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7 Articles in Volume 5, Issue #5
Effective Non-Drug Treatment of Depression
First Line Treatment of Musculoskeletal and Neuropathic Pain
Pain Drug Use Policy
Targeted Peripheral Analgesics in Chronic Pain Syndromes
Therapeutic Drug Monitoring
Tiredness and Chronic Pain Management
TMD/Facial Pain and Forward Head Posture

Tiredness and Chronic Pain Management

Understanding and treating the causes and symptoms of tiredness among chronic pain sufferers helps clinicians restore alertness and vitality, increase mental and physical activity, minimize depression and apathy, and optimize pain management.

“Doctor, I feel tired a lot.” Is this person sleepy, fatigued, depressed, apathetic, or suffering the secondary effects of pain? Certain disorders that generate a daytime condition of drowsiness or fatigue include, but are not limited to:

  • Lowered arousal and level of consciousness
  • Fatigue due to a reduced energy state
  • Depressed mood and anhedonia
  • Apathy and lack of motivation
  • Sleep apnea
  • Testosterone deficiency
  • Non-restorative or poor quality of sleep

Lowered Arousal and Level of Consciousness

It is normal to feel drowsy at bedtime or at other times when sleep is desired for cultural and health reasons, such as midday naps (the siesta in Spain and Spanish-speaking countries, the qailula in Arabic-speaking countries). When sleepiness occurs at the wrong time, when one wants to or should be awake and fully alert, it may represent a disorder. Excessive drowsiness, or hypersomnolence, is a disorder of arousal, and in office settings it is the most common level of lowered arousal or consciousness. Some individuals feel sleepy only when passive and understimulated; others are drowsy even when actively engaged.

The Epworth Sleepiness Scale1 is a self-assessment questionnaire to determine the general level of daytime sleepiness, and a score=0 suggests a need for further evaluation to determine the cause of excessive sleepiness. In hospital and nursing home settings, patients may be obtunded (difficult to arouse, confused, requiring constant stimulation to keep awake), stuporous (semicomatose, responding only to vigorous and persistent stimulation; grumbling and moaning) or comatose (no behavioral response to stimulation).

Elevated arousal may occur as well. Mildly demented individuals may compensate for cognitive impairment by hyperalertness. Hypervigilance is common in individuals suffering from Posttraumatic Stress Disorder. Caffeine and other psychostimulants, including medicinal and illicit drugs, may induce hyperarousal. Manic and psychotic patients may become agitated, excited and hyperaroused. In chronic pain management, one finds that hypersomnolence is the most common disturbance of arousal.

Any general medical condition, psychiatric syndrome, sleep disorder or pain itself that interferes with quantity and/or quality of sleep at night will tend to cause residual daytime drowsiness, fatigue, apathy and cognitive disruption. Primary sleep disorders are common and include periodic limb movement disorder (PLMD or restless legs syndrome, RLS), obstructive sleep apnea (OSA), teeth grinding (bruxism), and circadian rhythm disturbances (advanced and delayed sleep phase disorders). Parasomnias such as sleeptalking (somniloquy), sleepwalking (somnambulism), and rapid eye movement (REM) sleep behavior disorders may be found. Narcolepsy may affect as many as 140,000 Americans,2 but it may be underdiagnosed and should be considered. A few patients will not report abnormal phenomena during sleep, but sleep architecture during nighttime polysomnography (NPSG) may reveal paucity or absence of delta sleep (slow-wave sleep, stages III and IV), paucity or absence of REM sleep, or frequent alpha intrusions (electrical arousals or awakenings that might or might not be recalled or reported the next day by the sleeper).

Fatigue and Decreased Energy

Fatigue represents a reduced energy state, described as a sensation of weariness, lessened capacity for work, and decreased efficiency of accomplishment. It may be confined to a single organ. It is normal at some point to experience physiological fatigue, especially after a period of vigorous physical or mental activity. Pathological fatigue occurs in persons who either have not exerted themselves or who encounter fatigue too early during the accomplishment of activities or in disproportion to their intensity or duration.

Various scales such as the Functional Assessment of Cancer Therapy Fatigue (FACT-F), Fatigue Severity Scale (FSS)3 and Modified Fatigue Impact Scale (MFIS) have been used to assess fatigue in specific patient populations such as cancer,4 Parkinson’s disease,5 multiple sclerosis6 and rheumatoid arthritis.7

A differential diagnosis of fatigue includes:

  1. neurological diseases (multiple sclerosis, traumatic brain injury, Parkinson’s disease)
  2. infections diseases (mononucleosis, cytomegalovirus infection, chronic hepatitis, acquired immune deficiency syndrome)
  3. metabolic diseases (thyroid diseases, diabetes mellitus)
  4. connective tissue disorders (rheumatoid arthritis, systemic lupus erythematosus)
  5. lymphoma and other carcinomas

A number of prescription medications and drugs of abuse can also cause drowsiness and fatigue. The list of disorders that can cause fatigue is very long, and the medical workup can be extensive and invoke a range of specialty consultations, laboratory studies and diagnostic imaging.

Depressed Mood and Anhedonia

Primary depression is a common cause of fatigue. Depression is pathological sadness not expected as part of normal loss (grief, bereavement). It may be milder and chronic (dysthymia) or moderate to severe and episodic (major depression, bipolar depressed). Most depressed patients have some degree of anhedonia: partial or complete loss of the ability to experience pleasure when anticipating or participating in activities that usually bring joy and gladness. However, depressed mood and anhedonia may be decoupled and occur without the other. Some partially recovered and treated depressed patients may experience remission of painful melancholy, yet they still may not feel complete joy and gladness with normally pleasurable activities. Recovering cocaine addicts may report emotional emptiness and lack of pleasure, even in the absence of depression.8 Anhedonia may be part of a broader apathy syndrome, in which the intensity of all mood and affective states, including reactive pleasure, is undermodulated.

Apathy and Lack of Motivation

Apathy describes a general lack of intensity of most or all emotions not attributable to decreased level of consciousness, cognitive disorder or emotional distress. It is an across-the-board reduction in amplitude of mood and affective states. A common clinical variant is apathy interrupted by sudden and brief outbursts of irritability or agitation if provoked. The differential diagnosis includes abulia, akinesia and akinetic mutism, depression, dementia, delirium, despair and demoralization.9

In order to feel motivated, one must have the desire (e.g., must “want” or feel “moved”) to initiate mental or physical activities, and the pleasure or “reward” for performing them might be sooner (e.g., money paid immediately) or later (a paycheck at the end of the month). Motivation may occur not only for the sake of pleasure, but for reduction of pain. Consider a person motivated to perform some unpleasant task or duty because of guilt. Impairment of hedonic functioning, possibly associated with dysregulation of dopamine in the mesocorticolimbic pathyway10 occurs in depression and apathy syndromes, and it governs both the anticipation and direct experience of pleasure, which also are necessary at some level for motivation. One study showed that the neurotransmitter dopamine was not necessary for mice to like or learn about rewards, but it was necessary for them to seek (want) rewards during goal-directed behavior.11

Sleep Apnea

Primary and secondary sleep disorders are a major source of excessive sleepiness and fatigue in chronic pain patients. Sleep apnea can be central (no respiratory effort), obstructive (respiratory efforts against upper airway resistance), or mixed. Obstructions or apneas occur with complete collapse or blockage of the upper airway; significant apneas persist for =10 seconds and lead to a drop of =3% in oxygen saturation (possibly followed by an arousal). Hypopneas are due to partial upper airway obstruction with significantly reduced air flow (=50%) in comparison to normal respiration. An apnea/hypopnea index (AHI) of >5 events per hour during polysomnography (PSG) confirms a diagnosis of OSA. The estimated prevalence of OSA in middle-aged adults is 2-4%.12

The main risk factor for OSA is overweight condition, and the most common site of obstruction is the soft palate extending to the area at the base of the tongue. Aging, with decreased tissue turgor, is a factor. Fat deposits accumulate along the sides of the upper airway, narrowing the passageway and predisposing to collapse and closure when muscles relax during sleep. Testosterone may cause structural changes in the upper airway of males. Other predisposing factors are receding chin, enlarged tonsils and adenoids, positive family history of OSA, alcohol and sedative drugs that relax upper airway musculature, smoking (which causes inflammation, swelling and narrowing of the oropharynx), hypothyroidism, nasal congestion (e.g., seasonal allergies), nasal polyps, and deviated nasal septum.

Treatments for OSA include continuous positive airway pressure (CPAP), biphasic airway pressure (BiPAP), weight reduction, avoidance of alcohol and sedative-hypnotics, oropharyngeal surgery (uvulopalatopharyngoplasty [UPPP] and related procedures), mandibular advancement and related surgeries, nasal reconstruction (septoplasty, turbinectomy, polypectomy), use of oral appliances, and modafinil (Provigil).

Management of chronic pain with opioids in patients with OSA requires special considerations. First of all, before initiating opioid therapy, the general medical history and physical examinations should look for evidence of OSA. Overweight and obese condition, increased age, receding jaw, history of snoring, history of observed apnea, trouble breathing through the nose (e.g., consider nasal congestion, septal deviation, polyps) and family history of OSA all should raise suspicions of OSA. When possible opioid therapy can be delayed until the patient has seen a sleep specialist and undergone polysomnography.

If opioids must be used before a sleep study, consider using controlled-release drugs in the morning only, short-acting agents later in the day, and avoiding opioids at bedtime. The patient can be instructed not to take naps or go to sleep during the period of activity of the opioid. The “start low, go slow” principle should be modified to “start even lower, go even slower.” After OSA has been evaluated with polysomnography and any indicated treatments instituted and maintained, then the opioid therapy can be expanded cautiously and titrated upward to achieve the best pain control.

Testosterone Deficiency

Low testosterone (hypogonadism) is a frequent cause of fatigue in chronic pain patients. It may be idiopathic, but other causes include sleep apnea, adrenal suppression from intractable pain and general hypocorticism secondary to opioids.13 Serum total (bound and free) testosterone concentrations

Nonrestorative or Poor Quality of Sleep

The fact that opioids can cause drowsiness may obscure a very common problem: difficulty initiating and maintaining sleep at night and poor quality of sleep. Pain perception tends to decrease when a person is distracted by other stimuli, so that chronic pain may be worse in the evening and over the weekend when there are fewer activities competing for attention.14 It is not surprising that pain medications tend to be used (and overused) at bedtime, along with non-analgesic hypnotics and sedatives, as part of relief-seeking behavior. If a person cannot fall or stay asleep at bedtime due to pain, then the best sleeping medication might not be a hypnotic but an analgesic, along with other interventions, to relieve the pain. Hypnotics may be useful, but they should substitute analgesic treatments when pain is the targeted cause of insomnia.

The use of analgesic and hypnotic medication at bedtime needs to be discussed carefully with patients, since relief-seeking behavior may lead to inappropriate medication use. Sometimes patients actually are doing the medically correct thing by taking pain medication at bedtime to relieve pain in order to sleep. However, if the prescribing clinician does not know the circumstances and authorize effective pain medication in the evening, then the patient may violate the opioid treatment agreement. This behavior falls into the category of “pseudoaddiction,” or what one writer has termed “iatraddiction.”15

Corrective Treatments

Whenever possible, clinicians should prescribe corrective treatments that address disorders at the most fundamental levels. Many diseases are due to, or greatly aggravated by, lifestyle factors such as low activity levels, poor nutrition, emotional stress, poor sleep hygiene and unhealthy work environments. Changing lifestyles and social conditions usually is much more difficult than prescribing medicines or procedural interventions. A key factor in motivating lifestyle change is the quality of the doctor-patient relationship or the “therapeutic alliance.” Adequate time spent with patients, good bedside manner by clinicians, and caring attitudes and practices of office staff together have a major therapeutic impact, not to mention the reduction in risk of malpractice suits and other expressions of patient dissatisfaction and anger. Treatment of underlying general medical and psychiatric disorders in chronic pain patients generally should follow the standard indications.

Palliative Arousal Management

Clinicians who treat chronic pain patients need to evaluate and manage arousal. Full alertness and wakefulness should be the normal level of consciousness at all times other than during healthy and desired sleep. If arousal is abnormally decreased or increased, try to identify and treat each cause at the most fundamental, corrective level. When corrective management is not possible or sufficiently effective, then consider palliative or symptomatic interventions to raise or lower arousal levels.

Excessive daytime sleepiness (EDS) is a major focus for arousal management in chronic pain, and achieving full alertness can have a profoundly positive effect on quality of life. It is not acceptable for clinicians to recognize pathological sedation but then fail to consider efforts to relieve it. On the other hand, transient sedation may occur during the titration of pain and psychotropic drugs. Treating EDS also improves energy, cognition, mood, pain and nighttime sleep, so there are several potential “bonuses” to effective arousal management.

An example of palliative arousal management is the use of modafinil for the treatment of EDS in OSA. Modafinil does not correct the fundamental problems in OSA. It does not directly stimulate respiratory drive or unblock airways. At the same time, helping a person with OSA feel alert, energetic and more cognizant can lead to higher activity levels, greater caloric consumption, better compliance with treatment, and in so doing contribute to weight reduction and better sleep at night.

An important cause of arousal management is the chronic pain patient on opioids and other coanalgesic drugs such as antidepressants and anticonvulsants. Some patients do not experience sedation when opioids are titrated gently. Others do, but it is mild and transient, so they do not require specific therapy. A smaller number of patients on opioids, as well as a number of other drugs, experience significant or persistent EDS and require ongoing and palliative arousal management.

Therapeutic Psychostimulants

There are two groups of commonly used therapeutic psychostimulants (also referred to as stimulants or CNS stimulants) approved for use in the United States: methylphenidate (Ritalin, Ritalin SR, Ritalin LA, Metadate, Metadate CD, Methylin, Methylin ER, Concerta) and the amphetamines (Adderall, Adderall XR, Dexedrine, Dexedrine Spansules, Dextrostat). Dexmethylphenidate, the disomer of methylphenidate, is available as Focalin. Adderall is a combination of mixed salts of a single-entity amphetamine product (amphetamine sulfate, amphetamine aspartate monohydrate, dextroamphetamine saccharate, dextroamphetamine sulfate). Dexedrine and Dextrostat contain dextroamphetamine, the d optical isomer of amphetamine. Methamphetamine (Desoxyn) is approved for Attention-Deficit/Hyperactivity Disorder (ADHD) and short-term treatment exogenous obesity refractory to alternative therapy.

Caffeine, a mild psychostimulant in coffee, other beverages and foods, is the most commonly used psychoactive drug in the world.16 It is used to potentiate analgesia in prescription headache medications, usually in combination with butalbital17 (a barbiturate) and/or a mild analgesic (acetaminophen, aspirin).18 When used excessively it can lead to caffeinism19 and chronic headaches.20 Illicit amphetamine (“speed”), methamphetamine (“crystal,” “ice”), cocaine (“coke,” “snow”) and methylene dioxy-methamphetamine (MDMA, “ecstasy”) are drugs of abuse. Nicotine is used medicinally for treatment of smoking cessation.

New Wakefulness-promoting Class of Drugs

Modafinil is the first in a new class of drugs called wakefulness-promoting agents. Psychostimulants are thought to exert their effects by inhibiting the reuptake of norepinephrine and dopamine in the CNS, thus increasing these monoamines in the synaptic cleft. In contrast, modafinil has no direct effect on norepinephrine or dopamine. It appears to work by activating the tuberomammillary nucleus (TMN) in the hypothalamus, resulting in broad cortical arousal. Psychostimulants are sympathomimetic drugs; modafinil is not. Psychostimulants tend to activate the cardiovascular system and increase pulse and blood pressure; modafinil is less likely to do so, especially at recommended doses. These two types of drugs have different mechanisms of action, and they can be used together to treat more difficult cases of sleepiness and fatigue.

Psychostimulants and Modafinil as Adjuvants to Opioids

In the author’s experience, psychostimulants and the wakefulness-promoting agent, modafinil (Provigil), are underused in the management of chronic pain. The classic literature on chronic pain management generally makes reference to methyl-phenidate and dextroamphetamine as adjunctive drugs (coanalgesics) that improve opioid analgesia and reverse opioid-induced sedation. This literature was developed when chronic pain management with opioids mostly comprised cancer pain. One study showed that when dextroamphetamine 10 mg was added to morphine 6 mg for postoperative pain, the combination provided about the same amount of pain control as morphine 12 mg alone.21 Studies of methylphenidate have shown it to have significant analgesic effects in cancer pain.22 A more recent study showed that dextroamphetamine had preventive effects on chronic tension-type headaches and migraine headaches in some subjects.23

The analgesic impact of psychostimulants appears to be mediated through their dopaminergic and noradrenergic properties.24 Naloxone, an opioid antagonist, does not reverse amphetamine-induced analgesia, whereas haloperidol, a dopamine agonist, does.25 Modafinil, having no dopaminergic or noradrenergic activity, does not tend to have a direct analgesic impact,26 but it might help indirectly with pain control by improving wakefulness and energy, which in turn increase activity levels. Psychostimulants may be opioid-sparing, but in the author’s experience, they have a permissive effect. They allow adequate doses of opioids to achieve the best pain relief while boosting arousal and energy levels that might be lowered when higher doses of opioids are needed.27

Psychostimulants are useful clinically for treating sleepiness, low energy, pain, attention-deficit/hyperactivity disorder (ADHD), cognitive disorder due to other conditions, apathy, depression and narcolepsy. Among psychiatrists, psychostimulants are widely used not only for ADHD, but as adjunctive drugs in the treatment of depression.28-31 Psychostimulants, as well as bupropion (Wellbutrin),32 are added to serotonin selective reuptake inhibitors (SSRIs) to improve mood, and they also may relieve apathy,33,34 increase alertness and energy,35-37 and enhance attention and concentration. Psychostimulants can be useful in appetite and weight management,38,39 although they have been much abused in this context,40 so patient selection and close monitoring are critical. With the worldwide epidemic of obesity and metabolic syndrome, greater consideration should be given to drugs that do not contribute to these problems.

Psychostimulants and Modafinil Dosing Considerations

Doses of dextroamphetamine and methylphenidate cited in classic pain literature tend to be low, up to 20 mg/day. In earlier psychiatric literature, doses trended higher, up to 40 mg/day and occasionally higher.41 The package insert for Adderall XR refers to treatment of adults with up to 60 mg/day. The maximum recommended dose for children is 30 mg/day. Similarly, the package insert for Ritalin LA does not recommend daily doses >60 mg. The recommended starting dose of Adderall XR is 10 mg for children and 20 mg for adults. Ritalin LA can be started up to 20 mg for children and adults. For both drugs, dosage should be individualized according to the therapeutic needs and response of the patient. In the author’s experience, doses above 80 mg/day are infrequent.

Amphetamine and methylphenidate psychostimulants are schedule II controlled drugs. Some states have special regulations. In Michigan, amphetamines may be prescribed only for ADHD, in which case the diagnosis must be written on the prescription blank. For all other indications including narcolepsy, augmentation of antidepressants, sedation and fatigue from opioids and other drugs, and as analgesic adjuvants, it is necessary to apply for a special amphetamine waiver.42

Modafinil is a schedule IV controlled drug. The recommended daily dose is 200 mg, although clinicians may start patients on 100 mg. The package insert refers to doses up to 400 mg. In the author’s experience, doses above 400 mg/day are infrequent.

Sodium Oxybate: Innovative Use for EDS, Fatigue, and Pain

Sodium oxybate (Xyrem), a CNS depressant, is approved for treatment of cataplexy in patients with narcolepsy. Its effects in narcolepsy include increased slow-wave sleep (delta sleep, stages III and IV) and improvements in excessive daytime sleepiness.43 Sodium oxybate reduces pain and fatigue in patients with fibromyalgia,44 a disorder characterized by frequent awakenings (alpha intrusions) likely due to pain that interrupts delta sleep.45 Deficits in slow-wave sleep are associated with psychiatric and neurodegenerative disorders.46,47 Newer medications that specifically improve slow-wave sleep may find broader use in managing a number of conditions associated with slow-wave sleep deficit, EDS and fatigue.


Sleepiness and fatigue are common problems among chronic pain sufferers. Patients on opioids who appear drowsy or tired should be evaluated thoroughly to identify all factors that might be contributing to these symptoms. Clinicians should not assume that opioids are causing sedation and fatigue merely because they are being prescribed. Sleep apnea, other primary sleep disorders, general medical conditions, neurological disorders, psychiatric syndromes and side effects of medicines and drugs all should be considered. Whenever possible, treat the causes of EDS and fatigue correctively, and always consider palliative arousal and energy management. Pain itself often interferes with sleep initiation and restorative sleep. More complete relief of pain improves sleep and may relieve daytime sleepiness, fatigue, apathy and cognitive impairment.

Chronic pain management has evolved through several eras: cancer pain, non-malignant chronic pain, advances in regional pain management and the development of controlled-release opioids and newer drugs. The current era marks the challenges of drug abuse and diversion with institutionalization of risk management strategies. It is the author’s hope that the coming era will prioritize behavioral health and quality of life that stream not only from relief of pain but from alert consciousness, full energy and vitality, nimble cognition, and the capacity to experience full joy and gladness.

Last updated on: January 4, 2012
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