Richards John R, Lapoint Jeff M, Burillo-Putze Guillermo
a Department of Emergency Medicine , University of California Davis Medical Center , Sacramento , CA , USA.
b Department of Emergency Medicine, Southern California Permanente Medical Group , San Diego , CA , USA.
Clin Toxicol (Phila). 2018 Jan;56(1):15-24. doi: 10.1080/15563650.2017.1349910. Epub 2017 Jul 21.
Cannabinoid hyperemesis syndrome is a clinical disorder that has become more prevalent with increasing use of cannabis and synthetic cannabinoids, and which is difficult to treat. Standard antiemetics commonly fail to alleviate the severe nausea and vomiting characteristic of the syndrome. Curiously, cannabinoid hyperemesis syndrome patients often report dramatic relief of symptoms with hot showers and baths, and topical capsaicin.
In this review, we detail the pharmacokinetics and pharmacodynamics of capsaicin and explore possible mechanisms for its beneficial effect, including activation of transient receptor potential vanilloid 1 and neurohumoral regulation. Putative mechanisms responsible for the benefit of hot water hydrotherapy are also investigated.
An extensive search of PubMed, OpenGrey, and Google Scholar from inception to April 2017 was performed to identify known and theoretical thermoregulatory mechanisms associated with the endocannabinoid system. The searches resulted in 2417 articles. These articles were screened for relevant mechanisms behind capsaicin and heat activation having potential antiemetic effects. References from the selected articles were also hand-searched. A total of 137 articles were considered relevant and included. Capsaicin: Topical capsaicin is primarily used for treatment of neuropathic pain, but it has also been used successfully in some 20 cases of cannabinoid hyperemesis syndrome. The pharmacokinetics and pharmacodynamics of capsaicin as a transient receptor potential vanilloid 1 agonist may explain this effect. Topical capsaicin has a longer half-life than oral administration, thus its potential duration of benefit is longer. Capsaicin and transient receptor potential vanilloid 1: Topical capsaicin binds and activates the transient receptor potential vanilloid 1 receptor, triggering influx of calcium and sodium, as well as release of inflammatory neuropeptides leading to transient burning, stinging, and itching. This elicits a novel type of desensitization analgesia. Transient receptor potential vanilloid 1 receptors also respond to noxious stimuli, such as heat (>43 °C), acids (pH <6), pain, change in osmolarity, and endovanilloids. The action of topical capsaicin may mimic the effect of heat-activation of transient receptor potential vanilloid 1. Endocannabinoid system and transient receptor potential vanilloid 1: Cannabinoid hyperemesis syndrome may result from a derangement in the endocannabinoid system secondary to chronic exogenous stimulation. The relief of cannabinoid hyperemesis syndrome symptoms from heat and use of transient receptor potential vanilloid 1 agonists suggests a complex interrelation between the endocannabinoid system and transient receptor potential vanilloid 1. Temperature regulation: Hot water hydrotherapy is a mainstay of self-treatment for cannabinoid hyperemesis syndrome patients. This may be explained by heat-induced transient receptor potential vanilloid 1 activation. "Sensocrine" antiemetic effects: Transient receptor potential vanilloid 1 activation by heat or capsaicin results in modulation of tachykinins, somatostatin, pituitary adenylate-cyclase activating polypeptide, and calcitonin gene-related peptide as well as histaminergic, cholinergic, and serotonergic transmission. These downstream effects represent further possible explanations for transient receptor potential vanilloid 1-associated antiemesis.
These complex interactions between the endocannabinoid systems and transient receptor potential vanilloid 1, in the setting of cannabinoid receptor desensitization, may yield important clues into the pathophysiology and treatment of cannabinoid hyperemesis syndrome. This knowledge can provide clinicians caring for these patients with additional treatment options that may reduce length of stay, avoid unnecessary imaging and laboratory testing, and decrease the use of potentially harmful medications such as opioids.
大麻素呕吐综合征是一种临床病症，随着大麻和合成大麻素使用的增加而愈发普遍，且难以治疗。标准的止吐药通常无法缓解该综合征特有的严重恶心和呕吐症状。奇怪的是，大麻素呕吐综合征患者常称热水淋浴和泡澡以及局部使用辣椒素能显著缓解症状。
在本综述中，我们详细阐述辣椒素的药代动力学和药效学，并探讨其有益作用的可能机制，包括瞬时受体电位香草酸受体1的激活和神经体液调节。我们还研究了热水水疗有益效果的假定机制。
对PubMed、OpenGrey和谷歌学术从创立到2017年4月进行广泛检索，以确定与内源性大麻素系统相关的已知和理论性体温调节机制。检索结果有2417篇文章。对这些文章筛选出辣椒素和热激活背后具有潜在止吐作用的相关机制。还对所选文章的参考文献进行了手工检索。共137篇文章被认为相关并纳入。辣椒素：局部使用辣椒素主要用于治疗神经性疼痛，但也已成功用于约20例大麻素呕吐综合征患者。辣椒素作为瞬时受体电位香草酸受体1激动剂的药代动力学和药效学可解释这种作用。局部使用辣椒素的半衰期比口服长，因此其潜在的有益持续时间更长。辣椒素与瞬时受体电位香草酸受体1：局部使用辣椒素结合并激活瞬时受体电位香草酸受体1，触发钙和钠的内流，以及炎性神经肽的释放，导致短暂的灼烧、刺痛和瘙痒。这引发一种新型的脱敏镇痛。瞬时受体电位香草酸受体1也对有害刺激有反应，如热（>43°C）、酸（pH<6）、疼痛、渗透压变化和内源性香草酸。局部使用辣椒素的作用可能模拟瞬时受体电位香草酸受体1热激活的效果。内源性大麻素系统与瞬时受体电位香草酸受体1：大麻素呕吐综合征可能源于慢性外源性刺激导致的内源性大麻素系统紊乱。热和使用瞬时受体电位香草酸受体1激动剂缓解大麻素呕吐综合征症状表明内源性大麻素系统与瞬时受体电位香草酸受体1之间存在复杂的相互关系。体温调节：热水水疗是大麻素呕吐综合征患者自我治疗的主要方法。这可能由热诱导的瞬时受体电位香草酸受体1激活来解释。“感觉分泌”性止吐作用：热或辣椒素激活瞬时受体电位香草酸受体1会导致速激肽、生长抑素、垂体腺苷酸环化酶激活多肽和降钙素基因相关肽以及组胺能、胆碱能和5-羟色胺能传递的调节。这些下游效应是瞬时受体电位香草酸受体1相关止吐作用的进一步可能解释。
在内源性大麻素系统与瞬时受体电位香草酸受体1之间的这些复杂相互作用中，在大麻素受体脱敏的情况下，可能为大麻素呕吐综合征的病理生理学和治疗提供重要线索。这些知识可为照顾这些患者的临床医生提供更多治疗选择，可能缩短住院时间，避免不必要的影像学和实验室检查，并减少使用潜在有害药物如阿片类药物。
