Overriding the blockade of antinociceptive actions of opioids in rats treated with extended-release naltrexone

Dean, Reginald L.; Todtenkopf, Mark S.; Deaver, Daniel R.; Arastu, Mahin; Dong, N.; Reitano, Krystal; O'Driscoll, Kevin; Kriksciukaite, Kristina; Gastfriend, David R.

doi:10.1016/j.pbb.2008.02.006

Cited by 24 publications

(20 citation statements)

References 30 publications

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“…Naltrexone treatment produced similar antinociceptive potency shifts for heroin and its metabolites 6-AM and morphine. These results were consistent with previous studies showing chronic naltrexone antagonized other behavioral effects of opioid agonists (Dean et al, 2008;Sakloth and Negus, 2018). Naltrexone plasma levels were dose-dependent in the present study, but maximum naltrexone levels were less than levels after naltrexone extended-release (XR-NTX) formulation administration in rats (Todtenkopf et al, 2009).…”

Section: Schwienteck 14supporting

confidence: 93%

Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

Schwienteck

Blake

Bremer

et al. 2019

Preprint

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Background: One emerging strategy to address the opioid crisis includes opioid immunopharmacotherapies. This study compared effectiveness of a heroin-tetanus toxoid (TT) conjugate vaccine to antagonize heroin, 6-acetylmorphine (6-AM), morphine, and fentanyl antinociception in rats. Methods: Adult male and female Sprague Dawley rats received three doses of active or control vaccine at weeks 0, 2, and 4. Vaccine pharmacological selectivity was assessed by comparing opioid dose-effect curves in 50°C warm-water tail-withdrawal procedure before, during, and after active or control heroin-TT vaccine. Route of agonist administration [subcutaneous (SC) vs. intravenous [IV)] was also examined as a determinant of vaccine effectiveness. For comparison, continuous naltrexone treatment (0.0032-0.032 mg/kg/h) effects on heroin, 6-AM, and morphine antinociceptive potency was also determined. Results: The heroin-TT vaccine decreased potency of SC heroin (5-fold), IV heroin (3-fold), and IV 6-AM (3fold) for several weeks without affecting IV morphine or SC fentanyl potency. The control vaccine did not alter potency of any opioid. Naltrexone dose-dependently decreased antinociceptive potency of SC heroin, and treatment with 0.01 mg/kg/h naltrexone produced similar, approximately 8-fold decreases in potencies of SC and IV heroin, IV 6-AM, and IV morphine. The combination of naltrexone and active vaccine was more effective than naltrexone alone to antagonize SC heroin but not IV heroin. Conclusions: The heroin-TT vaccineformulation examined is less effective, but more selective, than chronic naltrexone to attenuate heroin antinociception in rats. The combination of naltrexone plus heroin-TT vaccine may be more effective than either treatment alone to block opioid effects under some conditions.

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Section: Schwienteck 14supporting

confidence: 93%

Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

Schwienteck

Blake

Bremer

et al. 2019

Preprint

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“…In a preclinical experiment, rats were studied in a pain‐analgesia paradigm using the hot plate test to determine whether opioid analgesics could override the blockade of XR‐NTX and whether the analgesic response would be accompanied by excessive respiratory depression or signs of sedation. The competitive opioid receptor blockade of XR‐NTX was overcome with higher doses of opioids that were sufficient to achieve analgesic responses to the pain stimulus, however, compared to placebo, these doses did not show further effects on respiratory depression or locomotor activity 81 . The relevance of animal research to the human clinical setting, however, is unclear.…”

Section: Safety Tolerability and Other Potential Concerns About Usementioning

confidence: 99%

“…The competitive opioid receptor blockade of XR-NTX was overcome with higher doses of opioids that were sufficient to achieve analgesic responses to the pain stimulus, however, compared to placebo, these doses did not show further effects on respiratory depression or locomotor activity. 81 The relevance of animal research to the human clinical setting, however, is unclear. Therefore, it has been suggested that the management of patients with pain when reversal of XR-NTX blockade is required can include regional analgesia or use of nonopioid analgesics (Vivitrol R Package Insert).…”

Section: Pain Management: Basic Science Findings and Clinical Implicamentioning

confidence: 99%

Intramuscular extended‐release naltrexone: current evidence

Gastfriend

2011

Annals of the New York Academy of Sciences

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Extended-release naltrexone (XR-NTX; Vivitrol), developed to address poor adherence in addictive disorders, is approved for use in alcohol and opioid-dependence disorders. In alcohol-dependent adults with ≥ 4-day initial abstinence, XR-NTX increased initial and 6-month abstinence. An fMRI study found that XR-NTX attenuated the salience of alcohol visual and olfactory cues in the absence of alcohol, and post hoc analyses demonstrated efficacy even during high cue-exposure holiday periods. Safety and tolerability have generally been good, without adverse hepatic impact or intractable acute pain management. XR-NTX use appears feasible in primary care and public systems, and retrospective claims analyses have found cost savings and decreased intensive service utilization relative to oral agents. In opioid dependence, following detoxification, XR-NTX shows efficacy for maintaining abstinence, improving retention, decreasing craving, and preventing relapse. Trials are also exploring its use for the treatment of stimulant dependence. XR-NTX appears compatible with counseling and self-help attendance. While more research is needed, current findings suggest that a formulation of naltrexone that was sought beginning over three decades ago is fulfilling its promise as an extended-release pharmacotherapeutic.

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“…There is some evidence that patients who are chronically maintained on this drug may experience an upregulation of their opioid receptors, resulting in an exaggerated response to opioid agonists administered for the treatment of acute pain [14]. In this case, the naltrexone was stopped prior to surgery (though it is not indicated for how long), and the authors were able to successfully manage this patient's postoperative pain with 50-100 mg of tramadol every 6 h. If a greater degree of analgesia is required, the competitive blockade of naltrexone can be overcome with opioid agonists, but the required doses are on the order of 10-20 times the usual doses by weight [15].…”

Section: Naltrexonementioning

confidence: 97%

The perioperative management of patients maintained on medications used to manage opioid addiction

Bryson

2014

Current Opinion in Anaesthesiology

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When possible, patients maintained on buprenorphine should be evaluated preoperatively to assess the feasibility of discontinuing the buprenorphine 72 h before surgery. If buprenorphine is continued during the perioperative period, patients may require significantly increased doses of standard opioids for analgesia. Patients maintained on methadone are at increased risk for respiratory-related complications and should receive a higher level of monitoring during the perioperative period. Patients who are on chronic methadone should continue their maintenance dose during the perioperative period. Where possible, nonopioid medications and regional anesthetic blockade are effective alternatives for analgesia in this population.

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Overriding the blockade of antinociceptive actions of opioids in rats treated with extended-release naltrexone

Cited by 24 publications

References 30 publications

Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

Intramuscular extended‐release naltrexone: current evidence

The perioperative management of patients maintained on medications used to manage opioid addiction

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