Clinical Pharmacology of Narcotic Antagonists*

O’Brien, Charles P.; Greenstein, Robert A.; Ternes, Joseph W.; Woody, George

doi:10.1111/j.1749-6632.1978.tb16779.x

Cited by 36 publications

(16 citation statements)

References 30 publications

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“…Because it is a competitive antagonist at the µ-opioid receptor, naloxone administered by the parenteral route to opioid-dependent individuals produces a rapid (within minutes), intense (dependent on level of dependence and dose of naloxone), and unpleasant opioid-withdrawal syndrome [36,37]. When administered by the sublingual route to individuals dependent on low dose methadone, naloxone is 10 to 20 times less potent than when administered by the parenteral route [38] and 125 to 150 times less potent when administered by the oral route [30].…”

Section: Pharmacology Of Buprenorphine/naloxone Supporting a Combinatmentioning

confidence: 99%

Buprenorphine and Naloxone for Heroin Dependence

Johnson

McCagh

2000

Curr Psychiatry Rep

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The pharmacology of buprenorphine is unique because of its partial agonist profile at the mu-opioid receptor (ie, high affinity, low intrinsic activity and slow dissociation). This unique profile results in greater safety, less physical dependence, and greater flexibility in dose scheduling. Buprenorphine has been investigated in combination with the opioid antagonist, naloxone, with the goal of decreasing abuse, misuse, and diversion. When combined with naloxone in a sublingual tablet, buprenorphine has been shown to be effective 1) in retaining patients in treatment, 2) in reducing opioid use and craving, and 3) when dosed less-than-daily. The pharmacologic effects of buprenorphine are not altered by the addition of naloxone when administered to the population in an appropriate combination ratio. However, if taken intravenously by individuals dependent on short- or long-acting opioids a precipitated withdrawal syndrome is observed, which should reduce its abuse potential. This review discusses the rationale for development and evidence supporting the use of a buprenorphine/naloxone combination product. The buprenorphine/naloxone combination product should be considered for use in primary care office-based settings as a safe and effective treatment that is likely to increase the availability of agonist treatment for opioid dependence.

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Section: Pharmacology Of Buprenorphine/naloxone Supporting a Combinatmentioning

confidence: 99%

Buprenorphine and Naloxone for Heroin Dependence

Johnson

McCagh

2000

Curr Psychiatry Rep

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“…In opiate-dependent subjects, however, intravenous administration of naloxone produces immediate physiological and behavioral responses characteristic of opiate withdrawal. These withdrawal responses show a quantitative dose/ response relationship in human addicts (8). If obese subjects have elevated tonic endorphin activity, they should be more sensitive to naloxone than are normal persons, reacting like ones minimally dependent on opiates.…”

mentioning

confidence: 99%

Absence of Naloxone Sensitivity in Obese Humans

1982

Psychosomatic Medicine

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Studies in rodents suggest the possibility of an association between elevated endogenous opiate activity and overeating and obesity. One measure of elevated opiate activity is sensitivity to the opiate antagonist naloxone. Seven massively obese human subjects showed no subjective or physiological sensitivity to large intravenous doses of naloxone. This finding fails to support a relationship between elevated endorphin activity and human obesity.

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“…IV buprenorphine 2 mg and naloxone placebo IV buprenorphine 2 mg and naloxone 1 mg combined (2:1 ratio) IV buprenorphine 2 mg and naloxone 0.5 mg combined (4:1 ratio) IV buprenorphine 2 mg and naloxone 0.25 mg combined (8:1 ratio) IV morphine 15 mg Placebo Peak e¤ects of IV administered buprenorphine, morphine, and naloxone occur rapidly and, for naloxone, dissipate rapidly (OBrien et al 1978;Gilman et al 1990). Due to the complex interactions between distribution, elimination, and receptor e¤ects of our drug combinations, the relative agonist and antagonist potencies were expected to vary in intensity over the Þrst hour following challenge.…”

Section: Buprenorphine / Naloxone and Morphine Challenge Proceduresmentioning

confidence: 97%

“…Naloxone has a relatively low SL absorption of 810 % (Weinberg et al 1988;Preston et al 1990;Mendelson et al 1997b), whereas buprenorphine is better absorbed (approximately 30 50%) and has signiÞcant pharmacologic activity when given SL (Olley and Tiong 1988;Weinberg et al 1988;Jasinski et al 1989;Mendelson et al 1989). The rapid and intensely unpleasant e¤ects of naloxone when administered IV to opiate-dependent people (OBrien et al 1978;Gilman et al 1990;Mendelson et al 1997a) suggest that it would be an ideal candidate for a combination formulation. An ideal ratio of buprenorphine to naloxone in a combination dose would preserve the therapeutic e¤ects of buprenorphine and minimize opiate antagonist e¤ects of naloxone when given SL.…”

Section: Introductionmentioning

confidence: 92%

“…After 5 days of stabilization on morphine, subjects were challenged, every other day, with IV doses of buprenorphine and naloxone combinations, morphine, or placebo. Since the e¤ects of parenteral naloxone in opiate-dependent subjects have been well described (OBrien et al 1978), to diminish unnecessary subject discomfort, a naloxone alone challenge was not performed. Moreover, naloxone at doses similar to those used in our study reliably precipitates opiate withdrawal in subjects maintained on 60 mg / day IM morphine (Schuh et al 1996).…”

Section: General Proceduresmentioning

confidence: 99%

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Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers

et al. 1999

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Sublingual buprenorphine is a promising new treatment for opiate dependence, but its opioid agonist effects pose a risk for parenteral abuse. A formulation combining buprenorphine with the opiate antagonist naloxone could discourage such abuse. The effects of three intravenous (IV) buprenorphine and naloxone combinations on agonist effects and withdrawal signs and symptoms were examined in 12 opiate-dependent subjects. Following stabilization on a daily dose of 60 mg morphine intramuscularly, subjects were challenged with IV doses of buprenorphine alone (2 mg) or in combination with naloxone in ratios of 2:1, 4:1, and 8:1 (1, 0.5, or 0.25 mg naloxone), morphine alone (15 mg) or placebo. Buprenorphine alone did not precipitate withdrawal and had agonist effects similar to morphine. A naloxone dose-dependent increase in opiate withdrawal signs and symptoms and a decrease in opioid agonist effects occurred after all drug combinations. Buprenorphine with naloxone in ratios of 2:1 and 4:1 produced moderate to high increases in global opiate withdrawal, bad drug effect, and sickness. These dose ratios also decreased the pleasurable effects and estimated street value of buprenorphine, thereby suggesting a low abuse liability. The dose ratio of 8:1 produced only mild withdrawal symptoms. Dose combinations at 2:1 and 4:1 ratios may be useful in treating opiate dependence.

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Clinical Pharmacology of Narcotic Antagonists*

Cited by 36 publications

References 30 publications

Buprenorphine and Naloxone for Heroin Dependence

Buprenorphine and Naloxone for Heroin Dependence

Absence of Naloxone Sensitivity in Obese Humans

Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers

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