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The sleep problems associated with chronic pain may also be a feature of the depression and anxiety that stem from physical, psychosocial, vocational, and economic concerns. Patients' negative beliefs and attitudes about themselves and their symptoms may benefit from cognitive behavioral therapy, improved sleep habits, and a suitable aerobic fitness program.[33,34] Although traditional analgesic, anxiolytic, or antidepressant medications are often used empirically to address pain and mood symptoms, their potential adverse effects on sleep and daytime functioning should be considered part of the overall management program.
Traditional analgesic or sedative medications may have beneficial or adverse effects on sleep and pain symptoms. Knowing whether patients have a coincident primary sleep disorder and having an understanding of the effects of such drugs on the sleeping-waking brain are the key principles for the management of patients with chronic pain problems. This awareness of the physiological and pharmacologic effects of these drugs on sleep physiology and especially primary sleep disorders, such as sleep apnea or RLS, may help or hinder the health and functional capabilities of patients with chronic pain problems.
Nonsteroidal anti-inflammatory drugs. Although analgesics traditionally have been used to manage pain, some pain medications, such as nonsteroidal anti-inflammatory analgesics, may alter EEG sleep and interfere with restorative sleep[35,36] or provide no beneficial effect for primary sleep disorders. For example, ASA, cyclooxygenase-2 inhibitors, and the opiate --tramadol -- depress slow-wave (deep) sleep.[37] One study found that although the administration of tenoxicam resulted in improvement in rheumatoid disease, no treatment-related changes were seen in sleep physiology, in which 8 of 13 patients were discovered to have sleep apnea and/or periodic limb movement disorders.[38]
Opioid drugs. Opiates have become common in the management of nonmalignant pain, but pose a core problem in achieving a balance between an effective dose and the risk for adverse effects.[39] In addition to the common concerns about which type of opiate to use and its addictive potential, there is the poorly recognized risk for depressing central respiratory drive. This central nervous system (CNS) depressant effect of narcotics, especially when given at night, is important in patients who are predisposed to sleep apnea. The sleep-related breathing disturbances and arterial oxygen desaturations may become aggravated, with potential consequent impairment in daytime functioning and added risk for cardiovascular diseases.[40] On the other hand, opiates are beneficial for suppressing RLS. That is, those patients with RLS who commonly experience lower limb discomfort, such as aching, burning, crawling, or cramping sensations, that interferes with sleep commonly experience improved sleep and daytime functioning with opioids, such as oxycodone, codeine, propoxyphene, and methadone.[41]
CNS drugs that were originally determined to be of use for specific brain disorders, such as Parkinson's disease and epilepsy, have found their way into the treatment of primary sleep disorders that are accompanied by chronic pain. Those that have a remedial effect on RLS include the following.
Dopaminergic drugs. Dopaminergic medications, originally used for Parkinson's disease, are now considered to be the first-line treatment for RLS-related sleep disorders and associated unpleasant sensations in the lower limbs. Initially, L-dopa was found to be helpful,[42] but because of its relatively short elimination half-life and potential for rebound and augmentation with increased limb discomfort and sleep fragmentation, longer acting dopamine agonists, such as pramipexole[43,44] and ropinirole,[45] are now preferred.
The timing of administration of these drugs is important, with the dose being tailored to the pharmacokinetics of the drugs and the natural circadian rhythm inherent to RLS. The restlessness and limb discomfort progressively worsen during the late afternoon and evening, with maximal discomfort at bedtime. The associated, sleep-related periodic limb movements subside after 3:00 or 4:00 am; thus, depending on the severity of symptoms, the initial dose should be given in the late afternoon or early evening. Patients should be monitored for potential acute side effects, which may be minimized by starting with a low dose and tailoring the subsequent dose increments to the response and sensitivity to the drug. Another important consideration is the potential for long-term acclimatization or augmentation of symptoms with such drugs.
Anticonvulsants. Although the dopaminergic drugs suppress the periodic limb movements during sleep, they may not alleviate difficulties in initiating and maintaining sleep. The anticonvulsant medications clonazepam[46,47] and gabapentin[48,49] provide sedative effects that facilitate and maintain sleep, and may remedy the symptoms of RLS. If excessive amounts of clonazepam are given late in the evening, patients may experience a hangover effect because of the drug's long elimination half-life. Gabapentin offers the additional benefit of analgesia,[50,51] an effect that is not evident in the dopamine agonists or benzodiazepines. Gabapentin is particularly effective in the treatment of reducing the pain and sleep interference in neuropathic pain disorders, such as postherpetic neuralgia.[52]
CNS medications that ameliorate anxiety, depression, or major psychoses may also supply analgesic effects and facilitate sleep.
Anxiolytics. Benzodiazepines are often used to reduce the anxiety that accompanies acute and chronic pain, but they do not inherently have specific analgesic properties. In one study, patients with chronic pain who had been given these products to improve sleep continue to report as many problems with sleep as those who were not given such medications.[53] Additional concerns about the long-term use of such drugs, especially those with active metabolites, include the risk for tolerance, dependency, incoordination, and impaired cognitive functioning.[54]
Hypnotics. As indicated, benzodiazepines, which are employed to promote sedation or sleep, have no specific analgesic effects. Such hypnotics and nonbenzodiazepines have not been properly evaluated for long-term use, but may be of benefit if used intermittently for chronic insomnia to help sleep quality and daytime functioning. Triazolam, an ultra-short-acting benzodiazepine hypnotic that has not been approved for long-term use because of its potential for rebound insomnia and anxiety, improves sleep, morning stiffness, and daytime sleepiness in patients with rheumatoid arthritis.[55]
The nonbenzodiazepine hypnotics, zolpidem[56] and zopiclone,[57] and investigational agents, such as 5-hydroxy-L-tryptophan[58] and growth hormone,[59] may improve sleep quality, but their impact on EEG sleep disturbances is uncertain. Large-scale studies are required to verify the recent report that sodium oxybate, a form of gamma-hydroxybutyrate, improves unrefreshing sleep by reducing the EEG alpha activity and increasing slow-wave sleep as well as improving pain and fatigue in patients with fibromyalgia.[60]
Antidepressants. Amitriptyline, a heterocyclic antidepressant agent, provides a favorable response in two thirds of patients with postherpetic neuralgia, three fourths of patients with painful diabetic neuropathy, patients with neurogenic pain syndromes that are often unresponsive to narcotic analgesics, and heterogeneous groups of patients with chronic nonmalignant pain, especially those with fibromyalgia.[61] Cyclobenzaprine, which has similar structural properties to amitriptyline but is marketed as a muscle relaxant, also improves the pain and sleep quality of patients with fibromyalgia.[62-65] However, such agents carry potential adverse effects, including anticholinergic, hypotensive, cardiac arrhythmia, and daytime sedative effects. The selective serotonin uptake inhibitor, fluoxetine, produces no consistent benefit for pain and sleep symptoms.[66,67]
Neuroleptic drugs. The traditional antipsychotic medications, ie, phenothiazines, are sedating and have analgesic properties.[68] For example, chlorpromazine not only facilitates sleep and increases slow-wave (deep) sleep, but also reduces muscular pain symptoms in patients with fibromyalgia.[69] However, because of the risk for orthostatic hypotension, anticholinergic symptoms, extrapyramidal effects, and tardive dyskinesia, phenothiazine drugs are not desirable for the long-term management of chronic pain disorders. Recently, atypical neuroleptics have been studied in animals for their analgesic properties. A comparison of the dibenzodiazepines, clozapine and olanzapine, shows that clozapine is a more potent analgesic than olanzapine, but troublesome hematologic, hypotensive, sedative, and seizure side effects would mitigate against its use.[70] Moreover, risperidone and quetiapine also have analgesic properties, but no large-scale, controlled drug trials have determined the risk/benefit of "atypical" neuroleptics on chronic pain disorders and sleep.[71]
