Opioid Induced Achalasia Treated with Naloxegol: A Case Report

JA is a 45 year old man with a 27 year history of opioid abuse and dependency. At age 18 he began smoking up to 3 grams of heroin daily. After being incarcerated in 2005 for drug possession, the patient wastreated  for 4 months at a methadone clinic. When initially evaluated on May 5, 2019 at our addiction center, the patient was experiencing symptoms of acute opioid withdrawal. An outpatient “induction” was performed during which time he received 8 mg of buprenorphine (a partial μ antagonist).  He was subsequently transitioned to Medication Assisted Therapy (MAT) receiving buprenorphine to relieve symptoms of opioid withdrawal and minimize his psychological cravings for heroin. MAT provides a safe and controlled level of a partial μ antagonist to overcome the desire to use heroin. The patient admitted to experiencing frequent episodes of heartburn, dysphagia, nausea, vomiting and constipation while abusing heroin.

Within 1 week of beginning MAT, the patient reported that his opioid cravings had stopped. However, his dysphagia, heartburn, and vomiting was becoming more frequent and severe. His weight decreased 11 lbs in 2 weeks. His sister reported that JA became anorexic for fear that he would vomit immediately upon consuming the meal. Physical examination performed 2 weeks after induction found the patient to be anxious, afebrile with no evidence of orthostasis. His abdominal examination was unremarkable. Pantoprazole 40 mg BID was prescribed empirically to treat the dyspepsia, yet the patient remained symptomatic.  Within 3 months of beginning buprenorphine, the patient’s weight declined from 195 to 175 lbs. He underwent an upper endoscopy which was entirely normal. Esophageal motility studies were not performed.

After consultation with a second gastroenterologist, the patient was diagnosed with opioid induced achalasia and placed on Naloxogel 25 mg/d. Within 24 hours of taking Naloxegol 25 mg, his symptoms of dysphagia, anorexia, heartburn and vomiting had resolved. His weight increased from 175-178 lbs in 10 days. Naloxegol was discontinued for four weeks and the patient remains asymptomatic while continuing to take buprenorphine 24 mg/d.

Opioids are commonly prescribed for chronic pain; per capita opioid prescription increased by 7.3 percent from 2007 to 2012 [1]. However, progressive increases in opioid-related deaths have prompted a significant reappraisal of the role of opioids in treating chronic non-cancer pain. Opioid prescribing has decreased since 2012 [1], but unintended overdoses associated with both prescription and non-prescription opioids remain unacceptably high.

Opioids bind to receptor subtypes including μ (MOR), κ (KOR), and δ (DOR) [2]. Opioids can also be classified according to their effect at opioid receptors. In this manner opioids can be considered as agonists, partial agonists and antagonists [2].

The physiological effects of opioids are mediated principally through μand kappa receptors in the CNS and periphery.  μ receptor effects include analgesia, euphoria, respiratory depression, and miosis. Kappa receptor effects include analgesia, miosis, respiratory depression, and sedation.  Two studies have demonstrated an acute decrease in Lower Esophageal Sphincter (LES) pressure by μ opioid receptor stimulation [3,4].

Two other opiate receptors that mediate the effects of certain opiates include sigma and delta sites. Sigma receptors mediate dysphoria, hallucinations, and psychosis; delta receptor agonism results in euphoria, analgesia, and seizures. The opiate antagonists (eg, naloxone, nalmefene, naltrexone) antagonize the effects at all four opiate receptors.

Activation of opioid receptor subtypes may affect both peripheral and central nervous system as noted in table 1. Side effects of opioid therapy include constipation, nausea, vomiting, drowsiness, impaired psychomotor function and urinary retention, muscle rigidity, and myoclonus. Patients who are physically dependent on opioid use may develop signs of withdrawal when the medications are abruptly discontinued. Signs of opioid withdrawal include tremor, nausea, vomiting, diarrhea, abdominal cramping, restlessness, tearing, yawning, insomnia and anxiety [5]. Prolonged use of opioids may lead to hypogonadism, neuroinflammation, physical dependence, and accidental overdose [5-7].

Common classifications divide the opioids into agonist, partial agonist, or agonist-antagonist agents and natural, semisynthetic, or synthetic. Opioids decrease the perception of pain, rather than eliminate or reduce the painful stimulus. Inducing slight euphoria, opioid agonists reduce the sensitivity to exogenous stimuli [2]. The GI tract and the respiratory mucosa provide easy absorption for most opioids.

Table 1: Medical Complications Associated with Opioid Usage [5,6].

Chronic use of opioids may result in increased tone of the circular muscle of the intestine resulting in Opioid Induced Constipation (OIC) [8]. Continuous activation of the μ receptor is associated with dysphagia and gastroesophageal reflux disease [3]. Dowlatshahi et al., in 1985 reported the effects of long-term opioids on esophageal dysmotility which can induce dysphagia, impaired relaxation of the Lower Esophageal Sphincter (LES), aberrant distal esophageal contractions and outflow obstruction [9-11]. Manometric studies and esophageal motility was assessed by González et al., in 5 consecutive patients treated with chronic opioid therapy. Each patient was noted to have evidence of achalasia or functional outflow obstruction of the LES due to sphincter hypertonia [12-14].

Achalasia is a disease of the esophagus characterized by absent peristalsis, impaired relaxation and increased resting pressure of the LES after swallowing. , and elevating resting pressure on the LES [13]. This functional obstruction of the lower esophagus results in dysphagia, regurgitation, chest tightness, heartburn, anorexia, and weight loss [14]. The physical and psychological frustrations associated with opioid induced achalasia may increase the risk of substance abuse disorder relapse. 

Naloxegol(movantik) is a μ -opioid receptor antagonist indicated for the treatment of opioid induced constipation in adults with chronic, non-cancer pain [15].  When administered orally, the drug binds selectively to μ -receptors in the GI tract to decrease the constipating effects of opioids. Fortunately, naloxegol “uncouples” μ -receptors activation only within the gut rather than in the central nervous system, thus precipitating acute opioid withdrawal. To date, the drug has not been tested or approved for use in patients with opioid induced achalasia. Peak plasma concentrations of naloxegol 12.5 and 25 mg are achieved within 2 hours of dosing and the half-life of the drug ranges between 6-11 hours, implying that a patient may experience rapid improvement in their opioid induced constipation or achalasia [15].

Acute morphine administration significantly decreases the rate of transient LES relaxations resulting in fewer reflux episodes. However, chronic opioid use results in impaired LES relaxation, dysfunctional esophageal motility waves, and esophagogastric junction outflow obstruction. Thus, different esophageal physiology may be dictate the GI outcomes of patients with acute and chronic opioid usage. Evidence suggests that treatment outcomes are worse in individuals with chronic opioid use achalasia [16]. The use of Naloxogel, a μ -receptor antagonist, may provide patients with chronic opioid induced achalasia, a rapid means of recovery.