a b s t r a c t

Low dose naltrexone (LDN) has been evaluated in several small studies for the treatment of inflammatory con- ditions. It is thought to work through modulation of Inflammatory mediators and upregulation of endogenous Opioid receptors. This may hypersensitize patients to exogenous opioids. Drug-drug interaction Screening tools built into electronic health records and other services identify the interaction as risk of Opioid withdrawal rather than hypersensitivity. We present a case of a drug-drug interaction in a patient who was receiving LDN treatment of Multiple sclerosis. The patient received a single dose of oxycodone 5 mg that resulted in obtundation unre- sponsive to painful stimuli necessitating the administration of naloxone boluses and infusion along with admis- sion to the intensive care unit for 1 night. The patient responded well to naloxone therapy. He was discharged in satisfactory condition.

(C) 2017

Introduction

Naltrexone is commonly known as an orally active competitive opi- oid receptor antagonist indicated for maintenance of opioid or alcohol abstinence and dosed in the range of 50 to 100 mg daily. Low dose nal- trexone (LDN) refers to doses that are less than 1/10th of the opioid ad- diction doses [1]. At low doses, naltrexone elicits paradoxical analgesic, neuroprotective and anti-inflammatory effects [2]. It is theorized that the up-regulation of opioid receptors with LDN can cause hypersensitiv- ity to opioid agonists, leading to respiratory decompensation and unre- sponsiveness even with the use of low-dose opioid agonists.

Patient case

A 66-year-old male presented to the emergency department with worsening of his existing ankle and buttocks wounds. His past medical history includes multiple sclerosis for which he is wheelchair bound. At the time of admission, his Home medications included only naltrex- one 2 mg daily. The vital signs included blood pressure of 147/71, heart rate of 98, oxygen saturation of 95% on room air, and a respiratory rate of 20 breaths per minute. Baseline laboratory studies were unre- markable except for a white blood cell count of 15.8 K/uL, a BUN of 81 mg/dL, a serum creatinine of 1.71 mg/dL, and a procalcitonin of

0.24 ng/mL. Two hours after admission, the patient was administered

* Corresponding author.

E-mail address: leonardj@wsu.edu (J.B. Leonard).

5 mg of oxycodone for pain from the wound in his buttocks. Approxi- mately, one-hour after oxycodone administration, the patient was found to be unresponsive to painful stimuli, but did not require intuba- tion. His blood glucose was checked and was found to be 104 mg/dL. A dose of 2 mg of naloxone was administered intravenously, after which the patient became aroused and alert. Two hours after oxycodone ad- ministration, the patient was started on a naloxone infusion at

0.4 mg/h for worsening trend in cognitive status. Naloxone infusion was discontinued after 4 h, but subsequently restarted 15 min later be- cause the patient was unarousable. Over the next 4.5 h, the naloxone in- fusion was tapered down and stopped. The naloxone infusion was stopped approximately 11 h after the oxycodone was administered. The patient did not require further naloxone.

Discussion

Oxycodone was selected and administered for pain management in the emergency department due to a reported allergy to acetaminophen and poor renal function. Based on the observed improvement of the patient’s cognitive status in the presence of naloxone, it can be postulat- ed that there might have been an apparent drug interaction with the given opioid agonist while on a chronic regimen of low-dose naltrexone. This apparent drug interaction may be attributed to potential up-regu- lation of opioid receptors secondary to chronic LDN use, which may lead to increased binding of the given opioid agonist to opioid receptors. drug-drug interactions may be cumbersome to manage when elec- tronic clinical decision making programs are not able to readily screen

http://dx.doi.org/10.1016/j.ajem.2017.04.012

0735-6757/(C) 2017

for drugs with rare interactions. This case represents a significant drug- drug interaction not commonly seen in the literature. A Drug Interaction Probability Score [3] of 6 identifies this as probable. Animal and cellular studies suggest that chronic treatment with naltrexone increases opioid receptor density and sensitivity [4] although the use of low-dose opioid antagonists in combination with opioids to reduce opioid dose require- ments has led to mixed results [5]. The use of low dose naltrexone as an anti-inflammatory and pain modulating agent has been summarized elsewhere [6]. Of note, one open-label observational and one placebo controlled cross-over study evaluated the effects of low dose naltrexone on fibromyalgia and pain [7,8]. In these trials, patients on chronic opi- ates were excluded to prevent inducing withdrawal; therefore, the drug interaction observed in this case would not have been seen in the trials.

Conclusion

opioid overdose from a single administration may have been precip- itated by chronic LDN use due to hypersensitivity. Physicians and other healthcare providers should remain alert to the prior chronic use of low- dose opioid antagonists when deciding appropriate pain management for such patients.

Consent

The patient provided informed consent for the publication of this manuscript with full knowledge of the course of his hospitalization.

Acknowledgements

No funding was sought for the publication of this manuscript.

References

1. Greeley JD, Le AD, Poulos CX, Cappell H. “Paradoxical” analgesia induced by naloxone and naltrexone. Psychopharmacology 1988;96(1):36-9.
2. Cree BAC, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol 2010;68(2):145-50.
3. Horn JR, Hansten PD, Chan L-N. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41(4):674-80.
4. Tempel A, Gardner EL, Zukin RS. Neurochemical and functional correlates of naltrex- one-induced opiate receptor up-regulation. J Pharmacol Exp Ther 1985;232(2): 439-44.
5. Burns LH. Ultra-low-dose opioid antagonists enhance Opioid analgesia while reducing tolerance, dependence, and addictive properties. Recent Dev Pain Res 2005;661(2): 115-36.
6. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti- inflammatory treatment for chronic pain. Clin Rheumatol 2014;33(4):451-9.
7. Younger J, Noor N, McCue R, MacKey S. Low-dose naltrexone for the treatment of fi-

   bromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum 2013; 65(2):529-38.

   Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med 2009;10(4):663-72.