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

Chindalore, Vishala; Craven, Richard; Yu, Kevin; Butera, P.; Burns, Lindsay H.; Friedmann, Nadav

doi:10.1016/j.jpain.2005.01.356

Cited by 100 publications

(70 citation statements)

References 20 publications

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“…The addition of ultralow-dose naltrexone has shown potential to enhance opioid analgesia and reduce physical dependence and tolerance but was not designed to be an abuse deterrent. 43,[45][46][47] The value of naltrexone combination formulations needs to be assessed clinically because of physician concerns of withdrawal or diminished pain control caused by naltrexone leakage in patients. In addition, extractability studies are needed to determine how easily this formulation can be modified for misuse or abuse.…”

Section: Pharmacological Strategiesmentioning

confidence: 99%

Issues in Long-term Opioid Therapy: Unmet Needs, Risks, and Solutions

Passik

2009

Mayo Clinic Proceedings

120

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Section: Pharmacological Strategiesmentioning

confidence: 99%

Issues in Long-term Opioid Therapy: Unmet Needs, Risks, and Solutions

Passik

2009

Mayo Clinic Proceedings

120

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“…In both preclinical and clinical studies, ultra-low doses of NTX enhance opioid analgesia and prevent opioid dependence or withdrawal signs. 22,25,61,62,78 Chronic pretreatment with ultra-low-dose NTX increases opioid sensitivity. 83 In addition, ultra-low-dose opioid antagonist cotreatment with opioids can attenuate tolerance-associated hyperalgesia.…”

Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

Largent-Milnes

Guo

Wang

et al. 2008

The Journal of Pain

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Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)-G protein coupling from G i/o to G s that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L 5 /L 6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G s in the damaged (ipsilateral) spinal dorsal horn. This MOR-G s coupling occurred without changing G i/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G s coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G s coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G s coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G s coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. KeywordsNeuropathic pain; G protein coupling; tolerance; opioids; hyperalgesia; allodynia; μ-opioid receptor Patients who have diseases such as cancer, arthritis, and diabetes often have development of painful neuropathies due to disease progression or medical treatment. HHS Public AccessAuthor manuscript J Pain. Author manuscript; available in PMC 2017 June 13. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript approaches used in the clinic to treat these neuropathies include tricyclic antidepressants, dual-acting reuptake inhibitors, and anticonvulsants (eg, gabapentin) or combinations of these with nonsteroidal anti-flammatory drugs (NSAIDs) and opioids. However, these options often cause side effects such as dizziness and sedation and may not treat the various classifications of neuropathic pain states with comparable efficacy. 30,32,55,77 Treatment of neuropathic pain that is not responsive to first-line therapies is often limited to opioids, which can be effective acutely but have decreased efficacy after chronic exposure, leading to the use of higher doses to achieve the same level of pain relief and often resulting in opioidinduced mechanical and thermal hypersensitivities. 5,7,9,29,30,32,[69][70][71]79,81 For patients taking higher doses of opioids to achieve pain relief, the presence of unwanted side effects including tolerance, dependence, respiratory depression, and constipation furthe...

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“…For example, ultra-low doses of competitive opioid receptor antagonists such as naltrexone have been shown to paradoxically augment spinal morphine analgesia and inhibit or reverse the development of this opioid tolerance (Powell et al, 2002;Chindalore et al, 2005;Mattioli et al, 2010). Interestingly, the ultra-low dose phenomenon is not restricted to opioid antagonists but is also produced by ultra-low dose adrenergic antagonists.…”

Section: Introductionmentioning

confidence: 99%

Stereo-selective inhibition of spinal morphine tolerance and hyperalgesia by an ultra-low dose of the alpha-2-adrenoceptor antagonist efaroxan

Milne

Jhamandas

Sutak

et al. 2013

European Journal of Pharmacology

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a b s t r a c tUltra-low doses of alpha-2 (a 2 )-adrenoceptor antagonists augment spinal morphine antinociception and inhibit tolerance, but the role of receptor specificity in these actions is unknown. We used the stereo-isomers of the a 2 adrenoceptor antagonist, efaroxan to evaluate the effect of receptor specificity on the induction of spinal morphine tolerance and hyperalgesia. Tail flick and paw pressure tests were first used to evaluate high dose efaroxan (12.6 mg) and its stereo-isomers on clonidine analgesia in intrathecally catheterized rats. Ultra-low doses of individual isomers (1.3 ng) were then coadministered with morphine (15 mg) to determine their effects on acute antinociceptive tolerance and hyperalgesia induced by low dose spinal morphine (0.05 ng). Results demonstrate that high dose ( þ) efaroxan antagonized clonidine-induced antinociception, while ( À ) efaroxan had minimal effect. In addition, an ultra-low dose of (þ ) efaroxan (1.3 ng), substantially lower than required for receptor blockade, inhibited the development of acute morphine tolerance, while ( À ) efaroxan was less effective. Racemic (7 ) efaroxan effects were similar to those of (þ ) efaroxan. Furthermore, low dose morphine (0.05 ng) produced sustained hyperalgesia in the tail flick test and this was blocked by coinjection of ( þ) but not ( À ) efaroxan (1.3 ng). Given the isomer-specific efaroxan effects and their different receptor potencies, we suggest that inhibition of opioid tolerance by ultra-low dose efaroxan involves a specific interaction with spinal a 2 -adrenoceptors in this model. Likewise, inhibitory effects of adrenoceptor antagonists on morphine tolerance may be due to blockade of opioid-induced hyperalgesia.

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

Cited by 100 publications

References 20 publications

Issues in Long-term Opioid Therapy: Unmet Needs, Risks, and Solutions

Issues in Long-term Opioid Therapy: Unmet Needs, Risks, and Solutions

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

Stereo-selective inhibition of spinal morphine tolerance and hyperalgesia by an ultra-low dose of the alpha-2-adrenoceptor antagonist efaroxan

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