Benzodiazepine Oncogenesis as Mediated via Diminished Restorative Sleep Effected Sympathoadrenal Activation

The valuable cohort contribution by Kao et al¹ associating narcotic zolpidem consumption with heightened iatrogenic malignancy risks would be considerably more compelling if accompanied by proposition of a distinct plausible pathophysiologic mechanism. The most favorably received mechanism would define associations between the physiologic effects of zolpidem that are common to other pharmacologic agents and diagnoses that effect similar intermediary stepwise events epidemiologically linked to oncogenesis.

Though newer benzodiazepine controlled substances are marketed as “nonbenzodiazepines,” zolpidem activates identical benzodiazepine sleep modulation γ-aminobutyric acid type A receptors as classic benzodiazepines,² enhancing superficial stage 1/2 sleep interval at the expense of restorative rapid eye movement and stage 3/4 deep slow wave sleep (SWS).^2,3 Benzodiazepines thereby enhance sleep duration, but at the expense of restorative sleep. Similarly, all benzodiazepines suppress afferent carotid body⁴ and medullary ventilatory centers, enhancing central sleep apnea perils.⁵ Nocturnally ingested opioids are also well characterized as enhancing sleep duration but suppressing SWS⁶ and inducing central sleep apnea,⁵ with potential oncogenesis.

A 22-year study of obstructive sleep apnea has suggested that malignant lesions are potentially mediated by hypoxemic angiogenesis.⁷ However, sleep apnea induced hypoxemia propagates awakenings, fragmenting SWS architecture,⁸ alternatively explaining reported epidemiologic findings. Polysomnographic SWS findings were unreported. In addition, the authors did not discuss decreased oncogenesis in SWS preserved, chronically iron-depleted anemic hypoxemic, non-apnea conditions bereft of carcinogen exposure.⁹

Further challenging the angiogenesis hypothesis, non-hypoxemic circadian sleep impaired shift work decreases melatonin, which effects parallel rapid eye movement and SWS duration decrements,¹⁰ diminishing sleep duration by 1 to 4 hours to compromise restorative sleep quality and concomitantly increase cancers.¹¹ In addition, without sleep apnea hypoxemia, 42,351 patients with sleep disorders with unknown extent of SWS deficit revealed a substantially elevated risk of cancer.¹²

Analogous to benzodiazepine and opioid impaired restorative SWS without decrement in overall sleep duration, experimentally laboratory simulated selectively fragmented SWS impairment without compromise of total sleep duration induced sympathoadrenal hyperactivity, increasing circulating cortisol and catecholamines⁸ as well as hyperglycemic dyshomeostasis.¹³

Impaired restorative SWS effects daytime cognitive impairment and neurobehavioral anxiogenesis, with attendant augmentation of nocturnal sympathoadrenal hyperactivity,¹⁴ perpetuating and magnifying hyperglycemia.

The constant aberrant serologic hyperglycemic environment detrimentally compromises white cell optimal cancer scavenging immunosurveillance, facilitating unimpeded microscopic tumor growth to macroscopic tumor bulk. Clinically expressed immunosuppression facilitates oncogenesis, as witnessed in patients with diabetes, those with human immunodeficiency virus, and patients treated pharmacologically after consumption of rheumatologic modifier biologic agents or transplant anti-rejection medications.¹⁵

Newer and classic benzodiazepine narcotics, opioids, shift work, sleep deprivation, and sleep apnea have individually been epidemiologically associated with overlapping breast, liver, lung, colorectal, and bladder enhanced oncogenesis, with all conditions potentially etiologically, unifyingly, pathophysiologically linked by impaired restorative SWS, initiating sympathoadrenal hyperactive hyperglycemic dyshomeostasis induced immune dysfunction as a final common viable pathway.

Given the validity of cumulative and compelling basic science and epidemiologic evidence, it is reasonable to robustly direct investigational resources towards prospective, highly powered, polysomnographic randomized controlled trials to scrutinize causality.

Deaths due to cancer are ubiquitous and copiously etiologically idiopathic. If precise modifiable iatrogenic risk factor stratification such as clinician prescribing pattern is clarified, a portion of unnecessary deaths due to cancer may be averted. In addition, if the zolpidem findings of Kao et al¹ are validated, nocturnally consumed pharmacologic agents that promote deep restorative sleep without initiating central sleep apnea can be preferentially prescribed, potentially more safely treating the burden of insomnia and truly enhancing patient care.