The use of opioids for chronic pain management has increased exponentially since the early 2000s leading to the worst drug overdose epidemic in the history of the United States (1,2). The number of opioid prescriptions has increased from 164 million in 2000 to more than 234 million in 2010 (2) with approximately 4% of the US population under opioid treatment for non–cancer-related chronic pain (3). Overdose deaths from prescription drugs have increased by nearly 345% between 2001 and 2016 leading the department of health and human services to declare this as a public health emergency in 2017 (4). Although the detrimental effects of opioids on the lower gastrointestinal tract are well known, the opioid health crisis has certainly brought this to the forefront of gastroenterology with recent data regarding their impact on esophageal and gastroduodenal motility. In this review, we analyze the current literature on effects of opioids on esophageal, gastric, and duodenal motility and discuss the pathophysiology, diagnostic modalities, and treatment options for patients with suspected opioid-induced foregut dysfunction. The effects of opioids on the gallbladder, biliary dyskinesia, and colon will not be addressed in this article.
The anesthetic and sedating properties of opium have been known since the ancient times, but Paul Trendelenburg was the first to discover that morphine inhibits the peristaltic reflex in the gut (5,6). Subsequently, in 1975, Hans Kosterlitz and John Hughes identified leucine-enkephalin and methionine-enkephalin as the first endogenous opioid receptor (OR) agonists (7). These pentapeptides were also found to occur in the gut (8) and interacted with the enteric nervous system to regulate gastrointestinal motility, secretion, and analgesic properties (9–13). Subsequently, 3 types of ORs have been found in the enteric nervous system: μ, Κ, and δ receptors (14,15). These receptors are G (i/o) G-protein coupled receptors that regulate several functions based on location. Receptors located in the central nervous system control pain transmission, respiration, mood, and dependence, while receptors in the peripheral nervous system regulate various gastrointestinal functions. Although the 3 main ORs (μ, Κ, δ) have high degree of sequence homology, they differ in ligand selectivity (16,17). Enkephalins are the preferred ligands for δOR, while dynorphins have some selectivity for ΚOR and endorphins bind both μOR and δOR with similar affinity (15,18). Opiates used clinically have high selectivity and preferentially activate μOR (15,19). ORs are predominantly localized to neuronal structures within the gastrointestinal tract with high abundance in the myenteric and submucosal plexus of the enteric nervous system (20,21). Differential expression of these receptors is shown in animal models with μOR in highest density in the ileum followed by duodenum, stomach, and colon in guinea pigs (15). These receptors are coupled with different downstream effector pathways that lead to decreased cyclic adenosine monophosphate formation, inhibition of voltage-gated calcium channels, and increase in transmembrane potassium current, which lead to inhibition of neuronal activity and decrease in neurotransmitter release as shown in Figure 1 (22). Furthermore, given opioids facilitate pain pathways, use of these types of medications can also lead to escalation of pain and need for more medications with ongoing use due to opioid-induced hyperalgesia.
PHARMACOLOGIC EFFECTS OF OPIATES ON THE ENTERIC NERVOUS SYSTEM
Motility of the gastrointestinal tract is primarily controlled by the enteric nervous system, which modulates the contractions and relaxations of the longitudinal and circular muscle layers using combination of excitatory (acetylcholine [Ach] and substance P) and inhibitory neurotransmitters (β-nicotinamide adenine dinucleotide, nitric oxide (NO), and vasoactive intestinal peptide [VIP]) (23–25). The effect of opiates on gastrointestinal motility is primarily an effect of suppression of neuronal excitability (26–28). The action of morphine at the presynaptic enteric neuron terminal suppresses release of Ach, reducing the overall stimulatory potential (27). Substance P release is also suppressed (29). It subsequently affects the inhibitory musculomotor neurons of the gut suppressing the release of inhibitory neurotransmitters: NO and VIP (24,30). Overall, studies support the proposed mechanism of suppressed excitability of the inhibitory musculomotor neurons and unchecked tonic contraction of the autogenic musculature (such as the lower esophageal sphincter [LES] and the pylorus) (14).
OPIOID-INDUCED ESOPHAGEAL DYSFUNCTION
The smooth muscle of the esophagus is phasic in nature and is innervated by intramural inhibitory (NO/VIP) and excitatory (Ach) neurons that receive inputs from preganglionic neurons located in the dorsal motor nucleus of vagus (31). Unlike the striated muscle of the esophagus, the smooth muscle exhibits 2 unique responses to intramural nerve stimulation to facilitate peristalsis: (i) the offbound or rebound contraction and (ii) the latency gradient (32,33). The esophageal circular muscle contraction occurs as a rebound after stimulation of the inhibitory nerves, and there is an inbuilt latency gradient in the wall of the smooth muscle that increases from the proximal to distal esophagus (32). Thus, the local inhibitory nerves (secreting NO/VIP) are responsible for peristalsis in the esophageal smooth muscle (31). The cholinergic influence is most marked in the proximal parts of the esophagus and decreases distally along the esophagus, while the inhibitory nerve influence is least prominent in the proximal esophagus and increases distally (34). Given opiates suppress excitability of the inhibitory neurons, the proposed mechanism of opioid-induced esophageal dysfunction (OIED) likely involves loss of the latency gradient (controlled by inhibitory musculomotor neurons) in the smooth muscle of the esophagus, which results in high-amplitude, simultaneous contractions in the distal esophagus (Figure 2). This might explain manometric findings of distal esophageal spasm (DES), type III achalasia, and Jackhammer esophagus in this population.
On the other hand, given the LES is a tonic muscle that maintains closure due to its myogenic property, opioid-induced inhibition of the NO/VIP secretion leads to lack of relaxation. This might explain manometry findings of type III achalasia and esophagogastric junction outflow obstruction (EGJOO) in patients with OIED. However, it is important to recognize that the localization and expression of ORs in the esophageal body and LES have not been well characterized and need to be evaluated, but ORs have been found in the opossum LES (35).
Current literature has been limited to assessing the impact of primarily μOR agonist/antagonist on esophageal physiology. Dowlatshahi et al. studied the effect of subcutaneous morphine (0.2-mg/kg body weight) in 10 healthy adults using conventional manometry and found that morphine increased the LES pressure and decreased sphincter relaxation with maximal effect occurring 30 minutes after the injection (36). In patients with gastroesophageal reflux disease (GERD), morphine administration has been shown to reduce the rate of transient LES relaxations resulting in less reflux episodes and decrease of esophageal acid exposure time at pH < 4 (37). Chronic opiate use has also been associated with esophageal body abnormalities with high-amplitude contractions and simultaneous esophageal waves (38). One small case series evaluated 5 patients on opioid therapy with dysphagia and noted that 2/5 met criteria for type III achalasia, while 3/5 met criteria for EGJOO (39). Another retrospective study studied 121 chronic opioid users (66 patients ON medication and 55 patients OFF medication for at least 24 hours) and found that patients on opioids were significantly more likely to have EGJOO (27% vs 7%), spastic peristalsis (lower distal latency), and higher integrated relaxation pressure (IRP) on manometry (40). Similar results were also found in a cross-sectional study of 33 patients with noncardiac chest pain on chronic opiates, who were noted to have higher IRP, greater mean distal contractile integral (DCI), and increased prevalence of hypertensive motility disorders compared with nonusers (41).
In another retrospective review of 225 patients, OIED was present in 24% of patients (42). This was also the first study to show differential effects of opioids and found that OIED was significantly more prevalent with oxycodone or hydrocodone compared with tramadol (31% vs 28% vs 12%, P = 0.01), and there might be a dose effect as they found that patients with OIED had higher median 24-hour opioid dose compared to those without OIED (45 vs 30 mg, P = 0.06) (42). The largest retrospective study was recently published by Babaei et al. (43), which included 2,342 patients (1,890 were opioid-naive, and 224 were on chronic daily opioids). They found that patients on opioids were more likely to report dysphagia (62% vs 43%, P < 0.01) and were more likely to having following manometric abnormalities: type III achalasia (13% vs 1%, P < 0.01), EGJOO (13% vs 3%, P < 0.01), and DES (3% vs 0.5%, P < 0.01). They also found that the morphine equivalent dose (MME) was significantly higher in patients with type III achalasia and EGJOO. Furthermore, MME correlated with all manometry pressure metrics (IRP, intrabolus pressure, contractive front velocity, distal latency, and LES pressure) except DCI (43). Table 1 summarizes the current available literature on effects of opioids on esophageal motility.
CLINICAL PRESENTATION AND DIAGNOSIS
The clinical presentation of patients with possible OIED is similar to other spastic esophageal motility disorders. They often present with dysphagia to solids and/or liquids, regurgitation, and chest pain. They might also have refractory heartburn or early satiety due to delayed gastric emptying. Clinical symptoms alone are insufficient in distinguishing OIED, and thus, further work-up is often required. This should consist of upper endoscopy to assess the LES tone and rule out mechanical stricture or malignancy. Endoscopy will frequency show a puckered gastroesophageal junction similar to achalasia. Furthermore, high-resolution manometry should be obtained, which might show EGJOO or a spastic motility disorder (type III achalasia, jackhammer esophagus, or DES) as shown in Figure 3. These manometric patterns should prompt the clinician to perform a thorough medication reconciliation with the patient to evaluate for acute or chronic opioid use. If OIED is suspected, repeating the manometry off opiates should be considered (if patient is safely able to wean off).
Given OIED has just been recently described with only a few studies in the literature, there is currently a lack of evidence on optimal management for these patients (44). However, withdrawal of the opioid should be considered as the first-line option because some studies have shown reversal of motility dysfunction after withdrawal (38,40). There is currently a paucity of data that limits recommendation about use of μOR antagonist. One study evaluated the effect of methylnaltrexone (peripherally selective μOR antagonist) and naloxone (nonselective μOR antagonist) on esophageal motor function in 15 healthy adults and found that it did not alter transient LES relaxations, LES resting pressure, IRP, or DCI (45). However, it should be noted that this study was performed in nonopioid users, which limits its applicability.
Since OIED mimics hypercontractile esophageal disorders, therapies aimed at altering the LES tone (pneumatic dilatation or myotomy) can also be considered, but with extreme caution. It is important to alert the patient that response to any therapy would not be optimal if pain is the chief presenting symptom. In 1 small study with 5 patients with OIED, 3/5 patients underwent pneumatic dilatation with little improvement in symptoms (39). Thus, if opioid withdrawal is not an option, then it should be reduced to the lowest effective dose and injection on botulinum toxin can be considered (44,46). Pneumatic dilatation and myotomy (surgical or per-oral) should be reserved for refractory cases and after extensive review of risks and benefits with the patients, given lack of studies assessing these interventions for OIED.
STOMACH AND DUODENUM
Similar to other areas of the gastrointestinal tract, μ, Κ, and δ receptors are abundant and localized to the myenteric and submucosal neuronal plexus of the stomach and duodenum (15,47–49). Using autoradiography, μ and δ receptors were found in the submucosal and myenteric plexus in the fundus, corpus, and antrum (49). They were also found in the duodenal submucosal plexus and mucosa, but there were fewer μ receptors in the duodenal myenteric plexus (49). Using immunohistochemistry and mRNA quantification techniques, the highest concentration of both μ and Κ receptors were found in both the circular and longitudinal muscle of the stomach and colon and in a lesser concentration in the duodenum (48).
In the stomach, the corpus musculature has tonic contractility without phasic contractility and is mediated by the interplay between the activation of inhibitory motor neurons and systematic activation of excitatory motor neurons, which maintain tone and function (14). However, the antrum has phasic contractility, which works in connection with the pylorus and corpus for effective trituration and emptying (50). Opioid administration results in significantly lower myoelectric spike activity and regular slow wave activity in the antrum (51,52). This results in an increase in tonic contracture of the antrum and proximal duodenum after opiate administration (14,51). A dose-related stimulatory effect on pyloric phasic pressure has also been demonstrated (52). Overall, these support the proposed mechanism of suppressed excitability of the inhibitory musculomotor neurons and unchecked tonic contraction of the autogenic musculature leading to delayed emptying.
In the duodenum, opioid administration results in similar pathophysiology. The resting contractile tone of the small intestine is increased, and overall peristalsis is reduced (14). Premature migrating myoelectric complexes and uncoordinated smooth muscle electrical activity along with nonpropulsive, high-amplitude contractions resulting in segmentation of the intestine have also been reported to occur in the duodenum and proximal jejunum (52,53). In addition, intestinal secretion is reduced in the small intestine by the inhibitory effects of opiates on the secretomotor neurons located within the submucosal plexus (14). Secretomotor neuron excitability is suppressed as the membranes become hyperpolarized through direct effects of opioid agonists on ORs (40). The combination of decreased secretion, decreased propulsive peristalsis, and increased intestinal absorption times all may contribute to symptoms of opioid-induced intestinal dysmotility, including opioid-induced constipation (not discussed here).
Multiple studies have demonstrated the effect of opiate administration on gastric emptying. Surgical literature and anesthesia literature show that use of intrathecal morphine results in delayed postoperative gastric emptying (54), while epidural fentanyl injection delayed gastric emptying in women in labor (55). Morphine and alfentanil have also been shown to delay gastric emptying in 20 women undergoing minor gynecologic surgery (56). Even in healthy volunteers, codeine, tramadol, and morphine have been shown to delay gastric emptying with greater degree of delay with morphine compared with tramadol (partial agonist) (57,58). Other studies, also in healthy individuals, reported delayed gastric emptying with morphine (59), tapentadol (60), oxycodone (60), and codeine (61). One study failed to show an effect of tramadol on gastric emptying (62). A recent study aimed at characterizing gastroparesis patients based on the degree of delay in gastric emptying also found that opiate use was associated with an increased degree of delayed gastric emptying with 50% of the opiate users having very delayed gastric emptying (63). Furthermore, severe delay in gastric emptying correlated with both increased hospitalizations and emergency department visits (63). Table 2 summarizes the current available literature on effects of opioids on gastric motility.
In the duodenum, opioid administration results in an increase in tonic contractions. The rise in phase III motor activity results in increased tonicity, which results in decrease forward propulsive action (51). Increased rhythmic contractile pressure has also been seen with intravenous administration of the endogenous opioid protein, beta-endorphin (52). This effect was dose-dependent and lasted between 5 and 24 minutes before a period of reduced activity ensued before resuming normal fed pattern activity (52).
CLINICAL PRESENTATION AND DIAGNOSIS
Symptoms of opioid-induced gastroduodenal dysfunction resemble that of non–opiate-related gastroparesis. Typical gastroparesis symptoms include nausea, early satiety, vomiting, postprandial fullness, and abdominal pain. However, it should also be noted that there is significant overlap between typical symptoms reported with gastroparesis and side effects which have been attributed to opiates alone. In self-reported questionnaires of patients on chronic opiates, the prevalence of nausea was between 23% and 27%, emesis in 5%–9%, GERD in 14–33%, and chronic abdominal pain in 22%–58% (64,65). Abdominal pain tends to predominate presentation compared with nausea and vomiting in patients with opiate-induced delayed gastric emptying (66). In patients with delayed gastric emptying, chronic opioid use is associated with higher severity of gastrointestinal symptoms compared with nonopioid users and higher overall financial burden from increased hospitalizations and lower employment rates (67,68). Furthermore, preoperative opioid use has been associated with reduced clinical success of gastric electrical stimulators (69). Opiate use has also been associated with increased incidence of retained food during endoscopy (70).
Patients with suspected opiate-related gastroduodenal dysfunction should undergo a formal gastric emptying study, given there is significant overlap between opiate-induced side effects of nausea, vomiting, and dyspepsia and symptoms of opiate-related gastroduodenal dysfunction. This can be accomplished with gastric scintigraphy or wireless motility capsule. Regardless of the diagnostic modality, medications known to alter gastric motility should be discontinued for 48–72 hours before the study. Most common group of these medications includes opiates, anticholinergics, and prokinetic agents (71). In clinical practice, patients are often unable to discontinue opiates before formal gastric emptying evaluation, and thus, results should be interpreted in this context. Gastric scintigraphy is considered the most validated method and typically uses a standardized meal, composed of a 99mTc sulfur colloid-labeled egg product combined with toast, jam, and water. Both the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine have recommended this (72). Imaging should be performed at 0, 1, 2, and 4 hours after meal ingestion to increase sensitivity (72). Gastric retention at 4 hours appears to be the most reliable parameter (73). The degree of delay in gastric emptying might also serve as a prognostic marker, given severe delay in gastric emptying has been shown as a risk factor for increased hospitalizations and emergency department visits (63). Wireless motility capsule (SmartPill; Given Imaging, Yokneam, Israel) has also been shown to correlate with gastric emptying scintigraphy and uses pH, pressure, and temperature to determine gastrointestinal transit times (74). The 300-minute cutoff time for gastric emptying time has sensitivity of 65% and specificity of 87% for diagnosis of gastroparesis (74). Alternatively, breath testing using either 13C-octanoate or -spirulina produce has also shown strong correlation with standardized gastric scintigraphy (75,76).
As opiate administration can affect the gastric body, antrum, pylorus, and duodenum, recent studies are now focusing on identifying modalities that might localize the area of dysfunction. Measurement of pyloric diameter and cross-sectional area using endoscopic functional luminal imaging probe (EndoFLIP; Crospon, Galway, Ireland) has been shown to inversely correlate with early satiety and postprandial fullness in both diabetic and idiopathic gastroparesis (77). Pyloric distensibility has also been shown to be lower in patients with gastroparesis compared to those with normal gastric retention (78). However, further studies are needed to determine how these diagnostics might be clinically meaningful and alter treatment options.
In patients with suspected opiate-induced dysfunction of gastroduodenal motility, cessation of opiates should be the first step. Symptoms of nausea, vomiting, and GERD may be managed with symptomatic treatment and expectant management as many of the symptoms may be self-limited. If symptoms persist, and delayed gastric emptying is confirmed, a gastroparesis diet should be initiated as the first line treatment. Prokinetic drugs (such as metoclopramide) can be considered as adjunct to dietary management but should only be used after extensive discussion about potential risks and should be discontinued if no improvement within 3 months.
Studies evaluating use of opioid antagonists to reduce the detrimental effects of opioids on gastric motility have produced mixed results. In a 1975 study, the addition of naloxone to pentozocine improved gastric emptying in 4 healthy volunteers (79). Conversely, naloxone administration did not show an improvement in gastric emptying when used with morphine in 10 healthy volunteers (80). However, it has been shown to reduce gastric tube reflux volume in patients on mechanical ventilation and sedation with fentanyl (81). Furthermore, methylnaltrexone has been shown to attenuate the effect of morphine on the gastric emptying in a small randomized, double-blinded, crossover placebo study of 11 healthy volunteers (82). Most recently, 72 healthy, opiate-naive adults were randomized to codeine, naloxegol, codeine and naloxegol, or matching placebo, but there were no significant difference in gastric emptying times between the groups (83). Thus, there are no current US Food and Drug Administration-approved pharmaceuticals for opiate-induced gastroparesis.
The detrimental effects of opioids on the lower gastrointestinal tract are well described, but the opioid health crisis and exponential rise in use of these medications over the past decade have brought to light the deleterious impact of these agents on esophageal and gastroduodenal motility. Multiple studies have now shown the effects of opioids on esophageal and gastroduodenal dysfunction with increased incidence of spastic esophageal disorders and delayed gastric emptying (Figure 3). More research is needed targeting localization of ORs in the foregut and developing newer peripheral antagonists that can neutralize the harmful effects of opioids on foregut motility.
CONFLICTS OF INTEREST
Guarantor of the article: Dhyanesh Patel, MD.
Specific author contributions: D.P.: drafting of manuscript, acquisition of data, and revision of the manuscript, J.C.: drafting of manuscript and acquisition of data, and M.V.: critical revision of the manuscript.
Financial support: None.
Potential competing interests: None.
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