Pentazocine

Brogden, Rex N.; Speight, T. M.; Avery, G. S.

doi:10.2165/00003495-197305010-00002

Cited by 97 publications

(8 citation statements)

References 128 publications

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“…Unlike μ opioid receptor (MOR) agonists, such as morphine, meperidine, and fentanyl, KOR agonists do not cause typical opioid-like effects, such as addiction, respiratory depression, and constipation. − This fascinating trait makes KOR agonists particularly appealing for the development of novel nonaddictive pain medications, , especially given the opioid epidemic in the United States . However, despite the fact that several KOR agonists (e.g., pentazocine, nalbuphine, and butorphanol; see Figure ) with mixed KOR/MOR activity are used as analgesics, − their clinical utility is severely limited owing to centrally mediated side effects, including dysphoria, hallucinations, and sedation. These adverse effects are associated with the antirewarding characteristics of KOR agonists, potentially connected to the stimulation of the KOR/Dyn systema natural addiction control mechanism in the brain. , Additionally, these aversive reactions have also been observed with the selective KOR agonists of representative scaffolds (e.g., arylacetamides and neo-clerodane diterpenes), − making them unappealing as potentially beneficial analgesics.…”

Section: Introductionmentioning

confidence: 99%

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

Li,

Ye,

et al. 2024

J. Med. Chem.

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Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, K i = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [ 35 S]GTPγS binding, EC 50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED 50 = 0.20−0.30 mg/kg, i.p.; abdominal constriction test, ED 50 = 0.20−0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED 50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

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Section: Introductionmentioning

confidence: 99%

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

Li,

Ye,

et al. 2024

J. Med. Chem.

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“…[ 1 2 ] It is commonly used for the relief of moderate to severe pain arising from various clinical conditions such as trauma, early postoperative period, and pain of vaso-occlusive crisis of sickle cell disease (SCD). [ 1 2 ] In most cases, it is used for a short duration, but in some cases, the course may be repeated or prolonged. [ 1 2 ] Prolonged use often results in dependence and addiction.…”

Section: Introductionmentioning

confidence: 99%

“…[ 1 2 ] In most cases, it is used for a short duration, but in some cases, the course may be repeated or prolonged. [ 1 2 ] Prolonged use often results in dependence and addiction. [ 1 2 ] It was initially thought to be nonaddictive, and the World Health Organization (WHO), through its expert committee on drug dependence, had recommended that it should not be subjected to narcotic control.…”

Section: Introductionmentioning

confidence: 99%

“…[ 1 2 ] It was initially thought to be nonaddictive, and the World Health Organization (WHO), through its expert committee on drug dependence, had recommended that it should not be subjected to narcotic control. [ 1 2 ] As a result, the drug was made readily available to the public. [ 1 2 ] Its abuse and dependence potential have remained controversial.…”

Section: Introductionmentioning

confidence: 99%

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Tissue necrosis: A burden of pentazocine abuse in South East Nigeria

Cosmas Mba,

Onyebueke,

Okwesili

et al. 2024

J West Afr Coll Surg

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Background: Tissue necrosis from pentazocine abuse is becoming a burden in our environment. Pentazocine is an opioid of the benzomorphan class. It is commonly used for post-traumatic and postoperative pain and vaso-occlusive pain of sickle cell disease (SCD). Its prolonged use can lead to addiction and may result in severe injection site necrosis, often worsened by infection due to a lack of aseptic principles during administration. Although pentazocine is a controlled drug in our environment, it is readily available. Objectives: To review patients with tissue necrosis from pentazocine injection, share the challenges in their management, and proffer solutions. Materials and Methods: Clinical summaries of patients with tissue necrosis and ulcers due to pentazocine addiction were reviewed. Results: Twenty-five patients, comprising nine females and 16 males aged 22–61 years, were recorded. Twenty had SCD, while five had other underlying conditions. The duration of abuse was 1–16 years, while the average maximum daily dose was 348.75 ± 346.04 mg. Most patients used multiple sites for injection. Lesions included abscesses, tissue necrosis with ulcers, lymphoedema, exposed necrotic bones, and osteomyelitis. Most had multidisciplinary care. The outcome of wound care was good in two. Three had major limb amputations, four died, three signed against medical advice, six were still receiving care while seven were lost to follow-up. None was completely weaned from the drug at the time of this report. Conclusion: Rising cases of tissue necrosis from pentazocine abuse are disturbing. Treatment is frustrating. Concerted efforts at prevention should be made to stem the tide.

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“…There is a clinical need for PTZ to be made available as a long-acting formulation for chronic pain management. 6) We have already reported the effects of glyceryl monocaprylate (GEFA-C 8 ) as an enhancer of the permeation of PTZ in isopropyl myristate (IPM) solution across excised hairless mouse skin. We found that the flux of PTZ combined with both GEFA-C 8 and IPM was approximately 4 times higher than that with IPM alone.…”

mentioning

confidence: 99%

Synergistic Effect of Isopropyl Myristate and Glyceryl Monocaprylate on the Skin Permeation of Pentazocine

Furuishi

Fukami

Suzuki

et al. 2010

Biological & Pharmaceutical Bulletin

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While most drugs are administered orally, there are numerous advantages to the percutaneous route. These advantages include the potential for sustained release, controlled input kinetics, improved patient compliance, and avoidance of first-pass metabolism in the gastrointestinal tract. However, the stratum corneum (SC), the outermost layer of the epidermis, is the principal rate limitation to percutaneous absorption. The SC layer is composed of keratin-enriched corneocytes embedded in a multilamellar lipid matrix, which mainly comprises ceramides, cholesterol and free fatty acids.1,2) Both physical methods (SC stripping, iontophoresis, phonophoresis and microneedle) and chemical methods (synthesis of lipophilic analogues and skin permeation enhancers) are used to promote the delivery of drugs across the skin. Of these methods, the most widely implemented approach to increase percutaneous absorption is the use of skin permeation enhancers, which ideally cause a temporary, reversible reduction in the barrier function of the SC in order to facilitate safe and effective drug delivery through the skin.3) In theory, there are two potential pathways through the SC: the transcellular pathway, which involves permeation across the corneocytes and multilamellar lipid matrix, and the intercellular pathway, which involves permeation via the lipid domains between the corneocytes. Within the corneocytes, the major site of action would be the keratin fibrils and their associated water molecules.4) Within the intercellular route, it is proposed that enhancers may interact with the polar head groups and between the hydrophobic tails of the lipid bilayers. The lipid matrix of the SC, therefore, is a target of action for permeation enhancers.5) Considering the structure of the SC and the continuity of the lipid barrier, interaction with SC intercellular lipids is of crucial importance for the effectiveness of permeation enhancers. 5)Pentazocine (PTZ, M w : 285.42, log P: 3.08 (pH 7.0)), a benzomorphan derivative, is an opioid analgesic that has mixed opioid agonist-antagonist function. It is considered to be a partial agonist or weak antagonist at the m-receptor and an agonist at the k-receptor. PTZ is used for the relief of moderate to severe pain. Oral administration of PTZ has the disadvantage of low bioavailability (approximately 20%) due to extensive first-pass metabolism. In addition, PTZ has a short half-life of 2-3 h and requires frequent dosing in order to maintain an optimal therapeutic concentration. There is a clinical need for PTZ to be made available as a long-acting formulation for chronic pain management. 6)We have already reported the effects of glyceryl monocaprylate (GEFA-C 8 ) as an enhancer of the permeation of PTZ in isopropyl myristate (IPM) solution across excised hairless mouse skin. We found that the flux of PTZ combined with both GEFA-C 8 and IPM was approximately 4 times higher than that with IPM alone. 7) Moreover, we demonstrated that a novel transdermal drug delivery system patch composed of Duro-Tak ...

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Pentazocine

Cited by 97 publications

References 128 publications

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

Tissue necrosis: A burden of pentazocine abuse in South East Nigeria

Synergistic Effect of Isopropyl Myristate and Glyceryl Monocaprylate on the Skin Permeation of Pentazocine

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