Aromatase inhibitor-induced joint pain: melatonin's role

Aromatase inhibitor-induced joint pain: melatonin's role.

Aromatase inhibitors (AIs) enjoy increasing use in breast cancer adjuvant therapy. But the joint pain associated with AIs significantly reduces patient adherence despite the clear survival benefits of this class of drugs. Two clues point to a novel hypothesis for this unexplained symptom. First, realizing that joint pain is associated with virtually all estrogen-depleting breast cancer treatments suggests that the cause is broader than this particular class of drugs. Second, the strongly circadian nature of these symptoms suggests circadian hormone involvement. This puts new light on some existing research findings: that estrogen depletion can increase pineal melatonin, that the ability of light to suppress pineal melatonin is more variable than once thought, and that an altered melatonin cycle is associated with rheumatoid arthritis patients, where identical circadian symptoms present. It is hypothesized that when AIs decrease estrogen levels, light-induced melatonin suppression (LIMS) loses efficacy, leading to an abnormal melatonin cycle as seen in rheumatoid arthritis patients, producing (via mechanisms not yet understood) the symptoms of morning stiffness. Not all frequencies of retinal light are equally effective at suppressing pineal melatonin; most artificial lighting has less relevant spectral density than sunlight. This hypothesis predicts that some patients can suppress the circadian joint pain associated with aromatase inhibitors merely by getting sufficient hours of daily retinal sunlight. A single patient history is discussed, in which a series of treatments had no effect on AI joint pain, while extended exposure to sunlight produced a definitive elimination of symptoms the next morning. To conclusively demonstrate the role of melatonin, light-emitting diodes of an appropriate frequency were mounted on a cap for the patient to wear. If worn first thing in the morning, the cap sharply curtailed the duration of morning stiffness. If worn for a sufficient number of hours during the day, the cap suppressed symptoms the next morning, just as sunlight did. Because of evidence for melatonin's oncostatic properties, this hypothesis potentially has implications beyond decreasing the number of patients that discontinue AIs. It may be that some portion of the survival benefit of AIs is due to their indirect effect on melatonin, not just their direct effect on estrogen.

Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials.

Much debate has focused on whether antioxidants interfere with the efficacy of cancer chemotherapy. The objective of this study is to systematically review the randomized, controlled clinical trial evidence evaluating the effects of concurrent use of antioxidants with chemotherapy on toxic side effects. We performed a search of literature from 1966-October 2007 using MEDLINE, Cochrane, CinAhl, AMED, AltHealthWatch and EMBASE databases. Randomized, controlled clinical trials reporting antioxidant-based mitigation of chemotherapy toxicity were included in the final tally. Searches were performed following a standardized protocol for systematic reviews. Only 33 of 965 articles considered, including 2,446 subjects, met the inclusion criteria. Antioxidants evaluated were: glutathione (11), melatonin (7), vitamin A (1), an antioxidant mixture (2), N-acetylcysteine (2), vitamin E (5), selenium (2), L-carnitine (1), Co-Q10 (1) and ellagic acid (1). The majority (24) of the 33 studies included reported evidence of decreased toxicities from the concurrent use of antioxidants with chemotherapy. Nine studies reported no difference in toxicities between the 2 groups. Only 1 study (vitamin A) reported a significant increase in toxicity in the antioxidant group. Five studies reported the antioxidant group completed more full doses of chemotherapy or had less-dose reduction than control groups. Statistical power and poor study quality were concerns with some studies. This review provides the first systematically reviewed evidence that antioxidant supplementation during chemotherapy holds potential for reducing dose-limiting toxicities. However, well-designed studies evaluating larger populations of patients given specific antioxidants defined by dose and schedule relative to chemotherapy are warranted.

Влияние антиоксидантов на химиотерапевтического токсичности : систематический обзор доказательств от рандомизированных контролируемых испытаний .
Блок К.И., Кох AC , Мид М. Н., Tothy ПК, Ньюман РА , Джилленхол С.
Большая дебаты сосредоточены на ли антиоксиданты мешать эффективности химиотерапии рака. Целью данного исследования является систематический обзор рандомизированное контролируемое клиническое испытание доказательств оценки влияния одновременное использование антиоксидантов с химиотерапией на токсических побочных эффектов . Мы выполнили поиск литературы с 1966 -октябре 2007 года с помощью MEDLINE, Cochrane , CINAHL , Amed, AltHealthWatch и базы данных EMBASE . Рандомизированные контролируемые клинические испытания отчетности антиоксидантной основе смягчение химиотерапии токсичности были включены в окончательный подсчет . Поиск проводили после стандартизованного протокола для систематических обзоров . Только 33 из 965 статьи рассматриваются, в том числе 2446 субъектов , соответствовали критериям включения . Антиоксиданты были оценены : глутатион (11), мелатонин (7), витамин A (1) , антиоксидант смесь (2) , N- ацетилцистеин (2) , витамин Е (5), селен (2) , L -карнитин (1 ), Co -Q10 (1) и эллаговая кислота (1). Большинство (24) из 33 исследований, включенных сообщил доказательства снизилась токсичности от одновременного использования антиоксидантов с химиотерапией. Девять исследований сообщили об отсутствии различий в токсичности между 2 группами . Только 1 исследование (витамин А) сообщили о значительном увеличении в токсичности в антиоксидантной группы . Пять исследований сообщили антиоксидант группа завершила более полные дозы химиотерапии или имели уменьшение менее дозы , чем в контрольных группах . Статистическая мощность и низкое качество исследования были опасения с некоторых исследований . Первоначально обеспечивает первую систематический обзор доказательств того, что антиоксидантные добавки во время химиотерапии держит потенциал для снижения ограничивающей дозу токсичности . Тем не менее, хорошо продуманные исследования, оценивающие крупные популяции пациентов, получавших конкретные антиоксиданты , определенные дозы и схемы по отношению к химиотерапии являются оправданными.

Prog Neurobiol. 2008 Jul;85(3):335-53. doi: 10.1016/j.pneurobio.2008.04.001. Epub 2008 Apr 16.