As aging comes , an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negatively impact sleep. Fortunately, good quality sleep can improve pain management. Because benzodiazepine receptor agonists (including the “Z” drugs) can reduce anxiety and improve sleep, they seem a convenient choice. However, their use in this population, particularly for more than short-term (guidelines range from 2 to 6 weeks max), is not recommended because of increased likelihood of falls, further disruption of sleep, dependence, and problems with discontinuation (withdrawal). Besides , this population is often likely to tak e concomitant medication for pain or other central nervous system depressants leading to potentially serious and even life-th reatening interactions involving synergistic amplification of respiratory depression (opioids being a particularly dangerous interaction). Therefore, insomnia in older adults should ideally be treated with a non-benzodiazepine receptor agonist; if indicated, they may be used, but should be closely monitored and tapered to avoid long-term adverse problems (direct or from withdrawal). Older adult patients with insomnia may be more optimally treated with sleep aids that do not interact with the GABA A receptor.
Roberts, M. and Drummond, P. (2016) Sleep Problems are Associated with Chronic Pain over and above Mutual Associations with Depression and Catastrophizing. The Clinical Journal of Pain, 32, 792-799. https://journals.lww.com/clinicalpain/pages/articleviewer.aspx?year=2016&issue=09000&article =00007&type=abstract https://doi.org/10.1097/AJP.0000000000000329
Dragioti, E., Bernfort, L., Larsson, B., Gerdle, B. and Levin, L.A. (2018) Association of Insomnia Severity with Well-Being, Quality of Life and Health Care Costs: A Cross-Sectional Study in Older Adults with Chronic Pain (PainS65+). European Journal of Pain, 22, 414-425. https://onlinelibrary.wiley.com/doi/abs/10.1002/ejp.1130 https://doi.org/10.1002/ejp.1130
Schroeck, J.L., et al. (2016) Review of Safety and Efficacy of Sleep Medicines in Older Adults. Clinical Therapeutics, 38, 2340-2372. https://www.clinicaltherapeutics.com/article/S0149-2918(16)30733-0/fulltext https://doi.org/10.1016/j.clinthera.2016.09.010
Expert Panel (2012) American Geriatrics Society updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society, 6, 616-631. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1532-5415.2012.03923.x
National Institutes of Health (2014) Despite Risks, Benzodiazepine Use Highest in Older People. National Institutes of Health, Washington DC. https://www.nih.gov/news-events/news-releases/despite-risks-benzodiazepine-use-highest -older-people
Maust, D.T., Blow, F.C., Wiechers, I.R., Kales, H.C. and Marcus, S.C. (2017) National Trends in Antidepressant, Benzodiazepine, and Other Sedative-Hypnotic Treatment of Older Adults in Psychiatric and Primary Care. Journal of Clinical Psychiatry, 78, e363-e371. https://www.psychiatrist.com/jcp/article/Pages/2017/v78n04/v78n0401.aspx
Maust, D.T., Kales, H.C., Wiechers, I.R., Blow, F.C. and Olfson, M. (2016) No End in Sight: Benzodiazepine Use in Older Adults in the United States. Journal of the American Geriatrics Society, 64, 2546-2553. https://onlinelibrary.wiley.com/doi/abs/10.1111/jgs.14379 https://doi.org/10.1111/jgs.14379
Barnard, E., et al. (1998) International Union of Pharmacology. XV. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Structure and Receptor Function. Pharmacological Reviews, 50, 291-314. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847512/pdf/nihms187538.pdf
Sieghart, W. (1994) Pharmacology of Benzodiazepine Receptors: An Update. Journal of Psychiatry and Neuroscience, 19, 24-29. http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC1188559&blobtype=pdf
Costa, E., Guidotti, A., Mao, C.C. and Suria, A. (1975) New Concepts on the Mechanism of Action of Benzodiazepines. Life Sciences, 17, 167-185. https://www.sciencedirect.com/science/article/abs/pii/0024320575905019 https://doi.org/10.1016/0024-3205(75)90501-9
Haefely, W., Kulcsar, A. and Mohler, H. (1975) Possible Involvement of GABA in the Central Actions of Benzodiazepines. Psychopharmacology Bulletin, 11, 58-59. https://www.ncbi.nlm.nih.gov/pubmed/242199
Haefely, W. (1985) Pharmacology of Benzodiazepine Antagonists. Pharmacopsychiatry, 18, 163-166. https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-2007-1017356.pdf https://doi.org/10.1055/s-2007-1017356
Soyka, M. (2017) Treatment of Benzodiazepine Dependence. New England Journal of Medicine, 376, 1147-1157. https://www.nejm.org/doi/full/10.1056/NEJMra1611832 https://doi.org/10.1056/NEJMra1611832
Zezula, J., Cortes, R., Probst, A. and Palacios, J.M. (1988) Benzodiazepine Receptor Sites in the Human Brain: Autoradiographic Mapping. Neuroscience, 25, 771-795. https://www.sciencedirect.com/science/article/abs/pii/030645228890036X?via%3Dihub
Möhler, H. and Okada, T. (1977) Benzodiazepine Receptor: Demonstration in the Central Nervous System. Science, 198, 849-851. http://science.sciencemag.org/content/198/4319/849.long https://doi.org/10.1126/science.918669
Squires, R.F. and Braestrup, C. (1977) Benzodiazepine Receptors in Rat Brain. Nature, 266, 732-734. https://www.nature.com/articles/266732a0
McEnery, M.W., Snowman, A.M., Trifiletti, R.R. and Snyder, S.H. (1992) Isolation of the Mitochondrial Benzodiazepine receptor: Association with the Voltage-Dependent Anion Channel and the Adenine Nucleotide Carrier. Proceedings of the National Academy of Sciences of the United States of America, 89, 3170-3174. https://www.pnas.org/content/89/8/3170 https://doi.org/10.1073/pnas.89.8.3170
Tu, L.N., et al. (2014) Peripheral Benzodiazepine Receptor/Translocator Protein Global Knock-Out Mice Are Viable with No Effects on Steroid Hormone Biosynthesis. Journal of Biological Chemistry, 289, 27444-27454. http://www.jbc.org/content/289/40/27444 https://doi.org/10.1074/jbc.M114.578286
Endres, C.J., Coughlin, J.M., Gage, K.L., Watkins, C.C., Kassiou, M. and Pomper, M.G. (2012) Radiation Dosimetry and Biodistribution of the TSPO Ligand 11C-DPA-713 in Humans. Journal of Nuclear Medicine, 53, 330-335. http://jnm.snmjournals.org/content/53/2/330 https://doi.org/10.2967/jnumed.111.094565
Anonymous (2009) Drugs for Insomnia. Medical Letter, 7, 23-26. https://flexiblelearning.auckland.ac.nz/pharmacy735/16/guide-medlet09.pdf
Buffett-Jerrott, S.E. and Stewart, S.H. (2002) Cognitive and Sedative Effects of Benzodiazepine Use. Current Pharmaceutical Design, 8, 45-58. http://www.eurekaselect.com/64616/article https://doi.org/10.2174/1381612023396654
Lader, M., Tylee, A. and Donoghue, J. (2009) Withdrawing Benzodiazepines in Primary Care. CNS Drugs, 23, 19-34. https://www.ncbi.nlm.nih.gov/pubmed/19062773
Mura, T., et al. (2013) Chronic Use of Benzodiazepines and Latent Cognitive Decline in the Elderly: Results from the Three-City Study. European Neuropsychopharmacology, 23, 212-223. https://www.sciencedirect.com/science/article/pii/S0924977X12001393?via%3Dihub https://doi.org/10.1016/j.euroneuro.2012.05.004
Pariente, A., de Gage, S.B., Moore, N. and Begaud, B. (2016) The Benzodiazepine-Dementia Disorders Link: Current State of Knowledge. CNS Drugs, 30, 1-7. https://link.springer.com/article/10.1007%2Fs40263-015-0305-4 https://doi.org/10.1007/s40263-015-0305-4
Gustavsen, I., Bramness, J., Skurtveit, S., Engeland, A., Neutel, I. and Morland, J. (2008) Road Traffic Accident Risk Related to Prescriptions of the Hypnotics Zopiclone, Zolpidem, Flunitrazepam, and Nitrazepam. Sleep Medicine, 9, 818-822. https://www.sciencedirect.com/science/article/pii/S1389945707004248?via%3Dihub https://doi.org/10.1016/j.sleep.2007.11.011
Smink, B.E., Egberts, A.C., Lusthof, K.J., Uges, D.R. and de Gier, J.J. (2010) The Relationship between Benzodiazepine Use and Traffic Accidents: A Systematic Literature Review. CNS Drugs, 24, 639-653. https://link.springer.com/article/10.2165%2F11533170-000000000-00000 https://doi.org/10.2165/11533170-000000000-00000
Wagner, A.K., et al. (2004) Benzodiazepine Use and Hip Fractures in the Elderly: Who Is at Greatest Risk? Archives of Internal Medicine, 164, 1567-1572. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/217249
Koyama, A., Steinman, M., Ensrud, K., Hillier, T.A. and Yaffe, K. (2013) Ten-Year Trajectory of Potentially Inappropriate Medications in Very Old Women: Importance of Cognitive Status. Journal of the American Geriatrics Society, 61, 258-263. https://doi.org/10.1111/jgs.12093 https://onlinelibrary.wiley.com/doi/abs/10.1111/jgs.12093
Pisani, M.A., Murphy, T.E., Araujo, K.L., Slattum, P., Van Ness, P.H. and Inouye, S.K. (2009) Benzodiazepine and Opioid Use and the Duration of Intensive Care Unit Delirium in an Older Population. Critical Care Medicine, 37, 177-183. https://insights.ovid.com/crossref?an=00003246-200901000-00026 https://doi.org/10.1097/CCM.0b013e318192fcf9
Berryman, S.N., Jennings, J., Ragsdale, S., Lofton, T., Huff, D.C. and Rooker, J.S. (2012) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Medical-Surgical Nursing, 21, 129-132. https://www.ncbi.nlm.nih.gov/pubmed/22866431
FDA (2016) FDA Requires Strong Warnings for Opioid Analgesics, Prescription Opioid Cough Products, and Benzodiazepine Labeling Related to Serious Risks and Death from Combined Use. Food and Drug Administration, Rockville. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518697.htm
Vukcevic, N.P., Ercegovic, G.V., Segrt, Z., Djordjevic, S. and Stosic, J.J. (2016) Benzodiazepine Poisoning in Elderly. Vojnosanitetski Pregled, 73, 234-238. http://www.vsp.mod.gov.rs/casopis/106/VSP_1_2017.pdf https://doi.org/10.2298/VSP141208025P
Carrière, I., et al. (2015) Elderly Benzodiazepine Users at Increased Risk of Activity Limitations: Influence of Chronicity, Indications, and Duration of Action—The Three-City Cohort. American Journal of Geriatric Psychiatry, 23, 40-51. https://www.sciencedirect.com/science/article/pii/S1064748114003169?via%3Dihub https://doi.org/10.1016/j.jagp.2014.10.006
Borbely, A.A. (1982) A Two Process Model of Sleep Regulation. Human Neurobiology, 1, 195-204. https://www.ncbi.nlm.nih.gov/pubmed/7185792
Krystal, A.D., Benca, R.M. and Kilduff, T.S. (2013) Understanding the Sleep-Wake Cycle: Sleep, Insomnia, and the Orexin System. Journal of Clinical Psychiatry, 74, 3-20. https://www.psychiatrist.com/JCP/article/Pages/2013/v74s01/v74s0101.aspx https://doi.org/10.4088/JCP.13011su1c
Peyron, C., et al. (1998) Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems. Journal of Neuroscience, 18, 9996-10015. http://www.jneurosci.org/content/18/23/9996.long https://doi.org/10.1523/JNEUROSCI.18-23-09996.1998
Saper, C.B., Cano, G. and Scammell, T.E. (2005) Homeostatic, Circadian, and Emotional Regulation of Sleep. Journal of Comparative Neurology, 493, 92-98. https://onlinelibrary.wiley.com/doi/abs/10.1002/cne.20770 https://doi.org/10.1002/cne.20770
Zeitzer, J.M., Nishino, S. and Mignot, E. (2006) The Neurobiology of Hypocretins (Orexins), Narcolepsy and Related Therapeutic Interventions. Trends in Pharmacological Sciences, 27, 368-374. https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(06)00130-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve %2Fpii%2FS0165614706001301%3Fshowall%3Dtrue https://doi.org/10.1016/j.tips.2006.05.006
Morgan, P.T., et al. (2012) Cortical GABA Levels in Primary Insomnia. Sleep, 35, 807-814. https://academic.oup.com/sleep/article/35/6/807/2709385 https://doi.org/10.5665/sleep.1880
Brisbare-Roch, C., et al. (2007) Promotion of Sleep by Targeting the Orexin System in Rats, Dogs and Humans. Nature Medicine, 13, 150-155. https://www.nature.com/articles/nm1544 https://doi.org/10.1038/nm1544
Johnson, B. and Streltzer, J. (2013) Risks Associated with Long-Term Benzodiazepine use. American Family Physician, 88, 224-225. https://pdfs.semanticscholar.org/94db/522d12555fdcae33baa58e2518a6bdff863e.pdf
Bain, K.T. (2006) Management of Chronic Insomnia in Elderly Persons. American Journal of Geriatric Pharmacotherapy, 4, 168-192. https://www.sciencedirect.com/science/article/abs/pii/S1543594606000286?via%3Dihub https://doi.org/10.1016/j.amjopharm.2006.06.006
Dowell, D., Haegerich, T. and Chou, R. (2016) CDC Guideline for Prescribing Opioids for Chronic Pain United States, 2016. Journal of the Medical Association, 315, 1624-1645. https://jamanetwork.com/journals/jama/fullarticle/2503508
American Geriatrics Society (2015) Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society, 63, 2227-4226. https://onlinelibrary.wiley.com/doi/full/10.1111/jgs.13702
Winkelman, J.W. (2015) Insomnia Disorder. New England Journal of Medicine, 373, 1437-1444. https://www.nejm.org/doi/full/10.1056/NEJMcp1412740 https://doi.org/10.1056/NEJMcp1412740
Bramoweth, A.D., et al. (2016) Deconstructing Chronic Low Back Pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment: Part VII: Insomnia. Pain Medicine, 17, 851-863. https://academic.oup.com/painmedicine/article/17/5/851/1753061 https://doi.org/10.1093/pm/pnw063
Asnis, G.M., Thomas, M. and Henderson, M.A. (2016) Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians. International Journal of Molecular Sciences, 17, 50. https://www.mdpi.com/1422-0067/17/1/50
Michelson, D., et al. (2014) Safety and Efficacy of Suvorexant during 1-Year Treatment of Insomnia with Subsequent Abrupt Treatment Discontinuation: A Phase 3 Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Neurology, 13, 461-471. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(14)70053-5/fulltext
Keks, N.A., Hope, J. and Keogh, S. (2017) Suvorexant: Scientifically Interesting, Utility Uncertain. Australasian Psychiatry, 25, 622-624. https://journals.sagepub.com/doi/abs/10.1177/1039856217734677?journalCode=apya https://doi.org/10.1177/1039856217734677
Keating, G.M. (2016) Tasimelteon: A Review in Non-24-Hour Sleep-Wake Disorder in Totally Blind Individuals. CNS Drugs, 30, 461-468. https://link.springer.com/article/10.1007%2Fs40263-016-0330-y https://doi.org/10.1007/s40263-016-0330-y
Williams 3rd, W.P., McLin 3rd, D.E., Dressman, M.A. and Neubauer, D.N. (2016) Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders. Pharmacotherapy, 36, 1028-1041. https://accpjournals.onlinelibrary.wiley.com/doi/full/10.1002/phar.1822 https://doi.org/10.1002/phar.1822
Reddy, A., Puvvada, S.C., Kommisetti, S., El-Mallakh, R.S. and Lippmann, S. (2015) Suvorexant: Something New for Sleep? Acta Neuropsychiatrica, 27, 53-55. https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/suvorexant-something-new-for-sleep/2D3602EC0A761E88A2C996E6AE27781A
Kuriyama, A. and Tabata, H. (2017) Suvorexant for the Treatment of Primary Insomnia: A Systematic Review and Meta-Analysis. Sleep Medicine Reviews, 35, 1-7. https://www.sciencedirect.com/science/article/pii/S108707921630096X?via%3Dihub
Neubauer, D.N. (2008) A Review of Ramelteon in the Treatment of Sleep Disorders. Neuropsychiatric Disease and Treatment, 4, 69-79. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515902/ https://doi.org/10.2147/NDT.S483
Lockley, S.W., et al. (2015) Tasimelteon for Non-24-Hour Sleep-Wake Disorder in Totally Blind People (SET and RESET): Two Multicentre, Randomised, Double-Masked, Placebo-Controlled Phase 3 Trials. The Lancet, 386, 1754-1764. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60031-9/fulltext https://doi.org/10.1016/S0140-6736(15)60031-9
McCleery, J., Cohen, D.A. and Sharpley, A.L. (2016) Pharmacotherapies for Sleep Disturbances in Dementia. Cochrane Database of Systematic Reviews, 11, Cd009178. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD009178.pub3/full
Schutte-Rodin, S., Broch, L., Buysse, D., Dorsey, C. and Sateia, M. (2008) Clinical Guideline for the Evaluation and Management of Chronic Insomnia in Adults. Journal of Clinical Sleep Medicine, 4, 487-504. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2576317/pdf/jcsm.4.5.487.pdf
Siegel, S. (2005) Drug Tolerance, Drug Addiction, and Drug Anticipation. Current Directions in Psychological Science, 14, 296-300. https://journals.sagepub.com/doi/abs/10.1111/j.0963-7214.2005.00384.x https://doi.org/10.1111/j.0963-7214.2005.00384.x
Ramsay, D.S. and Woods, S.C. (1997) Biological Consequences of Drug Administration: Implications for Acute and Chronic Tolerance. Psychological Review, 104, 170-193. https://www.ncbi.nlm.nih.gov/pubmed/9009884
Nitsche, J.F., Schuller, A.G.P., King, M.A., Zengh, M., Pasternak, G.W. and Pintar, J.E. (2002) Genetic Dissociation of Opiate Tolerance and Physical Dependence in δ-Opioid Receptor-1 and Preproenkephalin Knock-Out Mice. Journal of Neuroscience, 22, 10906-2002. http://www.jneurosci.org/content/22/24/10906.long
Baldwin, D.S., Aitchison, K., Bateson, A., Curran, H.V., Davies, S., Leonard, B., Nutt, D.J., Stephens, D.N. and Wilson, S. (2013) Benzodiazepines: Risks and Benefits. A Reconsideration. Journal of Psychopharmacology, 27, 967-971. https://journals.sagepub.com/doi/abs/10.1177/0269881113503509?journalCode=jopa https://doi.org/10.1177/0269881113503509
Lembke, A., Papac, J. and Humphreys, K. (2018) Our Other Prescription Drug Problem. New England Journal of Medicine, 378, 693-695. https://www.nejm.org/doi/10.1056/NEJMp1715050 https://doi.org/10.1056/NEJMp1715050
Pétursson, H. (1994) The Benzodiazepine Withdrawal Syndrome. Addiction, 89, 1455-1459. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1360-0443.1994.tb03743.x https://doi.org/10.1111/j.1360-0443.1994.tb03743.x
Robinson, T.E. and Berridge, K.C. (1993) The Neural Basis of Drug Craving: An Incentive-Sensitization Theory of Addiction. Brain Research Reviews, 18, 247-291. https://www.sciencedirect.com/science/article/pii/016501739390013P?via%3Dihub
Ashton, C.H. (2002) Benzodiazepines: How They Work and How to Withdraw. https://www.benzo.org.uk/manual/