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Hypnotic Prescriptions

For cancer patients, sleep can become difficult. A study in the British Medical Journal reported that prescription hypnotic aids (a.k.a. sleeping pills) are associated with an increase in death in those who take them, even in relatively small quantities. The authors reported that between 320,000 to 507,000 excess deaths associated with hypnotics occurred in the U.S. in 2010.

There were 10,529 patients in the treatment cohort and 23,676 in the matched control group.

  • “Receiving hypnotic prescriptions was associated with a greater than threefold increased hazard of death even when prescribed under 18 pills per year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription for patients in poor health did not explain the observed excess mortality” (Kripke 2012).

For people who took hypnotics more than 132 times per year, or about once every three days, the risk of death was 5.32 greater than for those who did not take them at all. Even taking them occasionally was associated with 3.60 times greater risk than not taking them all. There was a strong dose-response association, i.e., the more people took, the greater the risk.

There was also an excess of cancer in those who took the drugs more frequently.

  • “Our study is the 19th epidemiological study showing that hypnotics are significantly associated with excess mortality,” first author, Daniel F. Kripke, of the University of California at San Diego, told Medscape, noting however that it was the first to specify the drugs and to show a dose-response curve. 
  • “Even considering that the epidemiologic studies show association and do not prove causality, the risks look much larger than the benefits,” Kripke added.

The authors concluded:

  • “A higher proportion of females and users 65 years and older received a prescription for sedative-hypnotic/anxiolytic drugs. The indication for their use was unclear in a large number of patients. These findings will help us understand the state of the problem in primary care and inform future strategies for clinical research.

If these data hold up, there is certainly an extraordinarily negative effect from prescription sleep aids, although the mechanism for this effect is still unknown. Hazard ratios were elevated for several of the common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates, and sedative- antihistamines. How so many different drugs could have essentially the same result is part of the mystery. And how even fewer than 18 pills a year could triple one’s risk of death is equally mysterious. This topic deserves to be aggressively studied, to put it mildly.

Non-Pharmaceuticals for Sleep

In the meantime, I think it is prudent for patients (especially cancer patients) to seek non-pharmacological solutions to their sleep problems. As one gets older, it becomes increasingly difficult to sleep the whole night through. And the problem is compounded when one is battling a disease such as cancer, where worries of various sorts conspire with the effects of the disease or its treatment to rob the patient of a good night’s sleep.

This is an area in which complementary medicine has much to offer. First of all, the pineal gland hormone, melatonin, can be quite effective in helping one get to sleep. Because of its demonstrated anticancer effects, many patients take 20 milligrams before bedtime. But 1-3 milligrams may be sufficient for sleep purposes. The main aspect of melatonin is that it can induce vivid or persistent dreams. Patients may also feel groggy or fuzzy-headed after taking it. These effects may wear off over time.

Enter Honokiol for Cancer Patients

Another possibility of a natural sleep aid comes from the bark and seed cone of the magnolia tree,  Magnolia Officinalis. In Traditional Chinese Medicine (TCM) this is known as Hou Po, where it has been known and used for centuries. One highly active component of the bark is a small-molecule polyphenol, known as honokiol. Honokiol is being explored, among other things, for its anti-anxiety effects. Thus, it is not a sleeping pill per se, but reduces the effects of cortisol and therefore has anti-anxiety (anxiolytic) effects. In a product called “Relora®,” a combination of magnolia bark and Phellodendron amurense (Amur cork tree) reduced salivary cortisol by 18%. The combination was found to have the following effects: overall stress (-11%), tension (-13%), depression (-20%), anger (-42%), fatigue (-31%), and confusion (-27%), and higher indices of global mood state (+11%) and vigor (+18%) (Talbott 2013).

Benefits Other than as a Sleep Aid

The most important thing about honokiol is that, unlike prescription sleep aids, it seems to have generally beneficial effects on the body. Scientists are exploring its anti-inflammatory, antithrombosis, and antioxidative effects. It also seems to exert a destructive effect on many kinds of cancer cells. This work is still largely in the laboratory phase, but it presents fascinating leads.

Active against skin, breast, and squamous carcinoma cancer cells

There are presently hundreds of PubMed-listed articles on the effect of honokiol in cancer, but there are few clinical trials. It is active against breast cancer cells. It has also been found to increase the sensitivity of cancer stem cells (CSCs) to ionizing radiation (Ponnurangam 2012). This alone is a huge finding since CSCs are believed to be the most dangerous—and difficult to destroy—components of a tumor. It also works against human skin cancer cells:

  • “These findings indicate that honokiol provides its effects in squamous carcinoma cells by inducing cell cycle arrest at G0/G1 phase and apoptosis” (Chilampalli 2011).

Honokiol also potentiates the effects of the standard drug gemcitabine (Gemzar®) against human pancreatic cancer cells (Arora 2011). Here is another of the numerous instances in which natural agents increase and do not interfere with the effects of conventional treatments. There are many magnolia bark extracts available on the market. There are also now highly purified preparations of honokiol, which seem to have a more powerful and predictable pharmacological action.

References

  • Arora S, Bhardwaj A, Srivastava SK, et al. Honokiol arrests cell cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells. PLoS ONE. 2011;6(6):e21573. Chilampalli C, Guillermo R, Kaushik RS, et al. Honokiol, a chemopreventive agent against skin cancer, induces cell cycle arrest and apoptosis in human epidermoid A431 cells. Exp Biol Med (Maywood). 2011;236(11):1351–1359.
  • Javle M, Curtin NJ. The potential for poly (ADP-ribose) polymerase inhibitors in cancer therapy. Ther Adv Med Oncol. 2001;3:257–267.
  • Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open. 2012 Feb 27;2(1):e000850. doi: 10.1136/bmjopen-2012-000850. PMID: 22371848; PMCID: PMC3293137.
  • Liu X, Shi Y, Maag DX, et al. Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a Bona Fide PARP inhibitor. Clin Cancer Res. 2012 Jan 15;18(2):510–23. Epub 2011 Nov 29.
  • O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011 Jan 20;364(3):205–14. Epub 2011 Jan 5 (2011a). O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2011;29(supp;Abstr 1007) (2011b)
  • Ponnurangam S, Mammen JMV, Ramalingam S, et al. Honokiol in combination with radiation targets Notch signaling to inhibit colon cancer stem cells. Mol Cancer Ther. 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22319203.
  • Randall T. Sanofi lands cancer drug by paying $500 million for 18 people. Bloomberg. June 2009.
  • Talbott SM, Talbott JA, Pugh M. Effect of Magnolia officinalis and Phellodendron amurense (Relora®) on cortisol and psychological mood state in moderately stressed subjects. J Int Soc Sports Nutr. 2013 Aug 7;10(1):37. doi: 10.1186/1550-2783-10-37. PMID: 23924268; PMCID: PMC3750820.

Original Publication 2012, revised 2022.