title: Pharmacological interventions for sleepiness and sleep disturbances caused by shift work.
abstract: BACKGROUND
  Shift work results in sleep-wake disturbances, which cause sleepiness during night shifts and reduce sleep length and quality in daytime sleep after the night shift. In its serious form it is also called shift work sleep disorder. Various pharmacological products are used to ameliorate symptoms of sleepiness or poor sleep length and quality.
  
  
  OBJECTIVE
  To evaluate the effects of pharmacological interventions to reduce sleepiness or to improve alertness at work and decrease sleep disturbances whilst off work, or both, in workers undertaking shift work in their present job and to assess their cost-effectiveness.
  
  
  METHODS
  We searched CENTRAL, MEDLINE, EMBASE, PubMed and PsycINFO up to 20 September 2013 and ClinicalTrials.gov up to July 2013. We also screened reference lists of included trials and relevant reviews.
  
  
  METHODS
  We included all eligible randomised controlled trials (RCTs), including cross-over RCTs, of pharmacological products among workers who were engaged in shift work (including night shifts) in their present jobs and who may or may not have had sleep problems. Primary outcomes were sleep length and sleep quality while off work, alertness and sleepiness, or fatigue at work.
  
  
  METHODS
  Two authors independently selected studies, extracted data and assessed risk of bias in included trials. We performed meta-analyses where appropriate.
  
  
  RESULTS
  We included 15 randomised placebo-controlled trials with 718 participants. Nine trials evaluated the effect of melatonin and two the effect of hypnotics for improving sleep problems. One trial assessed the effect of modafinil, two of armodafinil and one examined caffeine plus naps to decrease sleepiness or to increase alertness.Melatonin (1 to 10 mg) after the night shift may increase sleep length during daytime sleep (mean difference (MD) 24 minutes, 95% confidence interval (CI) 9.8 to 38.9; seven trials, 263 participants, low quality evidence) and night-time sleep (MD 17 minutes, 95% CI 3.71 to 30.22; three trials, 234 participants, low quality evidence) compared to placebo. We did not find a dose-response effect. Melatonin may lead to similar sleep latency times as placebo (MD 0.37minutes, 95% CI - 1.55 to 2.29; five trials, 74 participants, low quality evidence).Hypnotic medication, zopiclone, did not result in significantly longer daytime sleep length compared to placebo in one low quality trial and we could not use the data from the study on lormetazepam.Armodafinil taken before the night shift probably reduces sleepiness by one point on the Karolinska Sleepiness Scale (KSS) (MD -0.99, 95% CI -1.32 to -0.67; range 1 to 10; two trials, 572 participants, moderate quality evidence) and increases alertness by 50 ms in a simple reaction time test (MD -50.0, 95% CI -85.5 to -15.5) at three months' follow-up in shift work sleep disorder patients. Modafinil probably has similar effects on sleepiness (KSS) (MD -0.90, 95% CI -1.45 to -0.35; one trial, 183 participants, moderate quality evidence) and alertness in the psychomotor vigilance test in the same patient group. Post-marketing, severe skin reactions have been reported. Adverse effects reported by trial participants were headache, nausea and a rise in blood pressure. There were no trials in non-patient shift workers.Based on one trial, caffeine plus pre-shift naps taken before the night shift decreased sleepiness (KSS) (MD -0.63, 95% CI -1.09 to -0.17).We judged most trials to have a low risk of bias even though the randomisation method and allocation concealment were often not described.
  
  
  CONCLUSIONS
  There is low quality evidence that melatonin improves sleep length after a night shift but not other sleep quality parameters. Both modafinil and armodafinil increase alertness and reduce sleepiness to some extent in employees who suffer from shift work sleep disorder but they are associated with adverse events. Caffeine plus naps reduces sleepiness during the night shift, but the quality of evidence is low. Based on one low quality trial, hypnotics did not improve sleep length and quality after a night shift.We need more and better quality trials on the beneficial and adverse effects and costs of all pharmacological agents that induce sleep or promote alertness in shift workers both with and without a diagnosis of shift work sleep disorder. We also need systematic reviews of their adverse effects.
authors.affiliation: Research and Development in Occupational Health Services, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, Helsinki, Finland, FI-00250.
authors.forename: Juha
authors.initials: J
authors.lastname: Liira
authors.forename: Jos H
authors.initials: JH
authors.lastname: Verbeek
authors.forename: Giovanni
authors.initials: G
authors.lastname: Costa
authors.forename: Tim R
authors.initials: TR
authors.lastname: Driscoll
authors.forename: Mikael
authors.initials: M
authors.lastname: Sallinen
authors.forename: Leena K
authors.initials: LK
authors.lastname: Isotalo
authors.forename: Jani H
authors.initials: JH
authors.lastname: Ruotsalainen
mesh_terms: D053961:Azabicyclo Compounds / Q000627:therapeutic use; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D002110:Caffeine / Q000627:therapeutic use; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D008550:Melatonin / Q000627:therapeutic use*; D000077408:Modafinil; D010879:Piperazines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012890:Sleep / Q000187:drug effects* / Q000502:physiology; D020178:Sleep Disorders, Circadian Rhythm / Q000188:drug therapy*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology; D064690:Wakefulness-Promoting Agents / Q000627:therapeutic use*
chemical_list: D053961:Azabicyclo Compounds; D001559:Benzhydryl Compounds; D006993:Hypnotics and Sedatives; D010879:Piperazines; D064690:Wakefulness-Promoting Agents; C515050:zopiclone; D002110:Caffeine; D008550:Melatonin; D000077408:Modafinil
references.citation: Am J Emerg Med. 2011 Nov;29(9):1034-6.e1
references.pmid: 20708878
references.citation: Scand J Work Environ Health. 1998;24 Suppl 3:18-27
references.pmid: 9916813
references.citation: Prim Care Companion J Clin Psychiatry. 2007;9(3):188-94
references.pmid: 17632651
references.citation: J Sleep Res. 2001 Sep;10(3):181-92
references.pmid: 11696071
references.citation: J Sleep Res. 2002 Jun;11(2):141-51
references.pmid: 12028479
references.citation: Pharmacol Rep. 2009 May-Jun;61(3):383-410
references.pmid: 19605939
references.citation: Ann Emerg Med. 1998 Jun;31(6):699-704
references.pmid: 9624308
references.citation: Aviat Space Environ Med. 2005 Jul;76(7):647-54
references.pmid: 16018347
references.citation: BMJ. 2006 Feb 18;332(7538):385-93
references.pmid: 16473858
references.citation: Chronobiol Int. 2008 Apr;25(2):413-23
references.pmid: 18484371
references.citation: Aviat Space Environ Med. 1997 Aug;68(8):688-94
references.pmid: 9262809
references.citation: J Clin Psychiatry. 2006 Apr;67(4):554-66
references.pmid: 16669720
references.citation: J Clin Sleep Med. 2007 Oct 15;3(6):595-602
references.pmid: 17993041
references.citation: Sleep. 1995 Jan;18(1):11-21
references.pmid: 7761738
references.citation: Chronobiol Int. 2002 Sep;19(5):915-36
references.pmid: 12405554
references.citation: J Clin Sleep Med. 2010 Oct 15;6(5):458-66
references.pmid: 20957846
references.citation: Neuropsychobiology. 2005;51(1):16-27
references.pmid: 15627809
references.citation: Lancet Oncol. 2007 Dec;8(12):1065-6
references.pmid: 19271347
references.citation: Sleep. 2007 Nov;30(11):1445-59
references.pmid: 18041479
references.citation: Int J Psychophysiol. 2001 Jul;41(3):251-63
references.pmid: 11448507
references.citation: Aviat Space Environ Med. 2003 Feb;74(2):153-63
references.pmid: 12602447
references.citation: Sleep. 2004 May 1;27(3):434-9
references.pmid: 15164895
references.citation: Sleep. 2006 Jan;29(1):39-50
references.pmid: 16453980
references.citation: N Engl J Med. 2005 Aug 4;353(5):519-21
references.pmid: 16079378
references.citation: Cochrane Database Syst Rev. 2002;(2):CD001520
references.pmid: 12076414
references.citation: Curr Med Chem. 2010;17(19):2070-95
references.pmid: 20423309
references.citation: Neuropsychopharmacology. 2006 Jul;31(7):1526-36
references.pmid: 16395298
references.citation: Sleep Med. 2012 Apr;13(4):335-41
references.pmid: 22353444
references.citation: Sleep Med Rev. 2013 Feb;17(1):41-54
references.pmid: 22560640
references.citation: Ann Emerg Med. 1998 Sep;32(3 Pt 1):334-40
references.pmid: 9737496
references.citation: Physiol Behav. 2006 May 30;87(5):925-31
references.pmid: 16574171
references.citation: Ann Thorac Surg. 2000 Feb;69(2):663
references.pmid: 10735731
references.citation: Ambul Pediatr. 2005 May-Jun;5(3):172-7
references.pmid: 15913411
references.citation: Pharmacol Biochem Behav. 2005 Jul;81(3):559-68
references.pmid: 15936062
references.citation: Occup Med (Lond). 2003 Mar;53(2):95-101
references.pmid: 12637593
references.citation: Semin Clin Neuropsychiatry. 2001 Oct;6(4):295-307
references.pmid: 11607924
references.citation: Neuropsychobiology. 1993;27(4):217-23
references.pmid: 8232842
references.citation: J Sleep Res. 2003 Jun;12(2):103-12
references.pmid: 12753347
references.citation: Cochrane Database Syst Rev. 2010 May 12;(5):CD008508
references.pmid: 20464765
references.citation: Scand J Work Environ Health. 2009 May;35(3):193-202
references.pmid: 19436924
references.citation: J Sleep Res. 1997 Mar;6(1):26-35
references.pmid: 9125696
references.citation: Sleep Med Rev. 2007 Jun;11(3):179-94
references.pmid: 17418596
references.citation: J Biol Rhythms. 2003 Dec;18(6):513-23
references.pmid: 14667152
references.citation: Sleep. 2004 Dec 15;27(8):1453-62
references.pmid: 15683134
references.citation: Acad Emerg Med. 2000 Aug;7(8):955-8
references.pmid: 10958143
references.citation: Rev Neurol (Paris). 2002 Nov;158(11):1102-6
references.pmid: 12451343
references.citation: Aviat Space Environ Med. 2002 Apr;73(4):341-50
references.pmid: 11952054
references.citation: Sleep Med. 2009 Oct;10(9):1016-24
references.pmid: 19342294
references.citation: Mayo Clin Proc. 2009 Nov;84(11):958-72
references.pmid: 19880686
references.citation: Neuropsychopharmacology. 2010 Aug;35(9):1910-20
references.pmid: 20505660
references.citation: Sleep Med. 2008 Sep;9 Suppl 1:S10-7
references.pmid: 18929313
references.citation: Med Klin Prax. 1982 Apr 9;77(8):52-5
references.pmid: 6123070
references.citation: Chronobiol Int. 2002 Sep;19(5):903-13
references.pmid: 12405553
references.citation: Chronobiol Int. 1993 Oct;10(5):315-20
references.pmid: 8261530
references.citation: Psychopharmacology (Berl). 1990;101(2):271-3
references.pmid: 2349369
references.citation: J Clin Sleep Med. 2010 Dec 15;6(6):565-71
references.pmid: 21206545
references.citation: Sleep. 1995 Jan;18(1):22-9
references.pmid: 7761739
references.citation: Scand J Work Environ Health. 2007 Jun;33(3):204-14
references.pmid: 17572830
references.citation: J Circadian Rhythms. 2008 Oct 29;6:10
references.pmid: 18957133
references.citation: Occup Med (Lond). 2003 Mar;53(2):83-8
references.pmid: 12637591
references.citation: Int J Neurosci. 1990 May;52(1-2):29-37
references.pmid: 2265922
references.citation: Sleep. 1984;7(3):223-9
references.pmid: 6148784
references.citation: J Occup Environ Med. 2011 Dec;53(12):1460-5
references.pmid: 22104981
references.citation: Sleep. 1991 Apr;14(2):140-6
references.pmid: 1866527
references.citation: Drugs. 2008;68(13):1803-39
references.pmid: 18729534
references.citation: Cochrane Database Syst Rev. 2014 Aug 12;(8):CD009776
references.pmid: 25113164
references.citation: Am J Emerg Med. 1998 Jul;16(4):367-70
references.pmid: 9672452
references.citation: Therapie. 1994 Mar-Apr;49(2):107-12
references.pmid: 7817332
references.citation: Am J Addict. 2012 Nov-Dec;21(6):576-7
references.pmid: 23082842
references.citation: Aviat Space Environ Med. 2007 Oct;78(10):937-43
references.pmid: 17955941
references.citation: Chronobiol Int. 2008 Apr;25(2):333-48
references.pmid: 18484368
references.citation: J Sleep Res. 2001 Dec;10(4):265-76
references.pmid: 11903856
references.citation: Aviat Space Environ Med. 2004 Aug;75(8):666-72
references.pmid: 15328782
references.citation: Ergonomics. 1994 Jun;37(6):1009-20
references.pmid: 8026448
references.citation: Chronobiol Int. 2006;23(5):973-83
references.pmid: 17050212
references.citation: Ann Clin Psychiatry. 2004 Apr-Jun;16(2):101-9
references.pmid: 15328903
references.citation: Chronobiol Int. 2005;22(5):873-88
references.pmid: 16298773
references.citation: Chronobiol Int. 2004;21(6):831-44
references.pmid: 15646231
references.citation: Acad Emerg Med. 2006 Feb;13(2):158-65
references.pmid: 16436796
references.citation: Prim Care. 2000 Dec;27(4):1057-79
references.pmid: 11072299
references.citation: N Engl J Med. 2005 Aug 4;353(5):476-86
references.pmid: 16079371
references.citation: Percept Mot Skills. 1979 Apr;48(2):495-506
references.pmid: 461051
references.citation: BMJ. 2003 Sep 6;327(7414):557-60
references.pmid: 12958120