Pharmaceutical Treatment of Insomnia In Intractable Pain Patients
Insomnia is a profound problem in patients with severe, intractable pain that is poorly controlled.1-4 These patients invariably have centralized pain with autonomic nervous system hyperactivity and a multitude of neurotransmitter abnormalities.5-8 These central disturbances may interrupt sleep to the point that patients cannot sleep longer than a few hours at a stretch. The lack of sleep in these individuals may be so severe that it not only increases pain but also produces mental confusion, depression, anxiety, anorexia, malnutrition, and severe fatigue—among other problems. Consequently, addressing both the patient’s chronic pain and secondary insomnia may require a complex regimen of treatments.
In this paper, I will outline my guidelines for the recognition, treatment, and monitoring of these ill and suffering patients. I will not discuss the usual behavioral, electromagnetic, nutritional, and over-the-counter approaches to insomnia, which are appropriate for mild to moderate forms of primary insomnia, and which are well described elsewhere.9,10 Discussed here are treatment options for patients with severe insomnia secondary to centralized, intractable pain—and who have not benefited from the usual therapies for primary insomnia.
Severe Insomnia and Chronic Pain
The hallmark of centralized, intractable pain is a patient who describes his/her pain as severe, debilitating, and constant.5-8 It seems logical to assume that if pain is constant and never remits, the patient simply cannot sleep until exhaustion manifests. In fact, most of my patients report that they have difficulty sleeping more than approximately 4 hours at a stretch.
In addition to insomnia, excess cerebral autonomic activity caused by intractable pain may cause mental confusion, memory loss, depression, anxiety, and fatigue. Peripheral autonomic hyperactivity, also known as excess sympathetic discharge, consists of tachycardia, hypertension, mydriasis, vasoconstriction (cold hands or feet), and hyperreflexia. The reason(s) for the autonomic hyperactivity is unclear.
In centralized pain there are inflammation, tissue destruction, sensitization, and deficiencies of neurotransmitters, which may interfere with sleep.6-8 Also, there is a loss of inhibition of efferent discharge, but it is unknown whether this is due to an anatomic or neurotransmitter abnormality (Table 1).11
When first addressing insomnia in patients with chronic pain, it is always important to review the basics of good sleep hygiene with the patient (Table 2). In addition, clinicians should take a careful medical/medication history to identify any comorbid conditions, such as depression or anxiety, which may be contributing to the patient’s sleep problems, as well as identify and manage any behaviors or medications that can worsen insomnia (Table 3). If the patient is on a medication that might be contributing to their insomnia, such as albuterol or theophylline, consideration should be given to adjusting the timing of administration (morning versus evening). As always, careful review of the patient’s pain regimen should be addressed to make sure that their pain is being adequately treated.
Several classes of medications have been used to treat insomnia. However, only three classes have FDA-approved labeling for insomnia. These include benzodiazepine receptor agonists (benzodiazepines and nonbenzodiazepine hypnotics), the antidepressant doxepin, and the melatonin receptor agonist ramelteon (Rozerem). Table 4 summarizes the FDA-approved medications, as well as other prescription products, which have evidence for use in managing insomnia.
Selection of an insomnia agent is not an easy decision in intractable pain patients. All of these agents have side effects and varying degrees of abuse potential. Moreover, the patient may, by necessity, already be taking a number of potent medications—including antiseizure agents, antidepressants, neuropathic agents, anti-inflammatory agents plus opioids, muscle relaxants, and stimulants.
For this reason, the safest and less toxic antidepressants, antiseizure agents, and nonbenzodiazepine agents should generally be the first selections. Reserve the more hazardous agents for when the safer agents prove ineffective. I try to initiate treatment with an antidepressant or antihistamine accompanied by melatonin, tryptophan, or valerian. If these don’t work, I move up to the other more potent classes. Benzodiazepines and carisoprodol (Soma) are reserved for the “last step,” as these agents have the most “hangover” effects, sedation, and abuse potential. They are particularly hazardous when they are used in patients who are taking opioids. Despite these problems, benzodiazepines and carisoprodol may be necessary. Benzodiazepines have been reported to have positive effects in pain patients.12
Unfortunately, it is sometimes very difficult to find an agent that is effective. It may be that you will have to try several agents to find one that works. In some severe pain cases, the best agent may only partially work at both putting the patient to sleep and keeping them asleep for more than 2 to 3 hours. Another factor to keep in mind is that the usual recommended starting dose might be woefully inadequate. It is not uncommon to require a dosage 2 to 4 times the standard starting dose.
In preparation for this paper, I gave a written questionnaire to 27 consecutive, stabilized, intractable pain patients. All were long-term adult patients who had been in my practice for at least 1 year and suffered from their pain for at least 5 years. All had constant pain and had taken opioids and ancillary agents for at least 5 years. Most importantly, all had endured insomnia secondary to intractable pain.
This small series reveals a considerable bit of information (Table 5). First, these patients take a wide variety of treatment agents. Some take more than one. Despite the use of a potent treatment agent(s), the length of sleep is woefully short in some patients. On the other hand, some patients simply take a regular opioid dosage before bedtime and find this adequate for sleep. Many take an opioid dosage when they awake during the night. Not surprisingly, most say their pain is better controlled the next day if they get a good night’s sleep. A number of studies document that sleep deprivation in pain patients is associated with increased pain and may interfere with other cerebral functions.13-15