Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-|linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Hidromorfona de liberação lenta: uma nova opção agonista opioide forte / Slow-release hydromorphone: a new strong opioid agonist option

JUSTIFICATIVA E OBJETIVOS: A dor crônica é uma condição frequente na população mundial, sendo causa de perdas emocionais e econômicas importantes. A busca por fármacos analgésicos potentes, de longa duração de ação, que possam proporcionar estabilidade no controle em longo prazo, melhora da adesão ao tratamento com o mínimo de eventos adversos, tem crescido na última década. O mais novo membro desta classe de analgésicos é a hidromorfona OROS®, opioide forte agonista µ, que incorpora a tecnologia OROS® push-pullTM (ALZA Corporation, Mountain View, CA, USA), liberado hidromorfona, administrada por via oral, de forma constante, por 24h. O objetivo deste estudo foi descrever os aspectos farmacocinéticos e farmacodinâmicos, indicações e contra-indicações, bem como sumarizar os resultados dos principais artigos publicados, de relevância clínica, sobre a hidromorfona OROS®.CONTEÚDO: O cloridrato de hidromorfona é um analgésico opioide forte para a administração em dose única diária. A liberação controlada promove uma analgesia dose-dependente contínua, durante 24h de intervalo entre duas doses. Está indicada no tratamento da dor de moderada à intensa, crônica, maligna ou benigna. A dose inicial deve ser de 8 mg a cada 24h para pacientes que não estejam recebendo nenhum outro analgésico opioide. Para pacientes que estejam recebendo opioidespor via oral, a razão sugerida de conversão é de 5:1 de equivalentes de morfina por hidromorfona. Os estudos clínicos demonstraram um efeito analgésico contínuo ao longo de 24h em pacientes com dor moderada à intensa, maligna e não maligna. A formulação de liberação lenta proporciona analgesia estável, segura, sem a condição que comumente chamamos de "picos e vales", que favorece o aparecimento de efeitos adversos e um controle analgésico não ideal. A adesão ao tratamento e a comodidade posológica são inquestionáveis, com apenas uma administração diária. CONCLUSÃO: A hidromorfona OROS® parece ser uma opção analgésica segura e eficaz para o controle da dor crônica, de intensidade moderada à forte, não incidentais, malignas ou benignas, ajustando-se às exigências da Escada Analgésica da Organização Mundial da Saúde (3º degrau) e da analgesia multimodal.

BACKGROUND AND OJBECTIVES: Chronic pain is a common condition worldwide, being responsible for major emotional and economic losses. The search for potent long lasting analgesic drugs to provide stability for long term pain control and to improve adherence to treatment with minimum adverse events has grown during the last decade. The latest member of this class of analgesics is hydromorphone OROS®, strong µ agonist opioid, which incorporates the OROS® push-pullTM (ALZA Corporation, Mountain View, CA, USA) technology, which releases oral hydromorphone in a constant way during 24 hours. This review aimed at describing pharmacokinetic and pharmacodynamic aspects, indications and counterindications, as well as at summarizing results of major published articles of clinical relevance on hydromorphone OROS®.CONTENTS: Hydromorphone hydrochloride is a strong opioid analgesic for single daily dose administration. Controlled release promotes a continuousdose-dependent analgesia during the 24-hour interval between two doses. It is indicated to treat moderate to severe, chronic, malignant or benign pain. Initial dose should be 8 mg every 24 hours for patients not receiving any other opioid analgesic. For patients receiving oral opioids, suggested conversion ratio is 5:1 of morphine equivalents by hydromorphone. Clinical studies have shown a continuous analgesic effect for 24 hours in patients with moderate to severe, malignant or not malignant pain. The slow release formulation provides stable and safe analgesia without the condition we commonly call "peaks and valleys", which favors the onset of adverse effects and a less than ideal analgesic control. Adherence to treatment and dose convenience are unquestionable, with just one daily administration.CONCLUSION: Hydromorphone OROS® seems to be a safe and effective analgesic option to control chronic moderate to severe, non incidental, malignant or benign pain, in compliance with the requirements of World Health Organization?s Analgesic Stair (3rd step) and of multimodal analgesia.