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12 Articles in this Series
Introduction
Central Post-Stroke Pain – How Central Is It?
False-Positive Urine Drug Monitoring Results and Aspirin
Medical Marijuana & Pain
More Potential Uses for Low-Dose IV Naloxone
On the Horizon: A Brief Look at Potential Analgesics of the Future
Preview of PAINWeek 2018 - Know Before You Go
Stem Cells & Beyond
Underlying Causes of Small Fiber Neuropathies
Understanding Sexual Pain – A Physical Therapist’s Perspective
Video: Drs. Gudin & Fudin on PAINWeek 2018 and PPM's Future
Where Does the Patient-Centered Pain Practitioner Stand Today?
Why Interventional Tactics Should be Used for Chronic Pain Patients Now, Not Later

More Potential Uses for Low-Dose IV Naloxone

Anecdotal evidence may pave way for this “forgotten gem'' to prevent or reverse opioid-induced side effects. A PAINWeek 2018 highlight with Charles Louy, PhD.

 

Mention naloxone, and many think of it only as the remedy to reverse opioid overdose, which it is. However, it may also work to prevent or treat opioid-induced side effects, according to Charles Louy, PhD, MD, MBA, medical director of the Inpatient Pain Service at Cedars Sinai Medical Center, Los Angeles. He presented his findings and experiences with his patient population at Cedars-Sinai on this off-label use in a talk at PAINWeek 2018 titled: "IV Naloxone Infusion: A Forgotten Gem."1

The Rationale & Evidence to Date

Despite the opioid crisis, opioids remain the mainstay of analgesic therapy, Dr. Louy began, noting that they are often linked with a multitude of side effects, such as pruritus, nausea, ileus, urinary retention, respiratory depression, and opioid-induced hyperalgesia. While doses vary from patient to patient, opioids may also induce a state of paradoxical hyperalgesia, Dr. Louy said, and these side effects may prolongate hospital stays unnecessarily.1

Enter naloxone: Naloxone is a mu-opioid receptor with suggested doses of  0.1 to 2 mg IV repeated every 2 to 3 minutes as needed.  Dr. Louy reminded the audience that high doses of naloxone can induce serious side effects, some of them lethal.  This may be one of the reasons why the 2010 revised guidelines issued by the American Heart Association recommend starting with the lower end of naloxone doses when resuscitating patients from opioid-induced respiratory depression.  In addition,  "the half-life of naloxone can be as short as 30 minutes, so you have to observe patients for at least two hours," he added. 

While the medication is FDA approved only for the reversal of opioid overdose, Dr. Louy noted that, “There is a lack of evidence regarding its optimization for preventing or treating opioid-induced side effects." In his talk, he presented data showing that naloxone may be able to prevent or treat those side effects, using a literature review and his own data from his Cedars Sinai patient population.

Research to Date

The earliest evidence that IV naloxone works was published in 1997.1 In that study, 60 patients scheduled for total abdominal hysterectomies were given post-operative morphine as a patient-controlled analgesia (PCA). They were randomized to either 0.25 or 1 mcg/kg/hr, or saline; both medication doses were equally effective in reducing nausea, vomiting, and pruritus compared with placebo (P < 0.05).2 Another finding: the cumulative morphine use was lowest in the low-dose naloxone group.

Other studies have demonstrated benefit with low-dose naloxone. Among those cited by Dr. Louy:

  • In a meta-analysis of eight randomized clinical trials using naloxone to treat post-operative pruritus in 800 patients, researchers assigned 424 to naloxone and 376 to saline. Naloxone was associated with a decrease in both pruritus and nausea with no increase in pain scores.3
  • In a study of 97 orthopedic patients receiving PCA morphine, those who received 0.1 mg of IV naloxone every 4 hours had lower post-operative urinary residuals, voided more frequently, and needed fewer catheterizations.4
  • Ultra-low-dose naloxone (0.25 mcg/kg/hr) added to remifentanil, provided a quicker recovery of bowel function and reduced the hospital stay after open colorectal surgery in 72 patients. They were assigned to a small dose of remifentanil, a large dose or a large dose with low dose naloxone. The large-dose remifentanil-naloxone group got return of bowl function faster (P < 0.05).5

·      Adding low-dose naloxone (0.05 mcg/kg/hr) to high-dose remifentanil reduced post-operative hyperalgesia in a study of 91 patients undergoing thyroid surgery. They were randomly assigned to three groups—high remifentanil, high remifentanil with naloxone, and low remifentanil. Post-operative pain intensity was similar between groups.6

The Cedars Sinai Experience

Dr. Louy shared starting and maximal doses used in his patient population:

  • For pruritis, nausea, vomiting: starting dose, 0.25 mcg/kg/hr up to 0.5 mcg/kg/hr
  • For ileus: starting at 0.25 mcg/kg/hr up to 0.5 mcg/kg/hr 
  • For urinary retention: starting at 0.35 mcg/kg/hr up to 0.5 mcg/kg/hr

He also reported on the 140 patients treated with low-dose naloxone at Cedars Sinai between January and June 2018. Patient population included those 10 years to 90 years; 41% male, 59% female. Side effects treated were:

  • Ileus, 48%
  • multiple indications, 15%
  • nausea and vomiting 19%
  • pruritus, 11%
  • urinary retention, 7%.

Dr. Louy further cited case histories for indications of nausea, ileus, pruritis, and urinary retention. Among them was the case of a 53-year-old woman who underwent a laminectomy and cerebrospinal fluid leak repair was on oxy IR and IV hydromorphone for pain.  A multimodal pain regimen was ordered, with 147 MEDD used on Day 1, and 112 MEDD used on Day 2. On Day 3, urinary retention was the patient's chief complaint, and a naloxone 100 mcg IV push was given. The patient voided 200 ml that day and was sent home on Day 4.

"If we receive a call from a nursing station that a patient has urinary retention and they are going to reinsert the catheter, we say stop," Dr. Louy said, and instead, recommend naloxone (100 mcg IV push). "In the great majority of patients, the patient voids within 20 minutes to 2 hours." At least one day of hospitalization is sometimes saved, he noted.

At the talk's end, Dr. Louy told attendees: "I hope I've convinced you that there is enough evidence to at least consider using low-dose naloxone for opioid-induced side effects."

Clarifications

Clinicians and others attending the PAINWeek session asked why this particular use of naloxone has not caught on, since it has been in use for about two decades. "I think because you have to be careful," Dr. Louy said, and follow specific regimens. "It [only] takes one negative outcome.”

What about oral naloxone? "No, it’s not on the formulary," Dr. Louy explained, noting that patients in the situation he is describing likely already have an IV in place.

Dr. Louy said he plans to conduct ongoing retrospective chart reviews for naloxone treatment outcomes, push for more proactive use of naloxone for prophylaxis, and hopes that prevention or treatment of opioid-induced hyperalgesia may be added as an additional indication for naloxone.

 

Sources

1 Louy C. “IV Naloxone Infusion: A Forgotten Gem,” presented at PAINWeek 2018, September 4-8, in Las Vegas, Nevada.

2Gan TJ, et al. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiol. 1997;87(5);1075-1081.

3Murphy JD, et al. Analgesic efficacy of intravenous naloxone for the treatment of postoperative pruritus: a meta-analysis. J Opioid Manag. 20117(4):321-327.

4 Gallo X, et al. A study of naloxone effect on urinary retention in the patient receiving morphine-controlled analgesia. Orthop Nurs.  2008;27(2):111-115.

5Xiao Y, et al. A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery. Acta Anaesthesiol Scan. 2015;59(9):1194-203.

6Koo CH, et al. Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial. Br J Anaesth. 20171;119(6):1161-1168.

Next summary: On the Horizon: A Brief Look at Potential Analgesics of the Future
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