Recognizing & Treating Insomnia in Cancer Patients

Is insomnia in cancer patients simply a temporary reaction to treatment, a symptom of an underlying disorder, or is it a syndrome unto itself? And, whatever its cause or classification, how might insomnia in this patient population be best treated? Those are the issues that some oncologists and sleep researchers are currently investigating in patients with cancer. Whether disrupted sleep occurs as a result of anxiety, hormonal changes, or treatment side effects, impaired sleep/wake cycles can persist and develop into chronic insomnia. Because insomnia itself has serious consequences for patients' physical and emotional well-being, the experts interviewed for this article agreed that much research is needed to further understand its etiology and treatment. Most patients and physicians accept that stress can disrupt sleep patterns. And few events are more stressful than being diagnosed and treated for cancer. Yet, this common perception may work against the understanding of insomnia as a syndrome, maintains Josée Savard, PhD, Professor of Psychiatry at Laval University Cancer Research Center in Quebec. “Insomnia, and sleep problems in general, are often seen as temporary and normal reactions to the diagnosis and treatment of cancer,” Dr. Savard explained in a recent telephone interview. “I think it is assumed that the sleep problem will disappear as time progresses.” Sonia Ancoli-Israel, PhD, Professor of Psychiatry at the University of California, San Diego, and Director of Veterans Affairs at San Diego Healthcare Systems, a sleep researcher and author of the book All I Want Is A Good Night's Sleep (Mosby Year-Book, Inc., 1996), agrees that sleep problems in cancer patients tend to be overlooked. “There are two reasons for this: One is that most physicians are not trained to think about sleep as being an important issue. That's true not just of oncologists, but of all physicians.Figure: Josée Savard, PhDFigure: Sonia Ancoli-Israel, PhDFigure: William Breitbart, MD“The second reason is that physicians don't know what to do about sleep problems when they identify them. And that's an education problem. This is most definitely a very common problem.” Establishing Prevalence Other correlates of cancer, such as cancer-related pain and cancer-related fatigue, are now receiving more attention from pain and psychosocial services in cancer centers. For instance, the Fatigue Coalition was formed in 1996 to specifically address that phenomenon, which experts now agree had been neglected for years. Studies since formation of the coalition have validated the prevalence of fatigue, with some series finding a prevalence of fatigue during chemotherapy as high as 76 percent. As with cancer-related fatigue, there has been little recognition on the part of researchers and clinicians, that insomnia can occur as a separate syndrome necessitating treatment, Dr. Savard notes. What starts as a temporary sleep disruption may continue long after treatment has ended, seriously affecting patients' quality of life. That was the finding that she and her coinvestigators from Laval University's School of Psychology recently reported in the journal Sleep (2001;24:583–590). The team, which included Sebastien Simard, MPs, Julie Blanchet, MPs, Hans Ivers, MPs, and Charles M. Morin, PhD, surveyed women who had been treated with radiotherapy for non-metastatic breast cancer. Of the 300 women completing an insomnia screening questionnaire, 51 percent reported having current sleep difficulties. Among those with current insomnia symptoms who were then further interviewed, 56 (corresponding to 19% of the total sample) met the diagnostic criteria for an insomnia syndrome. In 95 percent of those with an insomnia syndrome, the condition had become chronic (lasting six months or more). Variable Assessment Methods In a recent issue of the Journal of Clinical Oncology, Dr. Savard and her coauthor Dr. Charles Morin note that most studies reporting the incidence of insomnia in cancer patients have used variable assessment methods for evaluating the presence of insomnia. Thus, before the study was done, it was not known what proportion of cancer patients meet generally recognized clinical diagnostic criteria for insomnia. In the above-mentioned descriptive study and another ongoing randomized trial, Dr. Savard has worked closely with psychologist Dr. Morin, a specialist in sleep disorders, and uses the criteria from both the International Classification of Sleep Disorders and those listed in the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) to confirm a diagnosis of insomnia.Figure: Judith R. Davidson, PhDThose criteria include: ▪ Difficulty initiating sleep (taking 30 minutes or more to fall asleep). ▪ Difficulty maintaining sleep (more than 30 minutes of awakening during the night) and a sleep efficiency (ratio of sleep to time spent in bed) of less than 85 percent. ▪ Sleep disturbance at least three nights a week. ▪ Significant impairment of daytime functioning (fatigue, mood disturbances) caused by the sleep disturbance. If the insomnia lasts one month or less, it is considered transient or situational. Short-term insomnia lasts from one to six months, while chronic insomnia is characterized by a duration of six months or more. Common Reaction Dr. Savard said she became interested in insomnia in the context of cancer through her clinical work. “Based on my clinical experience, I found that it was a common reaction in patients,” she said. “But I found almost no good study that was done in this field.” Unbeknownst to Dr. Savard, however, another researcher from Kingston, Ontario (with whom she will soon be collaborating) was simultaneously studying the prevalence of insomnia in cancer patients. Judith R. Davidson, PhD, of the Radiation Oncology Research Unit at Kingston General Hospital conducted a survey of patients attending that regional cancer center. She and her colleagues found that 31 percent of 982 clinic attendees reported sleep difficulties (trouble falling asleep, waking up several times during the night, awakening for a long time, and/or waking up too early) that interfered with daytime functioning. “Patients with insomnia most often attributed it to thoughts, concerns, or pain/discomfort,” Dr. Davidson said. The survey, now in press for publication early this year in the journal Social Science and Medicine, then led Dr. Davidson's group to design a psychologic intervention program to help cancer patients with their insomnia. Complex Etiology Although some of the women in Dr. Savard's survey reported having sleep difficulties prior to their cancer diagnoses, the majority noticed that the onset of insomnia or at least an aggravation of insomnia symptoms followed the cancer diagnosis. William Breitbart, MD, Chief of the Psychiatry Service at Memorial Sloan-Kettering Cancer Center in New York City and a member of the Fatigue Coalition, points out that the “sleep/wake cycle is very sensitive to all sorts of disruptions.” During treatment for cancer, this can take several forms, he notes. “A very large segment of the insomnia that I encounter in working with patients is a function of other disorders, such as depression, untreated pain, or other untreated physical symptoms, such as dyspnea,” he said. “Mild confusional states can be manifested by sleep disruption, and symptoms of delirium can also include insomnia and sleep/wake cycle reversal.” Insomnia is also a known side effect of several medications given during the course of cancer treatment. Corticosteroids, such as prednisone, are probably the biggest culprits in this respect, he noted. In addition, some antiemetic drugs, such as Compazine, block dopamine in the brain and cause akathisia (restlessness) and resulting wakefulness at night. “There are multiple causes of insomnia,” Dr. Breitbart said, and it is often difficult to ferret out fatigue and insomnia from treatment side effects. “Sometimes it's hard to differentiate between someone who has a fatigue syndrome and someone who is sedated, for instance, on opioid drugs.” “Insomnia in anyone is often associated with fatigue,” Dr. Davidson pointed out. “The standard diagnostic classification systems [DSM-IV] recognize that fatigue frequently accompanies insomnia. Our survey study reported on variables that were associated with increased odds of insomnia. “Patients with excessive fatigue were 2.5 times more likely than those who did not report excessive fatigue, to have insomnia. We cannot say whether one triggers the other or not, based on this kind of study. However, clinically, insomnia should be considered as a possible contributor when patients report fatigue.” Dr. Savard's and Morin's JCO review article presented a compendium of predisposing, precipitating, and perpetuating factors that can lead to insomnia in cancer patients. Being a woman, being older, and having a family history of insomnia might predispose a cancer patient to develop insomnia, the researchers found by reviewing the literature on primary insomnia (i.e., not related to a medical problem). Insomnia might also be precipitated by such factors as mutilating surgery (with aesthetic or functional impairments), hospitalization, radiotherapy, chemotherapy or hormonal therapy. Faulty beliefs and attitudes about sleep, as well as maladaptive sleep behaviors (such as spending too much time in bed) are also likely to perpetuate the insomnia over time. Proceed to Treatment “Insomnia is sometimes secondary to depression, and it may sometimes be secondary to other aspects of the cancer or cancer treatment,” Dr. Ancoli-Israel said. “But the truth is, it doesn't matter what caused it. The insomnia is still there and needs to be dealt with. “We know, for example, that insomnia in non-cancer patients will lead to decreased quality of life, more memory problems, problems with concentration, problems in relationships, and more accidents. Those are all factors that become magnified with cancer.” For those reasons, Dr. Ancoli-Israel and others advise clinicians to ask their patients how they are sleeping. “Clinicians should ask about sleep at every visit, because it will change with the treatments. And just because the treatment is over does not mean that the sleep will get better. I know that physicians do not have a lot of time to spend with patients. But they could certainly ask, ‘How well are you sleeping?’ ‘Do you have complaints about your sleep?’ or ‘Are you sleepy during the day?’ A yes answer to any of those questions need not necessarily trigger a referral to a specialist, Dr. Ancoli-Israel noted. The physician could begin by treating the insomnia. Handouts on sleep hygiene, or prescription of sedative hypnotics may be in order. The hypnotic medications most commonly prescribed for sleep difficulties include benzodiazepines marketed as hypnotics (such as temazepam [Resteril/Novartis]; those marketed as anti-anxiety medications (lorazepam [Ativan/Wyeth-Ayerst]); or newer, nonbenzodiazepine hypnotics (zolpidem [Ambien/Pharmacia & Upjohn] and zaleplon [Sonta/Wyeth-Ayerst]. The latter drugs are shorter acting, have more specific hypnotic effects, and less residual effects the next day. Dr. Ancoli-Israel cautioned that clinicians should take the time to inform themselves about the drugs and make sure to choose a hypnotic “that matches the patient's complaints. Most physicians have one sleeping pill that they prefer, so they give it to everybody. That doesn't work. I try to teach physicians to choose the one that best matches the patient's complaint.” It is also essential, Dr. Savard said, to address any underlying physical or psychological factors contributing to the insomnia. Nonpharmacologic interventions have also been effective in addressing insomnia in the general population, and Dr. Savard is currently conducting a randomized trial in breast cancer patients to assess the efficacy of psychologic interventions. For that study, she has recruited women who have completed their radiation and/or chemotherapy treatments, and assigned them to either a “wait list” control group or an intervention group that receives a multimodal therapy consisting of stimulus control, sleep restriction, cognitive therapy, and sleep hygiene procedures. Every woman enrolled in the study will eventually receive the interventional treatments. Dr. Savard reports that the last group of six women has now been enrolled and will have completed their intervention phase by this spring. Data should be ready for analysis by next summer, she believes. Preliminary results are very encouraging and indicate that the psychological treatment is associated with improved sleep efficiency and reduced total wake time. Dr. Davidson's group will soon be launching a randomized controlled trial based on a pilot study of a sleep therapy program developed specifically for cancer patients with insomnia. Whereas Dr. Savard is focusing on treatments for breast cancer patients, treatments in Dr. Davidson's study will be offered to patients with all types of cancer. Twelve participants in the pilot program kept sleep diaries, rating sleep quality, mood and functioning at baseline, and then at Weeks 4 and 8. They participated in a six-session group program including stimulus control therapy, relaxation training, and other strategies aimed at consolidating sleep times and reducing cognitive-emotional arousal. Total sleep time and fatigue were significantly improved at Week 8, and patients reported an enhanced ability to perform daily activities [Davidson JR et al: Psychooncology 2001 Sep-Oct;10(5):389–97]. More Studies Necessary Drs. Savard and Ancoli-Israel note that much more research is necessary to understand how insomnia is triggered in patients. For her part, Dr. Savard is leaning toward future investigations of the role of hormonal factors in sleep disruptions for breast cancer patients, for whom treatment-caused onset of menopause is often abrupt and severe. Dr. Ancoli-Israel is two years into a five-year long study of sleep patterns in breast cancer patients. “I'm interested in the relationship between the report of fatigue, which has yet to be defined, to sleep and circadian rhythms. If you start with a robust, synchronized sleep rhythm before you begin chemotherapy, will you be less fatigued during treatment?” Accordingly, she and her co-investigator, Vickey Jones, MD, a clinical oncologist at UCSD, are studying women who have been diagnosed with breast cancer for the first time. They go to the women's homes prior to chemotherapy, administer questionnaires, and use an actigraph, a measuring device on a wristband, to record sleep and wake cycles within a 72-hour period. The principle of the actigraph, explains Dr. Ancoli-Israel, is that during sleep there is very little body movement, while during awakening, movement increases. Study participants wear the actigraph for another 72-hour period in the first three weeks of Cycle 1, and during the last week before Cycle 4 and the first three weeks of Cycle 4 of chemotherapy. The device makes a digital record of sleep/wake patterns, which is then edited and scored as an algorithm using specialized software. From these records, she said, the researchers can discern the percent of time spent sleeping and waking and extrapolate a circadian rhythm. Those will then be compared over the time course of chemotherapy. So far, although the data have not been analyzed, she observed that the patients' worst sleep and worst complaints of fatigue occur in Week 2 of the chemotherapy cycle, when blood counts are at their lowest levels. Dr. Ancoli-Israel became interested in exploring sleep in cancer patients after reading studies by a French group at the Laboratoire des Rythmes Biologiques et Chronotherapeutiques in Paris, on the use of circadian rhythms to reference the timing of chemotherapy administration in patients with metastatic colorectal cancer to elicit maximum effect. One study published in August 2000 in Clinical Cancer Research found that survival at two years was five times higher in patients who had regulated rest/activity cycles as opposed to patients whose circadian rhythms were altered. Dr. Savard also cited several studies in her JCO review article that seem to suggest that insomnia symptoms may have an impact on cancer course and survival. This is a rich area of investigation, Dr. Ancoli-Israel believes, and expressed hope that American researchers would follow the lead of European colleagues and conduct further studies in this area. “We know how to synchronize rhythms,” she said, “but before I can start a treatment trial in which I am synchronizing [patient's sleep] rhythms, I need to know more about what happens to the rhythms.” Are the growing numbers of cancer survivors driving current efforts to improve quality of life during treatment and beyond? Dr. Breitbart believes that the growth of pain and palliative care services may have contributed to increased interest about cancer-related fatigue and insomnia. “As a field like palliative medicine grows, it starts to expand. As psychiatrists and palliative care physicians in cancer centers build their research agendas, they start to focus on issues that haven't been addressed earlier.” Dr. Davidson said, “I think it is interesting that, in the previously under-studied area of sleep problems in cancer patients, Dr. Savard and I both began studies in this area a few years ago, but didn't know that we were doing similar work until earlier this year. So after a lull in the literature on this topic, several studies are now coming out.”

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