SUSTAINED-RELEASE ORAL HYDROMORPHONE FOR THE TREATMENT OF OPIOID USE DISORDER

Abstract

Objectives:

In 2017, almost 50,000 Americans and over 4000 Canadians died from an opioid overdose. Accordingly, an urgent need exists to improve access to evidence-based treatment for opioid addiction, and also to develop and evaluate alternative treatment options for opioid use disorder (OUD). We present a case of a patient with OUD who was successfully switched and managed on oral hydromorphone after development of a prolonged QTc interval on methadone.

Case:

A 51-year-old man with longstanding polysubstance use presented to an urban hospital in Vancouver, Canada, for management of alcohol intoxication and hyponatremia. At the time of admission, the patient was stable on 100mg of methadone daily, but was found to have a persistently elevated QTc (>550milli- milliseconds), putting him at increased risk for Torsades de Pointes. In an effort to find an alternative opioid agonist therapy for maintenance, a trial of slow-release oral morphine was attempted, but discontinued due to the development of myoclonus. Once-daily sustained-release oral hydromorphone was then started, which was found to manage cravings well without notable side effects.

Discussion:

The case presented offers promise for the use of once- daily sustained-release oral hydromorphone as a viable treatment option for patients with OUD for whom first-line therapies are not suitable or tolerated. This case report is the first to our knowledge to demonstrate the successful use of oral hydromorphone for treatment of opioid use disorder.

In 2017, almost 50,000 Americans died from an opioid number represents almost a 20% increase from just 1-year prior (National Institute on Drug Abuse, 2018). Similarly, in Canada, over 4400 individuals died as a result of opioid use in 2018 - a 33% increase from 2016 (Government of Canada, 2019). Beyond increased mortality, opioid use is also associated with significant morbidity and healthcare costs. More specifically, in the United States, the national rate of opioid- related presentations to a hospital emergency department increased by 99% between 2005 and 2014 (Healthcare Cost and Utilization Project, 2017). During the same timeframe, the number of US hospital admissions related to opioid use increased by 64% (Healthcare Cost and Utilization Project, 2017).

Accordingly, an urgent need exists to improve access to evidence-based treatment for opioid addiction. To address this, a Canadian national clinical practice guideline for the management of opioid use disorder (OUD) was published in 2018 (Bruneau et al., 2018). Buprenorphine/naloxone and methadone represent first and second-line treatment options, respectively, as outlined in the clinical guideline. For individuals unsuccessful on these therapies, a trial of oral slow- release morphine is recommended. Finally, injectable opioid agonist therapy (eg, diacetylmorphine or hydromorphone) is listed as a treatment option for those with severe OUD who have been unsuccessful on oral opioid agonist therapy (British Columbia Centre on Substance Use and BC Ministry of Health, 2017). Recommendations for OUD treatment in the United States currently include methadone, buprenorphine/ naloxone, and extended-release naltrexone as first-line therapies. Slow-release oral morphine and injectable opioid agonist therapy are not currently approved for OUD treatment in the United States. Though available in the United States, extended-release naltrexone is not currently available as an OUD treatment option in Canada.

Despite an increase in the number of available treatment options for OUD, a significant number of patients are unsuccessfully retained on first-line oral opioid agonist therapy. More specifically, US data demonstrate less than half (45%) of individuals started on buprenorphine/naloxone for OUD treatment to still be on treatment at 1 year (Manhapra et al., 2018). Similarly, British Columbian data demonstrate only one-third of patients started on methadone for OUD treatment to remain on treatment 12 months later (Office of the Provincial Health Officer, 2017). Though likely varied, some reasons for low retention among first-line oral opioid agonist therapy may include: patient preference, difficulty access to a prescriber (eg, geographic proximity to the patient), or ability to adhere to a daily witnessed ingestion schedule. Accordingly, alternative oral treatment options for OUD should continue to be evaluated. Given this, we present a case of a patient with OUD who was stable on oral methadone, but was successfully switched and managed on oral hydromorphone after development of a prolonged QTc interval.

CASE REPORT

A 51-year-old man was transferred from a community to urban hospital in Vancouver, Canada, for management of alcohol intoxication and hyponatremia (defined as a blood sodium concentration of <135 milliequivalents/L). His past medical history was significant for HIV infection (CD4 count 200 cells/mL, undetectable viral load), severe congestive heart failure secondary to an ischemic cardiomyopathy (ejection fraction 16%), an abdominal aortic aneurysm, chronic kidney disease related to obstructive uropathy (baseline creatinine approximately 2 mcmol/L), previous avascular necrosis of the left hip, a right below knee and left forefoot amputation (secondary to a motor vehicle accident and chronic osteomyelitis respectively), gout, hypertension, and chronic unhealed leg wounds secondary to peripheral vascular disease with concurrent chronic pain. At the time of admission, the patient’s daily medications included: Triumeq 1 tablet, ASA 81 mg, bisoprolol 10 mg, rosuvastatin 40 mg, Nitroglycerin patch 0.2 mg/h transdermal, hydralazine 10 mg 3 times daily, spironolactone 12.5 mg, furosemide 80 mg, allopurinol 200 mg, colchicine 0.6 mg, pantoprazole 20 mg, levothyroxine 50 mcg, and darbepoetin 30 mcg every 2 weeks. No alterations to the above listed medications were made in hospital. The patient had an allergy to contrast media (causing shortness of breath and rash). His social history revealed he was living with a friend and was financially supported by disability payments. The patient’s substance use history was significant for active cocaine use, nicotine use, and alcohol use disorders. More specifically, the patient was smoking approximately “dollars” worth of crack cocaine every 2 days, and also 10 cigarettes per day (with a 40 pack-year smoking history). The patient drank 5 beers per day since age 17, and did not report any history of withdrawal symptoms, seizures, or hallucinations. The patient also had an OUD for which he was on methadone maintenance therapy and had been in sustained remission since his last use of illicit opioids in 2015. His opioid use began after a motor vehicle collision in 1984, and, though the exact duration of methadone maintenance therapy was not documented, it is suspected the patient was started on the medication before buprenorphine/naloxone being available as an OUD treatment option (which was in 2008 in Canada). Before admission, the patient had been taking 100 mg of methadone daily witnessed ingestion at his local pharmacy and was consistently adherent, reporting no opioid cravings, withdrawal symptoms, or recent illicit opioid use.

At the time of hospital presentation the patient’s vital signs were stable. Investigations revealed the patient to be hyponatremic (sodium 126 mmol/L). His renal function was at baseline (creatinine 189mmol/L) and liver function was within normal limits. Chest x-ray revealed mild interstitial pulmonary edema and cardiomegaly. The patien0074’s electrocardiogram revealed a significantly prolonged QTc of 579 milliseconds. Prior electrocardiograms from the same year showed similar QTc prolongation with values that ranging from 550 to 579 milliseconds.

Given the prolonged QTc and need for methadone maintenance therapy during hospitalization, the inpatient addiction medicine service was consulted. No reversible cause could be identified for the patient’s prolonged QTc. Given the persistent risk that existed for Torsades de Pointes, the decision was made to reduce the patient’s daily methadone dose from 100 to 60 mg, to be administered in 3 doses throughout the day (of 20 mg each). To prevent abrupt opioid withdrawal, oral hydromorphone was also prescribed to be administered on an as- needed basis. The patient reported the dose reduction of his methadone to be inadequate to manage his cravings. Accordingly, the option to switch from methadone to buprenorphine/naloxone was offered, but the patient persistently declined due to concern for precipitated withdrawal. A trial of slow-release oral morphine was then attempted for treatment of the patient’s OUD. An initial dose of 240mg was prescribed daily, but, likely due to the patient’s chronic kidney disease, this resulted in the development of myoclonus and subsequent cessation of therapy. As the patient was previously stable on methadone, he was not a suitable candidate for initiation of injectable opioid agonist therapy. Instead, the patient was initiated on sustained-release oral hydromorphone (9 mg twice daily). His myoclonus resolved. Over the next 15 days, the patient’s dose was titrated to good effect at 33 mg twice daily. The patient denied ongoing opioid withdrawal or cravings with no reported change to the quality or intensity of his chronic pain. His QTc interval also shortened from 578 to 530 milliseconds. At the time of hospital discharge, the medication was switched to a 24-hour hydromorphone formulation at a dose of 24mg daily witnessed ingestion at his local pharmacy for ongoing management of both OUD and chronic pain. Unfortunately, this patient was lost to discharge and therefore no follow-up data are available to report.

DISCUSSION

Though current first-line treatment options for OUD include buprenorphine/naloxone or methadone, a significant proportion of patients are unsuccessfully retained on these medications long-term (Timko et al., 2016; Office of the Provincial Health Officer, 2017; Manhapra et al., 2018). Accordingly, continued evaluation of alternative treatment options for OUD should persist. Slow-release oral morphine is 1 such treatment option that has a growing body of literature in support of its use for OUD. A 2014 study comparing slow- release oral morphine to methadone for OUD treatment reported decreased heroin cravings, a shorter QTc interval, and no difference in treatment retention among those receiving slow-release oral morphine (Hammig et al., 2014). Injectable opioid agonist therapy is another alternative treatment option listed in Canada’s national OUD guidelines, and can be considered for individuals unsuccessful on oral opioid agonist treatment. Injectable hydromorphone has emerged as a viable option due to its ability to escape usual regulatory barriers and widespread availability. In the landmark trial comparing injectable hydromorphone to diacetylmorphine (ie, prescribed heroin) for the treatment of severe OUD, hydromorphone was found to be noninferior, with similar retention rates and reduction in illicit use (Oviedo-Joekes et al., 2016).

While slow-release oral morphine and injectable opioid agonist therapy have proven to be effective, evidence-based alternative OUD treatment options for patients unsuccessful on first-line therapies, individuals with complex medical comorbidities (eg, chronic renal failure), or those who have achieved sustained remission from illicit use may not be suited for these treatment options. Accordingly, a critical need exists to evaluate additional options for OUD treatment to ensure all individuals with OUD can access evidence-based care.

While limited by the lack of follow-up data, the case presented offers promise for the use of once-daily, sustained- release oral hydromorphone as a potential treatment option for individuals in sustained remission for OUD who are unsuccessful on other oral OAT medications. Similar to other opioids, hydromorphone binds at the mu-opioid receptors as a full opioid agonist. Furthermore, the medication is not renally excreted and therefore may pose a lower risk of opioid toxicity for patients with chronic kidney disease (Felden et al., 2011). The medication has an additional advantage of having no influence on the cardiac QTc interval. While further research is certainly needed, this case report is the first to our knowledge to demonstrate the successful use of oral hydromorphone for OUD treatment. To prevent misuse or diversion, however, the use of a 24-hour formulation administered via daily witnessed ingestion at a pharmacy should be considered in combination with random urine drug tests. Furthermore, given the need that exists for the use of short-acting hydromorphone during the transition from methadone to sustained-release oral hydromorphone (as tolerance and therapeutic dose is being established) it is suggested that such a transition be undertaken in a monitored, inpatient setting (eg, withdrawal management facility, hospital).

In the wake of North America’s worsening opioid epidemic, it is imperative that all potential treatment options for OUD be explored and evaluated to ensure that, regardless of comorbidity or severity of addiction, all individuals who require OUD treatment can access it.