Ultra-Low Dose Oral Naltrexone Decreases Side Effects and Potentiates the Effect of Methadone

Abstract

Ultra-Low Dose Oral Naltrexone Decreases Side Effects and Potentiates the Effect of MethadoneTo the Editor:The use of N-methyl-D-aspartate (NMDA) receptor antagonists to decrease opioid side effects, potentiate opioid actions, and decrease the development of tolerance has been a topic of substantial interest over the last decade. The pioneering work by Trujillo and Akil suggested that tolerance to opioids could be prevented by the non-competitive NMDA receptor antagonist MK-801. 1 Subsequent studies indicated that competitive NMDA receptor antagonists could prevent the development of opioid tolerance and reverse it once established. 2 To determine the clinical significance of these observations, numerous clinical trials have been performed with the widely used NMDA receptor antagonists ketamine and dextromethorphan. These studies suggest that both antagonists can improve pain scores in patients with certain types of pain, but, in general, the doses must be high, which predisposes to significant side effects. 3 The addition of dextromethorphan to morphine has been studied in both animals and humans. Mao et al. conducted animal studies to determine the optimal ratio and concluded that a 1:1 ratio was the most efficacious. 4 More recently, clinical trials performed to study this combination yielded inconclusive results, and more studies are needed to determine the correct ratio in humans. In view of the limited benefit obtained by this approach, other strategies to potentiate, decrease side effects, and prevent the development of tolerance to opioids are being explored.One novel strategy was suggested by work performed by Crain and Shen 5,6 about a decade

Adding Ultralow-Dose Naltrexone to Oxycodone Enhances and Prolongs Analgesia: A Randomized, Controlled Trial of Oxytrex

“…9,12 When considering the clinical studies that did not demonstrate enhanced analgesia by the addition of low doses of naloxone to morphine PCA, it should be noted that the naloxone doses in those studies were considerably higher than the naltrexone doses in this clinical trial. Although naloxone and naltrexone might not be equipotent, the dosing differences in the current clinical trial versus previous studies are substantial and are further augmented by the increased bioavailablility of intravenous administration of the earlier studies compared to the 20% bioavailability of oral naltrexone 13 used in this clinical trial.…”

“…7,20,25,26 Clinical experience with opioid antagonists combined with opiates is limited to case reports and a few small clinical studies. 2,3,9,10,12 In one case study, a diabetic polyneuropathy patient, who previously had no pain relief from a variety of treatments, reported profound analgesia when 2 g/ day of naltrexone was added to methadone. 9 The first controlled clinical study demonstrated an opioid-sparing effect and a reduction in side effects by a continuous infusion of naloxone at 0.25 g/kg/h added to morphine administered by patient-controlled analgesia (PCA).…”

“…2,3,9,10,12 In one case study, a diabetic polyneuropathy patient, who previously had no pain relief from a variety of treatments, reported profound analgesia when 2 g/ day of naltrexone was added to methadone. 9 The first controlled clinical study demonstrated an opioid-sparing effect and a reduction in side effects by a continuous infusion of naloxone at 0.25 g/kg/h added to morphine administered by patient-controlled analgesia (PCA). 10 In a subsequent study, patients receiving a single 15-or 25-g injection of nalmefene before morphine PCA reported decreased severity of pain 24 hours later and had a decreased need for antiemetics and antipruritics.…”

Gβγ that interacts with adenylyl cyclase in opioid tolerance originates from a Gs protein

“…Ultra-low-dose opioid antagonists were also shown to enhance and prolong the analgesic effects of opioids even acutely (Powell et al, 2002;Shen et al, 2002a,b) and to reverse the paradoxical hyperalgesic effect of low doses of opioids to provide strong analgesia (Crain and Shen, 2001). The effects of ultralow-dose opioid antagonists have been extended to small clinical studies or clinical trials showing enhanced analgesia (Joshi et al, 1999;Hamman et al, 2004;Chindalore et al, 2005), opioid sparing effects (Gan et al, 1997), profound analgesia in a severely opioid tolerant patient (Cruciani et al, 2003), and, in a recent Phase III clinical trial, reduced physical dependence (Webster et al, 2006).…”

Enhanced Analgesia with Opioid Antagonist Administration

“…12 Three cases in which naloxone "reset the receptors" in an opioid-tolerant patient with pain and a case in which naloxone caused analgesia are presented.…”