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Opioid Antagonists in Pain Management

Available evidence suggests that the opioid antagonists naloxone and naltrexone offer potential benefits for enhancing opioid analgesia as well as monotherapy for managing certain challenging pain conditions.
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  • In patients treated with buprenorphine (a mixed agonist-antagonist opioid) postoperatively and experiencing breakthrough pain, the addition of oral ultralow-dose naloxone (0.08–0.4mg) provided effective and long-lasting analgesia (median 22 hrs).20 A more recently reported investigation, by La Vincente and colleagues,21 also confirmed the enhancement of buprenorphine analgesia by ultra- low-dose oral naloxone (exact dose unspecified).
  • Oral naloxone alone, either 0.4 or 1.0 mg, produced significant analgesic effects compared with placebo for postoperative dental pain in a trial of 90 patients. In a second trial, oral naloxone (0.4mg) plus pentazocine (60 mg, a mixed agonist-antagonist opioid) produced greater dental-pain relief than monotherapy with pentazocine (60mg) or morphine (15mg). However, naloxone (0.4mg) plus morphine (8mg) produced less analgesia than morphine (8mg) alone, suggesting that analgesia augmentation by naloxone is influenced by the type and dose of opioid.22
  • In a study involving postoperative IV PCA (patient-controlled analgesia), 60 patients received morphine under patient control, plus either placebo or naloxone—0.00025 mg/kg/h or 0.001mg/kg/h—via steady IV infusion. Good pain relief was experienced in all groups; however, side effects (nausea, vomiting, pruritus) were reduced by naloxone at either dose and consumption of PCA morphine was significantly reduced by the lowest naloxone dose, suggesting a morphine-enhancement effect of the antagonist.23
  • Other postoperative trials compared IV PCA morphine alone versus IV PCA morphine plus an IV naloxone bolus (0.8mg) administered with each morphine dose (which was equivalent to 0.38 mg/kg/hr of naloxone on average). In the 92 patients studied, investigators found no differences between groups in pain relief, side effects, or morphine consumption.24 Comparing this study with the Gan et al.23 trial above suggests that a continuous naloxone infusion rather than bolus, and at doses of naloxone that are less than in this study, may be required to accrue beneficial effects during naloxone/morphine PCA.
  • A more recently reported case series, incorporating intravenous nalbuphine (5mg) plus naloxone (0.2mg IV), used postoperatively in 4 women undergoing outpatient gynecological procedures, found improved analgesia with this mixture.25
  • In a case report, a patient with chronic refractory pain following laminectomy was treated with an intrathecal combination of morphine (2mg) and ultralow-dose naloxone (.000020 mg; that is, 20 nanograms). Dramatic pain relief began within 20 minutes, peaked at 1 hour, and persisted with repeated infusions. Up to 80% improvement was reported by the patient while receiving an intrathecal infusion of 5mg morphine plus .000050mg naloxone daily during a 3-year followup period.26

The trials in postoperative patients suggest that combining low-dose naloxone with opioid agonists can be safe and enhance effectiveness of the analgesic. PCA-based studies further suggest that the augmentation of opioid-agonist effects during PCA is best with sustained ultralow-level antagonism of opioid receptors versus the more complete and intermittent blockade of those receptors by a somewhat higher dose of naloxone.13

Naloxone for Opioid-induced Constipation

Another proposed application of low-dose opioid antagonists has been to help prevent or relieve opioid-induced constipation that can be a problematic side effect of long-term opioid analgesics. Meissner et al.27 recently reported a clinical trial in 202 patients receiving oxycodone for chronic noncancer pain. Subjects administered 40, 60, or 80mg/day of extended-release oxy-codone were randomized to also receive either 10, 20, or 40mg/day of extended-release oral naloxone or placebo.

There was no loss of oxycodone analgesic efficacy in patients administered naloxone at any of these higher doses, probably due to naloxone’s limited oral bioavailability. However, bowel function significantly improved with increasing naloxone dose, and there were no unexpected adverse events. A 2:1 dose ratio of oxycodone/naloxone was judged as most efficacious. Other large, randomized, placebo-controlled trials had found the same favorable results in patients with chronic noncancer pain and back pain.28,29 A combination product—using extended-release oxycodone and extended-release naloxone; 2:1 ratio—was recently approved for marketing in Europe under the name Targin®, with an emphasis on its benefits for providing equipotent oxycodone analgesia while ameliorating opioid-induced constipation.30

Two other relatively new and specialized opioid antagonists, methylnaltrexone (Relistor®) and alvimopan (Entereg®), have been introduced for managing opioid-induced constipation. These agents block only peripheral opioid receptors in the gut. And, unlike naloxone and naltrexone, these antagonists do not cross the blood-brain barrier, so their actions potentially reverse opioid-induced constipation without precipitating withdrawal symptoms or altering analgesic qualities of opioids.31

The FDA approved oral alvimopan in 2008 to accelerate the restoration of normal bowel function in hospitalized adult patients who have undergone partial large or small bowel resection surgery.32 At about the same time, methylnaltrexone bromide was FDA-approved as an injectable medication to help restore bowel function in adult patients with advanced illness who are receiving analgesic opioids on a continuous basis.33

Naloxone Potential Side-Effects

On rare occasions, nausea, vomiting, hypertension, pulmonary edema, tachycardia, arrhythmia, and cardiac arrest have been implicated with naloxone doses as small as 0.1-0.4 mg.34,35

Applications of Naltrexone

As a longer-acting, orally-bioavailable antagonist, naltrexone is easy to administer and may offer advantages over naloxone. In opioid-tolerant animals, naltrexone was shown to produce increased response to morphine,6 possibly by upregulating the opioid-receptor system.8 Also of interest, animal experiments suggest that very low doses of naltrexone appear to enhance opioid analgesia to a greater extent when the amount of opioid drug is actually reduced,36,37 which proposes an opioid-sparing effect in humans. A number of investigations in human subjects have explored the potential of low- or ultralow-dose naltrexone as an opioid adjuvant and as monotherapy for the management of several pain-related conditions.

Last updated on: December 20, 2011
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