Αϋπνία. Τα φάρμακα βοηθούν;

[Θανάσης Αποστόλου]

Εδώ και πολύ καιρό μελετάω την αϋπνία, η οποία είναι και ένα συχνό σύμπτωμα της διακοπής του καπνίσματος που ευτυχώς δεν κρατά πάνω από λίγες εβδομάδες. Σε αυτό το θέμα, θα συγκεντρώσω επιλεγμένα αποσπάσματα ειδικών, στο θέμα των φαρμάκων κατά της αϋπνίας και στο αν αξίζει να τα λαμβάνει κάποιος.

Μετά από αρκετή μελέτη, είμαι βέβαιος ότι η καταφυγή στα φάρμακα για την αντιμετώπιση της αϋπνίας είναι η χειρότερη επιλογή, εκτός από ελάχιστες περιπτώσεις, και μόνο ως προσωρινό μέτρο. Ακόμα κι όταν τα χάπια βοηθούν, οι παρενέργειές τους προκαλούν ίδια ή και μεγαλύτερη δυσφορία με τη δυσφορία που προκαλεί ο κακός ύπνος. Δώρο άδωρο δηλαδή... Από την άλλη βέβαια, θα πρέπει να τονίσουμε ότι μία βαριά χρήση φαρμάκων για την αϋπνία καλό είναι να μην διακόπτεται απότομα, αλλά σταδιακά, και με καθοδήγηση γιατρού.

Σημείωση: Στο παρόν θέμα παρουσιάζεται κυρίως η αρνητική πλευρά των υπναγωγών φαρμάκων. Σαφώς υπάρχει και ωφέλιμη χρήση σε λίγες περιπτώσεις, όπως η βραχυπρόθεσμη χορήγηση σε έντονες περιπτώσεις jet lag, η ολιγοήμερη χορήγηση για να αποφευχθεί η μετατροπή μίας παροδικής αϋπνίας (πχ. λόγω τραυματικού γεγονότος όπως ένας θάνατος αγαπημένου προσώπου) σε χρόνια, ή σε περιπτώσεις έντονων πόνων και ασθενειών που εμποδίζουν τον ύπνο. Πάντως ακόμα και σε περιπτώσεις που ενδύκεινται, θα πρέπει να είναι η τελευταία λύση.

Το βασικό πρόβλημα τω υπναγωγών χαπιών είναι οι ενοχλητικές (και μερικές φορές επικίνδυνες) παρενέργειές τους, η εξάρτηση που προκαλούν και μακροπρόθεσμα (με τη διακοπή τους) η επιδείνωση της αϋπνίας. Επίσης έχει βρεθεί ότι ο ύπνος που επιβάλεται χημικά από ένα χάπι, είναι διαφορετικής φύσης και σίγουρα κατώτερης ποιότητας από τον φυσικό ύπνο.

Το απόσπασμα που ακολουθεί προέρχεται από άρθρο της ιατρού  Ιωάννας Ρέβελα (πηγή: in.gr)

Για την αντιμετώπιση της αϋπνίας χρησιμοποιούντα δύο μεγάλες κατηγορίες φαρμάκων: Οι βενζοδιαζεπίνες που διακρίνονται σε βραχείας και σε μακράς δράσης και τα υπναγωγά μη βενζοδιαζεπινικά νεότερα φάρμακα.

Αυτά τα φάρμακα δεν θεραπεύουν την αιτία που προκαλεί την αϋπνία αλλά προκαλούν μόνο παροδική ανακούφιση της με τις μυοχαλαρωτικές, αγχολυτικές και υπναγωγές ιδιότητες τους. Ο οργανισμός όμως μέσα σε σύντομο χρονικό διάστημα, περίπου δύο με τέσσερις εβδομάδες, συνηθίζει στα φάρμακα αυτά και έτσι χάνεται το μεγαλύτερο μέρος της αποτελεσματικότητας τους.

Για ορισμένους ασθενείς που πάσχουν από καρδιακά προβλήματα, αναπνευστικά προβλήματα και ψυχωσικές διαταραχές μπορεί τα υπνωτικά να είναι ιδιαίτερα επικίνδυνα. Ακόμη και για τους ασθενείς που δεν έχουν άλλο ιατρικό οργανικό πρόβλημα τα υπνωτικά χάπια μπορούν να εμφανίσουν πολλές ανεπιθύμητες ενέργειες.

Το ενδεχόμενο της σωματικής και ψυχικής εξάρτησης θα πρέπει να λαμβάνεται σοβαρά υπόψη μετά από τη χρήση αυτών των φαρμάκων μετά από μόλις δύο εβδομάδες συνεχούς λήψης. Ο κίνδυνος εξάρτησης αυξάνεται σε συνάρτηση με τη δόση και τη διάρκεια της αγωγής.

Από τη στιγμή που έχει αναπτυχθεί σωματική εξάρτηση, η απότομη διακοπή της αγωγής συνοδεύεται από συμπτώματα στέρησης. Αυτά μπορεί να είναι πολύ σοβαρά και να κυμαίνονται από πονοκέφαλο, μυϊκούς πόνους, άγχος, ευερεθιστότητα, ανησυχία, ταχυκαρδία, υπέρταση, ναυτία, κοιλιακά συμπτώματα έως την εμφάνιση παραισθήσεων, ψευδαισθήσεων και επιληπτικών κρίσεων.

Αν τα υπνωτικά φάρμακα διακοπούν απότομα, ακόμα και μετά από μικρό χρονικό διάστημα, τότε μπορεί να επανεμφανιστεί αϋπνία και άγχος σε εντονότερη μορφή από την αρχική (φαινόμενο rebound).

Η ταυτόχρονη πρόσληψη οινοπνευματωδών ποτών απαγορεύεται καθώς το αλκοόλ αλληλεπιδρά και αυξάνει την κατασταλτική δράση των υπνωτικών. Επίσης προσοχή χρειάζεται σε περιπτώσεις λήψης και άλλων φαρμάκων. Υπάρχουν φάρμακα που ενισχύουν τη δράση των υπνωτικών, όπως είναι τα αντιισταμινικά και ουσίες που επιβραδύνουν το μεταβολισμό τους, όπως τα αντιπηκτικά τα οποία παρατείνουν τη δράση τους.

Άλλες ανεπιθύμητες επιδράσεις είναι οι γαστρεντερικές διαταραχές, η ελάττωση της libido, οι δερματικές ή οι αλλεργικές αντιδράσεις, η υπνηλία κατά τη διάρκεια της ημέρας, και η αμνησία. Η τελευταία μπορεί να εμφανιστεί μερικές ώρες μετά από τη λήψη των υπνωτικών. Επίσης τα βραχείας δράσης υπναγωγά μπορούν να προκαλέσουν πρώιμη αφύπνιση και πρωινό άγχος την επόμενη μέρα της χορήγησης.

Σε γενικές γραμμές η υπερδοσολογία αυτών των φαρμάκων δεν απειλεί τη ζωή του ατόμου όπως γινόταν κατά το παρελθόν με τα βαρβιτουρικά τα οποία πλέον για το λόγο αυτό δεν χορηγούνται. Η υπερδοσολογία εκδηλώνεται στις ήπιες περιπτώσεις με υπνηλία, λήθαργο, διανοητική σύγχυση, στις σοβαρότερες περιπτώσεις με κώμα και πολύ σπάνια μπορεί να αποβεί θανατηφόρα.

Οι τέσσερις στους δέκα ενήλικες που παίρνουν υπναγωγά φάρμακα αναφέρουν ότι δεν καταφέρνουν να καταπολεμήσουν την αϋπνία τους, σύμφωνα με πρόσφατη βρετανική έρευνα. Περίπου το 42% όσων λαμβάνουν αγωγή για την καταπολέμηση της αϋπνίας έχουν κακή ποιότητα ύπνου για περισσότερο από έντεκα χρόνια.

Επιπλέον, το 22% των ερωτηθέντων έχουν αϋπνία τα τελευταία δύο έως πέντε χρόνια, ενώ ο ένας στους έξι υποφέρει για περισσότερα χρόνια – από έξι έως δέκα.

Σύμφωνα με τους ειδικούς τα συμπεράσματα της έρευνας υποδηλώνουν ότι τα υπναγωγά φάρμακα δεν καταπολεμούν την μακροχρόνια αϋπνία, καθώς και ότι η συμπεριφορική ψυχοθεραπεία φαίνεται να είναι πιο αποτελεσματική.

Πηγή: vita.gr

Διαβάστε επίσης: Επιδράσεις από τη μακροχρόνια χρήση βενζοδιαζεπινών (wikipedia)

[Θανάσης Αποστόλου]

Παρακάτω παραθέτω ένα απόσπασμα από το βιβλίο Say Good Night to Insomnia The Six-Week, Drug-Free Program του Gregg D. Jacobs. Το βιβλίο είναι λίγο παλιό (2009), αλλά έχει ενδιαφέρουσες ιδέες.

Διευκρίνηση: Στο παρακάτω κείμενο θα δείτε τα αρχικά CBT. Με αυτά εννούμε την Γνωσιακή Συμπεριφορική Θεραπεία (Cognitive Behavioral Τherapy- CBΤ), η οποία είναι μια μέθοδος ψυχοθεραπείας, κατά την οποία συνδυάζεται η Γνωσιακή και η Συμπεριφορική θεραπεία. Υπενθυμίζω ότι και στο βιβλίο μου για το κάπνισμα ακολουθείται η γνωσιακή θεραπεία, που ουσιαστικά δεν είναι τίποτα άλλο, από την επανασύνδεση με την πραγματικότητα, για κάποιον που έχει στρεβλωμένες αντιλήψεις, πχ. από τη χρήση ενός ναρκωτικού, από μία φοβία κλπ.

Let’s take a closer look at this important new research. Ten years ago, CBT was just beginning to emerge as a viable alternative to sleeping pills. Since that time, numerous studies published in major medical journals have shown that CBT is safer and works better than sleeping pills in the long run.1 For example, an analysis of over twenty studies showed that CBT helped people fall asleep faster than sleeping pills—and without any side effects.2

Another major review study showed that, in people over sixty, the side effects of sleeping pills outweigh their small benefits. In fact, seniors were twice as likely to experience side effects such as short-term memory loss, headaches, daytime fatigue, nausea, motor vehicle crashes, and dizziness. 3

In 2005, a National Institutes of Health “State of the Science” conference on insomnia found that there was no evidence that CBT produces any side effects.4 That continues to be the case. Since 1999, there have been three studies that have directly compared sleeping pills to CBT. In all three, CBT was more effective.5 My colleagues and I conducted one of these studies at Harvard Medical School with funding from the National Institutes of Health. The study compared CBT to the most widely prescribed sleeping pill, Ambien, demonstrating that CBT was more effective in the short term (four weeks) and in the long term (one year). Moreover, Ambien was only moderately effective while it was taken, and any benefit disappeared after patients discontinued the medication. We also found that 80 percent of patients treated with CBT fell asleep faster and over half fell asleep as quickly as normal sleepers.

My clinical work consistently shows that 90 percent of patients reduce or eliminate sleeping pills with CBT. As a result of these new findings, CBT has been recommended as the preferred treatment for chronic insomnia by the New England Journal of Medicine, the British medical journal the Lancet, Consumer Reports, the National Institutes of Health, and the American Psychological Association.6 Still, the treatment of insomnia has been hindered. Although insomnia is the most prevalent sleep problem, it receives the least amount of U.S. federal research funding of any sleep disorder. In 2004, the National Institutes of Health allocated less than 3 percent of its total sleep disorders budget for insomnia. Insomnia lags far behind other sleep disorders such as sleep apnea, which received close to 20 percent of the total NIH funding for sleep disorders in 2004.

Equally upsetting is the fact that, for numerous reasons, the vast majority of Americans have not had access to CBT. First, CBT is usually provided by a licensed clinician for a fee, but people lacking health insurance cannot afford these services. Second, due to a lack of training opportunities, there are only a few hundred well-trained CBT specialists for insomnia in the United States. Third, sleep clinics are often directed by pulmonologists, who specialize in treating sleep apnea, not insomnia. Fourth, many doctors and patients are not familiar with CBT because, unlike sleep medications, it is not advertised. In response to these challenges, self-help approaches like this book and online interactive programs have emerged as “next generation” CBT interventions that aim to make the treatment more widely available to insomnia sufferers.

Studies have already confirmed that self-help CBT approaches are effective for insomnia.7 The good news about CBT has been crowded out by the slew of new sleeping pills, including Ambien CR, Sonata, Rozerem, and Lunesta, that have become available in the United States since the late 1990s. (Ambien has been available since 1992 and is now available in generic form.) Who hasn’t seen the Lunesta moth or a ticking clock for Ambien? Although sleeping pill prescriptions declined from the 1970s to the early 1990s, extraordinary spending on direct-to-consumer advertising has led to a dramatic increase in sleeping pill prescriptions—a 60 percent increase from 2000 to 2005, with 43 million prescriptions written in 2005 alone. And the spending continues. In 2007, the makers of Lunesta, Ambien, and Rozerem spent over $600 million on advertising; at one point, Lunesta advertising expenditures alone totaled over a million dollars per day. Advertising expenditures for sleeping pills lead all other classes of medications. Sleeping pills now stand as a $4.5 billion annual market. Sleeping pill ads seduce patients with the message that if they take this pill, their sleep problems will disappear.

What the makers of these drugs don’t want you to know is that many of the newer medications, including Ambien CR and Lunesta, carry the same risks as their predecessors, such as daytime sleepiness, cognitive impairment (that can be hard to notice), dizziness, unsteadiness and loss of coordination, dependence, detrimental interaction with alcohol, and what doctors call “rebound insomnia” (when a patient stops using the medicine and insomnia returns, and may even be worse, for a few days).8 Less common but more problematic are sleepwalking or sleep driving, temporary amnesia or memory lapses, hallucinations, and abuse, which resulted in FDA-required label warnings stating that hypnotics can cause strange and dangerous behaviors. (Although primarily Ambien has been linked with sleep eating and sleep driving, this is probably because Ambien has been on the market a lot longer and has been used by many more people.) Collectively, these side effects explain why sleeping pills are still classified as controlled substances and are only available by prescription.

All four of the newer medicines (Ambien, Lunesta, Sonata, and Rozerem) are somewhat less likely to cause dependence and abuse problems than older insomnia medicines, but there have been reports of abuse and dependence with Ambien (again, perhaps because it has been used to date by more people). Although several studies indicate that previous generations of sleep medicines such as Restoril and Dalmane, which are still prescribed, cause more day-after sleepiness and grogginess and are associated with a higher risk of dependency and rebound insomnia, there have been very few studies directly comparing the new drugs with the old ones. The case has simply never been proved that the new sleeping pills are safer. In addition, many people take sleeping pills long-term despite the fact that most of the medications were never tested or approved for long-term use. Two-thirds of patients use them for more than a year and a third use them for more than five years. Yet, the side effects of these drugs have been tested over a short period of use and in a very limited fashion. And since many of the medications are still quite new, long-term side effects may not become known for many years.

One alarming potential long-term side effect of sleeping pills involves elevated mortality risk, as summarized by Dr. Dan Kripke of the University of California—San Diego and the Scripps Clinic in La Jolla, California.9 For example, in a study involving over a million people, those who reported taking sleeping pills nightly had 25 percent more mortality than those who said that they took no sleeping pills.10 The risk of taking sleeping pills nightly was not much less than the risks of smoking one pack of cigarettes a day.

As of 2008, fifteen epidemiologic studies have found that sleeping pill use predicted increased mortality risk, while no studies have shown that sleeping pills lower mortality risk. Three of these studies have specifically found that use of sleeping pills predicted increased risk of death from cancer. Most of these studies mainly looked at use of older barbiturate and benzodiazepine sleeping pills—for example, Dalmane, Halcion, and Restoril—but one showed a mortality risk linked with Ambien. The effectiveness of sleeping pills has not changed much with the new generation of drugs either.

There have been very few studies that have directly compared the efficacy of the new drugs with the old ones, and consequently there is little evidence that the newer sleeping pills are more effective. There is, however, plenty of research to suggest that they are only mildly effective—just like their predecessors. A meta-analysis of sleeping pill studies published in 2006 and funded by the National Institutes of Health found that when people were monitored in the lab, newer drugs like Ambien, Lunesta, and Sonata worked better than placebo pills, but the results were not overwhelmingly persuasive. Viewed as a group, the pills, compared to a placebo, reduced the average time to go to sleep by barely over ten minutes and increased total sleep time by approximately ten minutes.11 Further, the drugs may not actually improve sleep. Rather, because of the amnesic effects of these drugs, people think they sleep better under the influence of most sleep medications because they don’t remember being awake. And keep in mind that because most studies only assess efficacy for a few weeks, they may overstate the drugs’ effectiveness over the long term and understate the side effects.

A closer look at the two leading sleeping pills, Ambien and Lunesta, offers more evidence that these newer drugs are only mildly effective. In my research at Harvard Medical School, I found that, compared to a placebo, Ambien only reduced time to fall asleep by about twenty minutes after four weeks of nightly use and by only five minutes when it was discontinued.12 In other words, the sleeping pill did not produce enduring improvements in sleep.

Ads for Lunesta claim that it helps most people fall asleep quickly, stay asleep all through the night, and get an average of seven to eight hours of sleep.13 In reality, these assertions are far from accurate. The primary study on Lunesta was conducted by consultants and employees of Sepracor, the company that markets the pill, and even it showed that Lunesta only provides about six hours of sleep per night.14 Far from cured of insomnia, Lunesta users lay awake for over three-quarters of an hour before falling asleep and woke for another three-quarters of an hour during the night. Like Ambien, Lunesta only reduced time to fall asleep by about twenty minutes compared to a placebo.

These modest changes in sleep were statistically significant compared to a placebo but were not clinically significant. 15 Moreover, 40 percent of people who took Lunesta dropped out of the study even though they were paid to participate. Finally, there was no proof that Lunesta provided objective benefits using EEG recordings or other objective measures of sleep.

To make matters worse, many drugs currently prescribed for insomnia are done so “off-label,” meaning they have never even been tested or approved for the treatment of this disorder. A 2005 study showed that, of the top ten most frequently prescribed medications for insomnia, only Ambien, Restoril, and Sonata were approved for cases of insomnia.

The other seven medications, which have been approved for the treatment of anxiety or depression but not for insomnia, include (in order of use) Trazodone, Elavil, Remeron, Seroquel, Klonopin, Atarax, and Xanax.16 The off-label use of these medications means that many patients are taking prescription medications that are not proven to be more effective than a placebo and that may have significant side effects with long-term use. (Off-label use of medications is very common and is a physician’s prerogative; up to one-fifth of all drugs are prescribed this way.)

Given all the drawbacks, side effects, and lack of clinical effectiveness of these sleeping pills, why do so many doctors prescribe them and so many patients take them? Primarily because direct-to-consumer advertising has convinced the public that these drugs are safe and effective. Pharmaceutical companies also achieve this by exerting significant control over the information that reaches physicians, the media, and the public by:
• designing clinical trials, analyzing data, and publishing studies that maximize benefits while minimizing side effects in order to make drugs look safer and more effective than they really are;
• focusing on the statistical significance of very small benefits while ignoring the fact that the benefits are clinically meaningless;
• burying studies that show negative results (the FDA won’t release unfavorable research results without the drug company’s approval); and
• hiring public relations firms and academic scientists as consultants and speakers to trumpet biased studies as “breakthroughs.”

As with the Lunesta study, many publications about the favorable effects of drugs are written by company representatives, sometimes with attribution given to academic scientists, who lend credibility to the results. Indeed, almost all studies on sleeping pills are funded by the companies that market them, and a strong publication bias (that is, they’re more likely to show favorable results) has been demonstrated for studies of sleeping pills that are conducted by the drug makers.17 Most of the little that we know about sleeping pills is biased.

Unfortunately, physicians, the media, and patients have bought these ideas completely. Today, many scientists and clinicians, including myself, no longer view studies funded by drug companies as reliable sources of information—nor should you. Instead, these studies should be viewed as thickly veiled marketing strategies. Be skeptical of what you read and hear about sleeping pills and understand that you are assuming unknown risks if you use them regularly.

Παραπομπές:
1
 Morin, C. M., P. J. Hauri, C. A. Espie, et al. 1999. Nonpharmacologic treatment of chronic insomnia: an American Academy of Sleep Medicine Review. Sleep, 22(8): 1134-47. Nowell, P. D., Mazumdar, S. M., Buysse, D. J., et al. 1997. Benzodiazepines and Zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. Journal of the American Medical Association, 278 (24): 2170-77.
2
 Smith, M. T., M. L. Perlis, A. Park, et al. 2002. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. American Journal of Psychiatry, 159: 5-11.
3
 Glass, J., K. L. Lanctot, N. Herrmann, et al. 2005. Sedative hypnotics in older adults with insomnia: meta-analysis of risks and benefits. British Medical Journal, 331: 1169-73.
4
 National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep (2005), 28: 1049-57
5 Morin, C. M., C. Colecchi, J. Stone, et al. 1999. Behavioral and pharmacological therapies for late-life insomnia
6 ilber, M. 2005. Chronic insomnia. New England Journal of Medicine, 353(8): 803-10
7
 Morin C. M., S. Beaulieu-Bonneau, and M. LeBlanc. 2005. Self-help treatment for insomnia: a randomized controlled trial. Sleep, 28: 1319-27. Strom, L., R. Pettersson, and G. Andersson. 2004. Internet-based treatment for insomnia: a controlled evaluation. Journal of Consulting and Clinical Psychology, 72: 113-20.
8
 Rosenberg, R., J. Caron, T. Roth, and D. Amato. 2005
9
 Kripke, D. F. 2007. Hypnotics versus the alternatives. Psychiatry Investigation , 4: 57-60.
10
 Kripke, D. F., et al. 2002. Mortality associated with sleep duration and insomnia. Archives of General Psychiatry, 59: 131-36.
11
 Saul, Stephanie. 2007. Sleep drugs found only mildly effective, but wildly popular. New York Times, Oct. 23.
12
 Jacobs, G. D., E. F. Pace-Schott, R. Stickgold, and M. W. Otto. 2004. Cognitive behavior therapy and pharmacotherapy for insomnia. Archives of Internal Medicine , 164: 1888-96.
13
 www.lunesta.com accessed on July 27, 2008.
14
 Krystal, A. D., J. K. Walsh, E. Laska, et al. 2003. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double blind, placebo-controlled study in adults with chronic insomnia. Sleep, 26: 793-99.
15
 Jacobs, G. D. 2004. Is eszopiclone appropriate and effective for the long-term clinical management of chronic insomnia. Sleep, 27: 1.
16
 Walsh, J. K. 2004. Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based. Sleep, 27: 1441-42
17
 Kripke, D. F. 2007. Who should sponsor sleep disorders pharmaceutical trials? Journal of Clinical Sleep Medicine, 3: 671-73

Σε άλλο σημείο του ίδιο βιβλίου:

When Sleeping Pills May Be Appropriate

Occasional use of a sleeping pill for a few nights or even a few weeks may be appropriate if sleep is temporarily disturbed by jet lag or a stressful event such as the death of a loved one, separation, divorce, or a medical problem. In these circumstances, sleeping pills may help prevent short-term insomnia from evolving into chronic insomnia.

Some sleep experts also believe that keeping a small supply of sleeping pills in the medicine cabinet can be helpful for some insomniacs because the knowledge that a sleeping pill is available provides a sense of security and minimizes the fear of insomnia. Other experts maintain that short-term use of sleeping pills may also be appropriate to break the cycle of anxiety and disturbed sleep in severe, chronic insomnia.

No matter what the circumstances, however, you should always attempt to change the thoughts and behaviors that are causing insomnia before you resort to a pill, for if you take sleeping pills you may not have the self-control to use them occasionally and may therefore risk becoming dependent upon them. This is the reason many sleep experts recommend against ever using sleeping pills and why the National Institutes of Health state that the treatment of insomnia should always start with behavioral techniques.

If you cannot sleep and choose to take a sleeping pill, you will minimize the likelihood of side effects and dependence if you follow these guidelines:

• Use the nondrug techniques described in this book in conjunction with sleeping pills so that you can taper off their use more quickly

• Use the smallest possible dose of a sleeping pill and do not use it for more than two or three weeks
• Use sleeping pills intermittently, only after two consecutive bad nights of sleep, and never on consecutive nights; this will ensure that you do not use sleep medication more than twice a week

• Never escalate the dose or take a dose higher than your physician has prescribed, and always try to use sleep medications with a short half-life