledochofiberoscopy manometry. In this study, 67 patients having T-tubes after cholecystec-

tomy and choledochotomy were divided into glyceryl trinitrate group, isosorbide dinitrate group,

pentaerythritol tetranitrate group, morphine associated with glyceryl trinitrate group, morphine

associated with isosorbide dinitrate group, and morphine associated with pentaerythritol tetrani-

trate group. Within these groups, common bile duct pressure, sphincter of Oddi basal pressure,

duodenal pressure, amplitude, frequency, and duration, were analyzed.

Glyceryl trinitrate, isosorbide dinitrate, or pentaerythritol tetranitrate were administered

three times, once every 10 minutes to three groups. Morphine associated with glyceryl trinitrate,

morphine associated with isosorbide dinitrate, or morphine associated with pentaerythritol tetran-

itrate was administered to the other three groups four times. The dose of glyceryl trinitrate,

isosorbide dinitrate, and pentaerythritol tetranitrate showed an inhibitory effect on sphincter of

Oddi motility. Morphine showed an excitatory effect on sphincter of Oddi motility.

The basal pressure, amplitude of contractions, frequency of contractions, duration of con-

tractions, and common bile duct pressure were analyzed. It is well understood that nitroester

drugs have been shown to relax the smooth muscle of blood vessels. In this study, following solo

administration of the nitroester drugs, sphincter of Oddi contractions were decreased. This

demonstrates that the drugs effectively relax the sphincter. Even after 20 minutes, the effects still

continued. On the other hand, after the first administration of morphine, an immediate stimula-

tory effect on the sphincter of Oddi and common bile duct took place. Then, 10 minutes after ni-

troester drugs were administered, the stimulatory effects decreased markedly to normal levels.

Among the three drugs, the effect of isosorbide dinitrate was most significant.

One weakness of this study is that merperidine is not included. Also, the study is out-

dated, as t was published in 2005. An important strength to note is that clear tracings of pressure

and contractions were acquired. Also, every group had data of three or four times which were

compared and contrasted. Lastly, another important strength of this study is the use of Oddi’s

sphincter manometry, which is considered the gold standard method for evaluating the function

of Oddi’s sphincter. (Wu et al.).

Furthermore, the findings concerning the increase in biliary pressure due to morphine

was also confirmed in the study, Effects of morphine on the human sphincter of Oddi. The study

demonstrated that morphine causes increases in both the basal and phasic pressures of the

sphincter of Oddi. This means that morphine not only causes an increase in sphincter pressure,

but also creates spasms in the sphincter of Oddi, as shown by the increase in basal pressure. The

study looked at 19 patients aged 27-73 who were without evidence of biliary or pancreatic dis-

ease. Morphine was given in four doses of 2.5, 2.5, 5, and 10 µg/kg intravenously every five

minutes. Intraluminal pressures of the sphincter of Oddi were recorded by a manometric catheter

through endoscopic retrograde cholangiopancreatography (ERCP). All patients received 10-

15mg iv diazepam, which does not affect sphincter of Oddi function. Phasic and basal wave

pressures were measured and graphs demonstrated that morphine causes a significant increase in

both the wave pressures. Naloxone was administered to reverse morphine, which decreased the

sphincter pressures only a small amount. This concluded that receptors in addition to the mu

were being influenced by morphine in the sphincter of Oddi.

One weakness of this study was that the data studied did not include the patient’s percep-

tion of pain. The increase intraluminal pressures in the sphincter of Oddi due to morphine does

not equate to an increase in pain. The study would have benefited from subjective data from the

patients regarding pain level. This brings up another weakness in the study, which was that all

the patients were sedated with diazepam, which may have effected the validity of the results.

Furthermore, the 19 patients’ biliary and pancreatic ducts were found to be normal, which is an

implication for interpretation of results. With pancreatitis and cholecyctitis, the ducts are injured,

which can lead to a different outcome than that of the healthy biliary and pancreatic ducts used in

the study. In addition to this implication for interpretation, another weakness of this study is that

meperidine is not included. For the purpose of comparing effectiveness of the two, this study

only addresses the increase in sphincter of Oddi pressures for morphine. Lastly, this study is out-

dated, as it was published in 1988. (Helm et al.)

In a third study, Effects of meperidine on the pancreatic and biliary sphincter, the effects

of meperidine on the sphincter of Oddi is evaluated. This study is similar to the pervious study,

except in this case, meperidine is administered. According to Sherman et al. (1996), “Forty-

seven patients with disabling pancreaticobiliary pain with or without liver test abnormalities (n =

41) or idiopathic pancreatitis (n = 6) were prospectively studied” (Sherman et al.). Sphincter of

Oddi manometry was performed initially with just diazepam, then again 5 minutes after meperi-

dine iv at a dose of 1mg/kg over 2-3 minutes was administered. The pressure measurement were

analyzed by using an analysis variance model of the effects of treatment, site, and interaction of

treatment site. The treatment was either diazepam of meperidine, and the site was either bile or

pancreatic. An interaction was not found, so the effect of meperidine on the pancreatic and bil-

iary sphincter were able to be combined. The mean dose of meperidine administered was 56mg.

The effects of meperidine on the biliary sphincter, pancreatic sphincter, and combined sphincter

groups were shown to not be significantly altered by meperidine. The study also found that

76.6% of patients has interpretable phasic wave tracings before and after meperidine. 77.8% of

patients had an increase in phasic frequency and 72.2% had a decrease in phasic pressure and

phasic duration. 36% of tracings were shown to be qualitatively better after meperidine while

only 8.5% were better with diazepam alone. Meperidine was found to have little effect on the bil-

iary basal sphincter pressure and a great effect on the alteration of phasic wave characteristics.

Meperidine did not alter the basal sphincter pressure, but it did change the phasic wave patterns.

One weakness of this study was that there is some variability from recording to recording

pressure measurements according to Sherman et al. (1996), “Twelve patients had a basal sphinc-

ter pressure in the borderline range of 30 to 50 mm Hg. After meperidine administration, an ab-

normal basal sphincter pressure became normal in 2 and a normal basal sphincter pressure be-

came abnormal in 1” (Sherman et al.). The therapeutic decision would have changed in these

three patients, however this could be due to technique rather than from meperidine. Furthermore,

although the authors say that improved sedation was shown to result in a higher sphincter of

Oddi manometry success rate, sedation poses the possibility of producing unreliable results. Ac-

cording to Sherman et al. (1996), “Significantly more patients had better quality manometry trac-

ings after meperidine was administered than with diazepam alone” (Sherman et al.). Despite

higher quality tracings, the study was limited because of the lack of subjective data. Since the pa-

tients could not report pain relief, it is incorrect to conclude that a decrease in pressure leads to a

decrease in pain. Additionally, another weakness in the study was that the sphincter of Oddi

manometry was interpreted blindly by two investigators. When differences existed, the investiga-

tors interpreted them again through mutual agreement. The study did not mention how many dif-

ferences in interpretation between the investigators occurred, however, there could be a possibil-

ity of unreliable data from the study because of manner in which the tracings were read. A

strength in obtaining reliable data was that according to Sherman et al. (1996), “A basal sphinc-

ter pressure 40 mm Hg or more above the intraduodenal pressure was considered abnormal.

Tachyoddia was considered to be present when the phasic contraction frequency was greater than

10 per minute” (Sherman et al.).

In newer studies, researchers claim there is not solid evidence that proves meperidine

more effective than morphine. According to Latta et al. (2002), “Gaensler et al. performed stud-

ies on resting intra-biliary pressure, perfusion pain level, and pressure changes resulting from

drugs. The study findings revealed that meperidine caused spasm of the sphincter mechanism of

the common bile duct and that it also increased rather than relieved natural spasm” (Latta et al.).

Latte et al. (2002) also found that “1mg/kg of meperidine increased biliary pressure by 52.7%,

whereas 0.125 mg/kg of morphine increased biliary pressure by 61.3%. A later study using

10mg of morphine and 75 mg of meperidine for a 70kg individual showed an increase of 85%

with morphine and 54% with meperidine” (Latta et. al.)

Evidence Synthesis:

Prior to the development of Oddi’s sphincter manometry, sphincter of Oddi function was

measured by less reliable methods such as cineradiography, contrast media drainage time, and

transphincteric flow studies via a T-tube either during or after biliary tract surgery. The study

found that nitroester drugs are able to relax the muscle of the Oddi’s sphincter and can be used to

antagonize the sphincter spasms associated with morphine. Morphine, which has been proven to

cause spasm in the sphincter, is still widely used in patients with biliary tract disease. For exam-

ple, in the perioperative setting, morphine is used for analgesia, and also, with anesthesia. The

spasm morphine induced in the sphincter of Oddi and bile duct can have very serious conse-

quences. According to the authors, “spasm of the sphincter may yield a ‘pseudocalculus’ artifact

during cholangiography that is indistinguishable from impacted common bile duct stone and may

result in unnecessary bile duct exploration” (Wu et al.). It is crucial for healthcare providers to

understand the effect morphine has on the biliary pressure.

In the study Effects of morphine on the human sphincter of Oddi, the author explains that

receptors other than the mu were being influenced by morphine in the sphincter of Oddi. When

Naloxone was administer to reverse the morphine, the pressures only slightly decreased. Accord-

ing to Helm et al. (1988), “When given after naloxone, the largest cumulative morphine dose of

20 µg/kg significantly decrease the amplitude of phasic pressure waves. In contrast, this dose of

morphine given by itself increased phasic wave amplitude. Naloxone did not have significant ef-

fect on the increase in sphincter of Oddi basal pressure elicited by morphine in large cumulative

doses of 10 or 20 µg/kg iv.” (Helm et al.). Naloxone did not effect spontaneous sphincter of Oddi

phasic wave activity or basal pressure, which shows that mu opiod receptors are not involved in

spontaneous sphincter of Oddi motor function. In analyzing the graphs of sphincter of Oddi pha-

sic pressure waves, naloxone is shown to act as a competitive antagonist to the morphine dose.

The article states, “The increase in frequency of SO phasic pressure waves after morphine is

likely mediated by mu receptors, however, because naloxone antagonized the increase in phasic

wave frequency elicited by morphine” (Helm et al.). The morphine dose response curve shifts to-

wards the right after naloxone, suggesting that naloxone is acting as a competitive antagonist.

The evidence from this study shows that morphine causes increases in both the basal and phasic

pressures of the sphincter of Oddi. The increase in basal pressure indicates that in addition to an

increase in pressure, morphine also causes spasms in the sphincter of Oddi. (Helm et al.)

Effects of meperidine on the pancreatic and biliary sphincter serves as a comparison to

Effects of morphine on the human sphincter of Oddi. The meperidine study found that meperi-

dine in fact lowered phasic pressure in 72.2% of participants. The basal sphincter pressure, pan-

creatic sphincter pressure, and the combined sphincter group were not considerably altered by

meperidine. Meperidine increased pancreatic, biliary, and phasic frequency, and decreased the

phasic duration. The pancreatic and combined phasic pressures were reduced with meperidine.

In the older studies, it is important to understand that bile flow occurs between phasic

contractions and not during contractions. Meperidine was found to increase phasic frequency,

which compromises the interval between phasic contractions. This may increase bile duct pres-

sure without altering basal sphincter pressure. Morphine has been shown to increase sphincter

pressure, which the authors of the articles assume, would lead to irritation in the pancreas and

gallbladder for patients with cholecystitis or pancreatitis. The increase of pressure within the

sphincter of Oddi would cause a backup of bile or pancreatic enzymes.

In newer studies, researchers claim there is not solid evidence that proves meperidine

more effective than morphine. According to Narcotic analgesic effects on the sphincter of Oddi:

a review of the data and therapeutic implications in treating pancreatitis, the sphincter of Oddi

is sensitive to all narcotics, including meperidine. According to Thompson (2001):

“Narcotic-induced increases in phasic wave frequency interfere with SO filling and are responsi-

ble for the increase in bile duct pressure seen on the initial studies. No studies directly compare

the effects of meperidine or morphine on SO manometry and no comparative studies exist in pa-

tients with acute pancreatitis. No outcome-based studies comparing these drugs have been per-

formed in patients with acute pancreatitis. Morphine may be of more benefit than meperidine by

offering longer pain relief with less risk of seizures. No studies or evidence exist to indicate mor-

phine is contraindicated for use in acute pancreatitis.” (2001).

In fact, meperidine use is complicated due to side effects like serotonergic crisis and

normeperidine toxicity. The analgesic effects are not as strong as morphine’s, and also has multi-

ple drug interactions. Meperidine is metabolized into a neurotoxic metabolite, normeperidine,

which has a longer half life then meperidine. According to Latta et al. (2002), “ The active nono-

pioid neurotoxic metabolite normeperidine has half the analgesic potency of meperidine but two

to three time the potency as a central nervous system excitatory agent. As overlooked clinical ia-

trogenic event is the propensity of normeperidine to precipitate anxiety, hyperreflexia, my-

oclonus, seizures, and mood changes within 24 hours” (Latta et al.).

Newer studies have also found that meperidine acts by a nonopioid mechanism. Accord-

ing to Latta et al. (2002), “Direct application of meperidine to isolated guinea pig common bile

duct and gallbladder revealed that lower concentrations of meperidine decreased the response to

stimulation, whereas higher doses gave an increase in spontaneous contractions. This effect was

not responsive to naloxone, and thus it was concluded that meperidine acts by a nonopioid mech-

anism.” (Latta et al.). The study also found that even though sphincter of Oddi contractions de-

creased with meperidine, there are no significant changes in basal sphincter pressure, contraction

amplitude, or wave direction. Latta et al.’s (2002) study goes as far to say, “preference of

meperidine over morphine is the medical equivalent of an urban legend” (Latta et al.). The pref-

erence of meperidine over any other opioid cannot be supported by science.

Clinical and Research Recommendations:

References

Bloom, A. A. (2016, April 15). Cholecystitis. Retrieved May 12, 2016

Gardner, T. B. (2015, April 1). Acute Pancreatitis. Retrieved May 12, 2016

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(1988). Effects of morphine on the human sphincter of oddi. Gut, 29(10), 1402-1407. Retrieved from http://search.ebscohost.com.libproxy.unh.edu/login.aspx?direct=true&db=cmedm&AN=3197985&site=ehost-live

Latta, K. S., Ginsberg, B., & Barkin, R. L. (2002, January). Meperidine: A Critical Review. Retrieved May 10, 2017.

Sherman, S., Gottlieb, K., Uzer, M. F., Smith, M. T., Khusro, Q. E., Earle, D. T., Lehman, G. A. (1996). Effects of meperidine on the pancreatic and biliary sphincter. Gastrointestinal Endoscopy, 44(3), 239-242. doi:http://dx.doi.org.libproxy.unh.edu/10.1016/S0016-5107(96)70158-X

Thompson, D. (2001, April 26). Narcotic analgesic effects on the sphincter of Oddi: A review of the data and therapeutic implications in treating pancreatitis. Retrieved May 10, 2016.

Wu, S.-D., Zhang, Z.-H., Li, D.-Y., Jin, J.-Z., Kong, J., Tian, Z., … Wang, M.-F. (2005). Nitroester

drug’s effects and their antagonistic effects against morphine on human sphincter of Oddi motility. World Journal of Gastroenterology : WJG, 11(15), 2319–2323. http://doi.org/10.3748/wjg.v11.i15.2319