Levine JD, Gordon NC, Fields HL: Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain

Nature (Impact Factor: 41.46). 05/1979; 278(5706):740-1. DOI: 10.1038/278740a0
Source: PubMed


IF endorphins modulate pain, then naloxone should affect pain behaviour even in subjects who have not received exogenous opiates. However, some naloxone studies claim a lack of effect1,2, others a hyperalgesic effect3-5, and others both hyperalgesic and analgesic effects6,7. Such discrepancies may arise from the different methods used to induce and assess pain8, and from variation in dose. We know of only one previous human study which used multiple doses of naloxone6; this indicated a dose-dependent bi-directional effect. In the present study, a clinical pain paradigm was used to generate a dose-response curve for naloxone. We report that naloxone produces analgesia at low doses and hyperalgesia at high doses.


Available from: Howard L Fields, Mar 19, 2014
    • "Naloxone exerts the opposite effects on nociception.[10] The effects appear to be dose dependent and biphasic because high doses of naloxone, both in humans and animals, induce pain lowering the thermal and mechanical nociceptive threshold whereas low doses exert analgesia and increase the nociceptive threshold.[11] Naloxone increases pain at high doses in the presence of opioid drugs or activation of endogenous opioid system.[12] "
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    ABSTRACT: Role of nitric oxide (NO) in reversing morphine anti-nociception has been shown. However, the interaction between NO and naloxone-induced pain in the hippocampus is unknown. The present study aimed to investigate the involvement of molecule NO in naloxone-induced pain and its possible interaction with naloxone into cortical area 1 (CA1) of hippocampus. Male Wistar rats (250-350 g), provided by Pasteur Institute of Iran, were housed two per cage with food and water ad libitum. The animals' skulls were cannulated bilaterally at coordinates adjusted for CA1 of hippocampus (AP: -3.8; L: ±1.8- 2.2: V: 3) by using stereotaxic apparatus. Each experimental group included 6-8 rats. To induce inflammation pain, the rats received subcutaneous (s.c.) injections of formalin (50 μL at 2.5%) once prior to testing. To evaluate the nociceptive effect of naloxone, the main narcotic antagonist of morphine (0.1-0.4 mg/kg) was injected intraperitoneally (i.p.) 10 min before injection of formalin. Injections of L-arginine, a precursor of NO, and N(G)-Nitro-L-arginine Methyl Ester (L-NAME), an inhibitor of NO synthase (NOS), intra-CA1, were conducted orderly prior to the administration of naloxone. The pain induction was analyzed by analysis of variance (ANOVA). Naloxone at the lower doses caused a significant (P<0.01) pain in the naloxone-treated animals. However, pre-administration (1-2 min) of L-arginine (0.04, 0.08, 0.15, 0.3, 1.0, and 3.0 μg/rat, intra-CA1) reversed the response to naloxone. But, the response to L-arginine was blocked by pre-microinjection (1-2 min) of L-NAME (0.15, 0.3, 1.0, and 3.0 μg/rat), whilst, L-arginine or L-NAME alone did not induce pain behavior. NO in the rat hippocampal CA1 area is involved in naloxone-induced nociception.
    Indian Journal of Pharmacology 07/2012; 44(4):443-7. DOI:10.4103/0253-7613.99299 · 0.69 Impact Factor
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    • "However, other studies have successfully induced hyperalgesia with naloxone. Earlier studies used dental post-operative pain [6], [29], [30] or electric shocks [31], whereas a more recent study used a combination of capsaicin and naloxone [32]. Yet another study specifically targeted the mechano-insensitive nociceptors via transdermal electrical stimulation and concluded that it is not necessarily the magnitude of the perceived pain that is needed for endogenous opioid release, but rather the activation of the mechano-insensitive nociceptors [33]. "
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    ABSTRACT: The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.
    PLoS ONE 08/2010; 5(8):e12344. DOI:10.1371/journal.pone.0012344 · 3.23 Impact Factor
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    • "Although this combination seems paradoxical as a pain treatment, early research has shown promise. Naloxone alone has a bimodal effect on analgesia: low intravenous doses (1– 2 mg) produce analgesia and higher doses (3+ mg) produce hyperalgesia in healthy normal volunteers (Buchsbaum et al. 1977) and in postoperative patients (Levine et al. 1979). Clinical trials showed that intravenous and epidural opioids combined with naloxone could produce greater analgesia than opioids alone (Rawal et al. 1986; Gueneron et al. 1988; Gan et al. 1997); these studies revealed the importance of the ratio of opioid agonist to antagonist in enhancing analgesia, showing ultra-low naloxone doses (ng/kg to pg/kg) are needed for optimal effect. "
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    ABSTRACT: Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed. Preclinical and clinical studies have shown that opioids combined with ultra-low-dose naltrexone (NTX) may have increased analgesic potency and have suggested reduced abuse or dependence liability. This study addressed whether addition of ultra-low-dose naltrexone might decrease the abuse liability of oxycodone (OXY) in humans. This double-blind, placebo-controlled study systematically examined the subjective and physiological effects of combining oral OXY and ultra-low NTX doses in 14 experienced opioid abusers. Seven acute drug conditions given at least 5 days apart were compared in a within-subject crossover design: placebo, OXY 20 mg, OXY 40 mg, plus each of the active OXY doses combined with 0.0001 and 0.001 mg NTX. The methods were sensitive to detecting opioid effects on abuse liability indices, with significant differences between all OXY conditions and placebo as well as between 20 and 40 mg OXY doses on positive subjective ratings (e.g., "I feel a good drug effect" or "I like the drug"), on observer- and participant-rated opioid agonist effects, and on a drug-versus-money value rating. There were no significant differences or evident trends associated with the addition of either NTX dose on any abuse liability indices. The addition of ultra-low-dose NTX to OXY did not decrease abuse liability of acutely administered OXY in experienced opioid abusers.
    Psychopharmacology 04/2010; 210(4):471-80. DOI:10.1007/s00213-010-1838-3 · 3.88 Impact Factor
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