Tratamiento con agonistas opiáceos y prolongación del intervalo QTc: una revisión sistemática / Treatment with opioid agonists and QTc prolongation: a systematic review

En el presente trabajo, se pretende revisar las evidencias publicadas sobre la relación entre los agonistas opioides, concretamente la metadona y la buprenorfina, y el riesgo de prolongación del intervalo QTc. Se ha realizado una búsqueda bibliográfica en las bases de datos "PubMed", "UpToDate" y "Google Académico", filtrando entre los años 2005 y 2014 con las palabras clave: "QTc", "buprenorfina" y "metadona". La metadona y la buprenorfina son fármacos ampliamente utilizados en el tratamiento de la adicción a los opioides. En lo que respecta a su riesgo cardiovascular, en los últimos años se han publicados diversos estudios con resultados contradictorios, dado que en algunos se concluye que existe una asociación dosis-dependiente de la metadona y la prolongación del intervalo QTc, mientras que en otros no se ha observado dicha asociación. Los estudios publicados en la última década muestran importante limitaciones: tamaño insuficiente de la muestra, ausencia de ECG previo al inicio del tratamiento, corta duración del seguimiento o falta de valoración de la concomitancia con otros factores que prolongan el intervalo QTc tales como fármacos, drogas ilícitas o niveles plasmáticos de potasio o magnesio. Se ha evidenciado un aumento del riesgo del alargamiento del intervalo QTc asociado a la metadona. Aunque existen pocos estudios que investiguen la relación entre la buprenorfina y el intervalo QTc, en ninguno de los artículos revisados se ha detectado una asociación entre ambos. Todo ello hace necesario nuevos estudios, que subsanen las limitaciones encontradas en la bibliografía estudiada

The aim of this paper is to review the evidence published on the relationship between opioid agonists, specifically methadone and buprenorphine and the risk of QTc interval prolongation. A literature search using the "PubMed", "UpToDate" and "Google Scholar" databases was conducted for the years between 2005 and 2014, using the key words: "QTc", "buprenorphine" and "methadone". Methadone and buprenorphine are two medications widely used in the treatment of opioid addiction. With regard to the cardiovascular risk, several studies have been published in recent years, with contradictory findings: some studies have reported a dose-dependent relationship between methadone dose and QTc interval prolongation, while other studies have failed to find any such relationship. The studies published over the last decade display some major limitations: insufficient sample sizes, absence of a baseline ECG, short follow-up or failure to assess concomitant factors that may prolong the QTc interval, such as other medications, illegal drugs, or potassium or magnesium plasma levels. Evidence shows an increased risk of QTc prolongation associated with methadone. Although there are few reports exploring the relationship between buprenorphine and the QTc interval, none of the papers reviewed detected any relationship between both. All of this warrants the need for future studies to overcome the limitations in the literature reviewed

Altered states: the impact of immediate craving on the valuation of current and future opioids.

Based on prior research showing that people underestimate the influence of motivational states they are not currently experiencing, we predicted and found that heroin addicts would value an extra dose of the heroin substitute Buprenorphine more highly when they were currently craving (right before receiving BUP) than when they were currently satiated (right after receiving BUP) -- even when the extra BUP was to be received 5 days later. If addicts cannot appreciate the intensity of craving when they are not currently experiencing it, as these results suggest, it seems unlikely that those who have never experienced craving could predict its motivational force. Under-appreciation of craving by non-addicts may contribute to initial decisions to experiment with drugs.

Interaction of mu-opioid receptor agonists and antagonists with the analgesic effect of buprenorphine in mice.

Buprenorphine is a potent opioid analgesic with partial agonistic properties at mu-opioid receptors. This study investigated the interaction potential with several full mu-agonists in the tail-flick test in mice. We further examined the reversibility of buprenorphine antinociception by different mu-opioid receptor antagonists. Combination of buprenorphine with morphine, oxycodone, hydromorphone and fentanyl in the analgesic dose range resulted in additive or synergistic effects. When given after the decline of the acute buprenorphine effect, both morphine and fentanyl also showed full efficacy. A moderate antagonistic effect according to the partial mu-agonistic properties of buprenorphine was only seen when high doses exceeding the therapeutic dose ranges were combined. Under these conditions antinociception of morphine was reduced to the effect of buprenorphine alone. Prophylactic administration of naloxone (10 mg/kg i.v.), naltrexone (1 mg/kg i.v.) and clocinnamox (5 mg/kg s.c.) fully and persistently blocked the antinociception of a high dose of buprenorphine. An established effect of buprenorphine was less sensitive, although repeated administration of naloxone induced complete antagonism, as did the irreversible antagonist clocinnamox under prophylactic and curative treatment conditions. Our results suggest that the antinociceptive effect of buprenorphine is mainly, if not exclusively, mediated by activation of mu-opioid receptors. They confirm clinical experience that in the analgesic dose range a switch between buprenorphine and full mu-agonists is possible without loss of analgesic efficacy and without a refractory period between the termination of buprenorphine analgesia and the onset of action of the new mu-opioid treatment. Antinociception of buprenorphine is sensitive towards mu-opioid receptor antagonists and incomplete inhibition can be improved by increasing the dose or repetitive dosing.

From morphine clinics to buprenorphine: regulating opioid agonist treatment of addiction in the United States.

The practice of prescribing opioid drugs for opioid dependent patients in the U.S. has been subjected to special government scrutiny for almost 100 years. From 1920 until 1964, doctors who used opioids to treat addicts risked federal and/or state criminal prosecution. Although that period ended when oral methadone maintenance was established as legitimate medical practice, public concern about methadone diversion and accidental overdose fatalities, combined with political pressure from both hostile bureaucracies and groups committed to drug-free treatments, led to the development of unprecedented and detailed Food and Drug Administration (FDA) regulations that specified the manner in which methadone (and later, levo-alpha-acetyl methadol, or levomethadyl acetate, (LAAM)) could be provided. In 1974, Congress gave the Drug Enforcement Administration (DEA) additional oversight of methadone treatment programs. Efforts to liberalize the FDA regulations over the past 30 years have been resisted by both the DEA and existing treatment providers. Additional flexibility for clinicians may evolve from the most recent effort to create an accreditation system to replace some of the FDA regulations. The development of buprenorphine, a partial opioid agonist, as an effective treatment for opioid addiction reopened the possibility for having a less burdensome oversight process, especially because of its reduced toxicity if ingested by non-tolerant individuals. New legislation, the Drug Addiction Treatment Act (DATA) of 2000, created an opportunity for clinicians with special training to be exempted from both federal methadone regulations and the requirement to obtain a special DEA license when using buprenorphine to treat addicts. Some details of how the DATA was developed, moved through Congress, and signed into law are described.

Effect of mu-opioids morphine and buprenorphine on the development of adjuvant arthritis in rats.

OBJECTIVE AND DESIGN: On the basis that endogenous opioids play a role in the physiological response to inflammation, this study tests the anti-arthritic effects of a mu-opioid agonist, morphine and the partial mu-agonist, buprenorphine. MATERIAL: Male Lewis rats were used. TREATMENT: Rats were inoculated subcutaneously with 0.05 ml of Freund's complete adjuvant (5 mg/ml) into the right hind paw to produce adjuvant arthritis. Morphine (either 10 to 60 mg/kg/day s.c. bolus or 60 mg/kg/day s.c. infusion) and buprenorphine (0.65 +/- 0.06 mg/kg/day, orally), respectively, were administered for 3 days during the primary inflammatory phase of adjuvant arthritis. METHODS: The progression of adjuvant arthritis was monitored every three days by body weight change and hind limb oedema (ipsilateral and contralateral). On day 21 the animals were sacrificed and histology and radiography of the contralateral limb were performed. In rats receiving Freund's adjuvant and no drug treatment, the incidence of arthritis was 89%. Effect was expressed as the pooled severity index (PSI) derived from the arithmetic average of the volume, histology and radiography scores in the contralateral hind limb. RESULTS: Buprenorphine had no effect on experimental arthritis (PSI control vs treated: 242 +/- 28 vs 253 +/- 28%). In contrast, morphine by subcutaneous injection twice daily (10 to 60 mg/kg/day) but not by subcutaneous infusion (60 mg/kg/day) was found to attenuate the progression of adjuvant arthritis in a dose-dependent manner. This indicates that the anti-arthritic effects of morphine are opioid receptor mediated (ED50, 58 +/- 9 mg/kg) and suggests that the local concentration reached effective levels only after subcutaneous injection. It is also possible that the high doses of morphine were anti-inflammatory through effects at the kappa receptor. However, these high doses of morphine produced death in one third of the rats, the calculated lethal dose (LD50, 63 +/- 2 mg/kg) being close to the effective dose. CONCLUSION: Anti-arthritic effects of morphine are opioid receptor mediated but morphine use for this indication is restricted by its adverse effects.