by Michael Clark, M.D., M.P.H.
- Signs, Symptoms, and Prevalence
- Antidepressants as Analgesics
– Commonly Used Antidepressant Medications
Patients with chronic pain, when compared to those with almost all other medical conditions, suffer dramatic reductions in physical, psychological, and social well being, and their Health Related Quality of Life is lower (Atkinson et al. 1991; Becker et al. 2000; Skevington 1998). Many factors can interfere with the successful treatment of chronic pain including undiagnosed diseases, mental disorders, emotional distress, personality traits, and personal beliefs. These factors must be addressed directly to ensure that every barrier to the relief of chronic pain is addressed. Depression is one of the most common problems experienced by patients with chronic pain.
In several studies of patients presenting to clinics specializing in the evaluation of pain, the prevalence of psychiatric conditions was systematically assessed. Affective and anxiety disorders were the most commonly found (Reich et al. 1983). For example, the prevalence of major depression in patients with chronic low back pain is 3-4 times greater than in the general population (Sullivan et al. 1992). However, the causal relationship between these syndromes remains controversial.
Physical symptoms are common in patients suffering from major depression (Lipowski 1990). Approximately 60% of patients with depression report pain symptoms at the time of diagnosis (Magni et al. 1985; von Knorring et al. 1983). In a study of 1,016 members of an HMO, persons with moderate to severe depression at baseline were more likely to have developed headache and chest pain 3 years later (Von Korff et al. 1993). The presence of a depressive disorder has also been demonstrated to increase the risk of developing chronic musculoskeletal pain (Leino and Magni 1993; Magni et al. 1993; Magni et al. 1994). Older age increased the risk for neck, back, and hip pain even more. Even after 8 years, depressed patients remained twice as likely to develop a new chronic pain condition compared to non-depressed individuals.
In patients with chronic pain referred for evaluation to comprehensive pain programs, 8-50% have been reported to have current major depression (Smith 1992). In another analysis of the 1,016 HMO members, the prevalence of depression was 12% in individuals with 3 or more pain complaints compared to only 1% in those with one or no pain complaints (Dworkin et al. 1990). The U.S. Center for Health Statistics conducted an 8 year follow-up survey and found 32.8% of the general population reported chronic pain symptoms. Depression was the most important variable associated with persistent chronic pain (Magni et al. 1993). If pain resulted in a loss of independence or mobility that decreased an individual’s participation in social activities, the risk of depression was significantly increased (Williamson and Schulz, 1992).
Individuals with chronic physical complaints also have higher rates of lifetime major depression. In groups of patients with medically unexplained symptoms such as chronic back pain and chronic dizziness, 66% of patients have a history of recurrent major depression compared to less than 20% of control groups with medically explained symptoms (Atkinson et al. 1991; Katon and Sullivan 1990; Sullivan and Katon 1993). Katon and colleagues have demonstrated a linear relationship between lifetime depression and anxiety disorders and the number of medically unexplained symptoms including pain complaints (Katon et al. 1991).
Family studies have also supported the increased risk for depression in patients with chronic pain. Compared to the general population, patients with chronic pain had more first degree relatives with depression and depressive disorders (Magni 1990). Even in patients with chronic pain without a personal history of depression, significantly higher rates of depression have been found in family members (Magni et al 1987). A biological vulnerability to affective disorder in patients with chronic pain is also supported by studies of biological markers. Decreased REM latency, decreased serum melatonin and lower density of 3H-imipramine binding sites on platelets have been found in patients with chronic pain (Blumer et al. 1982; Magni et al. 1987; von Knorring and Ekselius 1994; von Knorring et al. 1983).
The diagnosis of depression in patients with chronic pain is controversial. Many of the criteria traditionally used to diagnose major depression overlap with the symptoms experienced by patients with chronic pain. It is important to distinguish these manifestations of a chronic pain condition from the general distress such a condition provokes and the psychiatric diagnosis of a mood disorder. In a comparison of measures of emotional distress, self-reported depressive symptoms, and the presence of major depression in 211 patients with chronic pain in a university pain clinic, major depression was significantly related to self-reported disability and negative thoughts about pain (Geisser et al. 2000). Self-reported depressive symptoms were also highly related to the evaluative or cognitive component of pain but affective distress was uniquely related to the sensory or emotional component of pain.
Alternative sets of diagnostic criteria for major depression in patients with chronic pain have been proposed and include: 1) disregarding symptoms that are caused by medical problems, 2) replacing somatic symptoms with non-somatic alternatives, and 3) including all symptoms regardless of presumed cause (Wilson et al. 2001). The prevalence of major depression ranged from 19 to 36% with disregarding symptoms producing the lowest rate. However, patients who were excluded from diagnosis by this method were comparable to those patients diagnosed with depression across all methods. These findings support the use of inclusive criteria for major depression to avoid neglecting patients who have significant distress and disability.
Depression is not simply a comorbid condition but interacts with chronic pain to increase morbidity and mortality. Depressed chronic pain patients report greater pain intensity, less life control, and more use of passive-avoidant coping strategies. They also describe greater interference from pain and exhibit more pain behaviors than chronic pain patients without depression (Haythornthwaite et al 1991; Herr et al. 1993; Weickgenant 1993). The presence of preoperative depression in patients undergoing lumbar discectomy was predictive of poorer surgical outcome at 1 year follow-up (Junge et al. 1995). In patients with rheumatoid arthritis, depressive symptoms were significantly associated with negative health and functional outcomes as well as increased health services utilization (Katz and Yelin 1993). Depression has been shown to be the best predictor of application for early retirement at 6 month follow-up in a study of 111 patients with acute radicular pain and lumbar disc prolapse/protrusion (Hasenbring et al. 1994).
The consequences of unrecognized and untreated major depression are substantial. The most severe consequence of major depression is suicide. For example, patients suffering from chronic pain syndromes including migraine, chronic abdominal pain, and orthopaedic pain syndromes report increased rates of suicidal ideation, suicide attempts, and suicide completion (Fishbain 1999; Fishbain et al. 1991; Magni et al. 1998). In a study of patients who attempted suicide, 52% suffered from a somatic disease and 21% were taking analgesics daily for pain (Stenager et al. 1994). In another similar study, patients with chronic pain completed suicide at 2-3 times the rate in the general population (Fishbain et al. 1991).
Oncology patients with concomitant pain and depression were significantly more likely to request assistance in committing suicide as well as actively take steps to end their lives. In contrast, those with pain in the absence of depression were unlikely to request the interventions of euthanasia and physician-assisted suicide (Emanuel et al. 1996). Depression, not suicidal status, consistently predicted lower levels of functioning, higher pain severity, more pain-related disability, less use of active coping, and more use of passive coping in patients with chronic pain on a university inpatient unit (Fisher et al. 2001). If a patient with chronic pain expresses suicidal ideation, he/she should receive immediate assistance to ensure safety and ensure evaluation for depression. Depression should be treated aggressively and not simply “understood” as an expected outcome of chronic pain.
The effectiveness of antidepressants for the treatment of major depression is well documented; however, the analgesic properties of this class of medication are under-appreciated. It is important for the patient to understand for which of these applications an antidepressant is being prescribed. Likewise, it is important that the physician understand that antidepressants can treat both pain and depression.
In 1960, the first report of imipramine use for trigeminal neuralgia was published (Paoli et al. 1960). Since then, the antidepressants, and in particular the tricyclic antidepressants (TCA), have been commonly prescribed for the treatment of many chronic pain syndromes, especially neuropathic pain. Animal models have been established for the study of nociception and neuropathic pain (Ollat and Cesaro 1995). Current research suggests that the analgesic effect of antidepressants is mediated by the blockade of reuptake of norepinephrine and serotonin. The resulting increase in the levels of these neurotransmitters enhances the activation of descending inhibitory neurons (King 1981; Magni 1987). Other aspects of monoaminergic systems have been implicated in the analgesic action of antidepressants. Beta-adrenoceptors have been demonstrated to mediate the analgesic effects of desipramine and nortriptyline (Mico et al. 1997). Imipramine demonstrated differential hypoalgesic effects depending on the experimental paradigm used to assess pain (Poulsen et al. 1995). TCA’s may reduce hyperalgesia but not tactile allodynia because different neuronal mechanisms underlie different manifestations of neuropathic pain (Jett et al. 1997). Generally, amitriptyline or TCA’s with a similar pharmacological profile are considered most effective analgesic agents but randomized controlled trials have not demonstrated consistent differences between the TCA’s (Bryson and Wilde 1996).
In a review of 39 placebo-controlled studies, antidepressants were reported to be superior to placebo in 80% (Magni 1991). The findings in a number of these studies have been challenged however because of poor study design and variable protocol criteria (Goodkin et al. 1995). A recent systematic review of randomized controlled trials and meta-analysis concluded that tricyclic antidepressants (TCA) are the only agents proven to benefit post-herpetic neuralgia (Volmink et al. 1996). Tricyclic antidepressants have been most effective in relieving neuropathic pain and headache syndromes (Gruber et al. 1996; MacFarlane et al. 1997; Max et al. 1987; McQuay et al. 1996; Vrethem et al. 1997; Wesselmann and Reich 1996). The analgesic efficacy was not dependent on mood elevation. A recent placebo-controlled, double-blinded, randomized clinical trial of nortriptyline for chronic low back pain in patients without depression demonstrated significant reduction in pain intensity scores (Atkinson et al. 1998).
A variety of treatment studies of post-herpetic neuralgia and painful diabetic peripheral neuropathy have employed TCA’s in mean daily doses ranging from 100-250 mg (Max 1994; Onghena and Van Houdenhove 1992). Over 60% of patients reported improvement usually beginning in the third week of treatment and serum levels of TCA’s were in the low end of the therapeutic range for the treatment of depression. The results of investigations to determine drug concentrations needed for pain relief remain contradictory and no clear guidelines have been established (Kishore-Kumar et al. 1990; Sindrup et al. 1989). In a study of TCA utilization, 25% of patients in a multidisciplinary pain center were prescribed these medications. However, 73% of treated patients were prescribed only the equivalent of 50 mg or less of amitriptyline suggesting the potential for additional pain relief (Richeimer et al. 1997). While tertiary amines have been used most commonly, they are metabolized to secondary amines that are associated with fewer side effects such as decreased GI motility and urinary retention. Desipramine and nortriptyline had significantly fewer side effects and led to discontinuation of the drug less frequently than clomipramine, amitriptyline, and doxepin. Nortriptyline, the major metabolite of amitriptyline, causes less sedation, orthostatic hypotension, and falls than imipramine and has been demonstrated to be as effective as amitriptyline in treating chronic pain (Roose et al 1981; Watson et al. 1988). The cost of TCA’s for pain treatment is generally much lower (less than $5.00 per month) than other antidepressants and medications with analgesic activity (Adelman and Von Seggern 1995).
The selective serotonin reuptake inhibitors produce weak antinociceptive effects in animal models of acute pain (Gatch et al. 1998; Paul and Hornby 1995; Schreiber et al. 1996). This antinociception is blocked by serotonin receptor antagonists and is enhanced by opioid receptor agonists. A large number of studies have investigated the potential role of serotonin receptor subtypes in both nociceptive and hyperalgesic mechanisms of pain but no definitive conclusions have been delineated. In human clinical trials, the efficacy of serotonin reuptake inhibitors (SRI’s) in chronic pain syndromes has been variable and inconsistent (Belcheva et al. 1995; Tokunaga et al. 1998). For example, desipramine was superior to fluoxetine in the treatment of painful diabetic peripheral neuropathy (Max et al. 1992).
However, paroxetine was not beneficial in a study of patients with diabetic neuropathy (Sindrup et al. 1990). In other studies, fluoxetine significantly reduced pain in patients with rheumatoid arthritis and was comparable to amitriptyline (Rani et al. 1996). Recently, the SRI’s were shown to be effective in the treatment of headache, especially migraine, and were well tolerated by patients (Bank 1994; Foster and Bafaloukos 1994; Saper et al. 1994). In contrast, in a study of chronic tension type headache, amitriptyline significantly reduced the duration of headache, headache frequency, and the intake of analgesics but citalopram, an SRI, did not (Bendtsen et al. 1996). Until the results with SRI’s are more consistent, they are not recommended as first choice medications unless a specific contraindication exists for TCA’s (Max et al. 1991).
Biogenic amines are the neurotransmitters of neurons from the cortex and hypothalamus responsible for descending inhibition of nociception at the level of the spinal cord. This mechanism for the neurobiology of pain suggests potential efficacy for all antidepressants, despite their different pharmacological actions, in the treatment of chronic pain. Norepinephrine and dopamine reuptake inhibitors such as buproprion produced antinociception in studies of thermal nociception (Gatch et al. 1998). Monoamine oxidase inhibitors have been found to decrease the frequency and severity of migraine headaches (Merikangas and Merikangas 1995). Buspirone has been found to be effective in the prophylaxis of chronic tension type headache however, buspirone-treated patients used more rescue analgesics for acute treatment of headache than those patients treated with amitriptyline (Mitsikostas et al. 1997). Protriptyline compared to placebo decreased chronic tension type headache frequency by 86% in a study of women with this condition (Cohen 1997). Trazodone was ineffective in decreasing pain in a double-blind, placebo-controlled study of patients with chronic low back pain (Goodkin et al. 1990; Marek et al. 1992). Venlafaxine inhibits the reuptake of both serotonin and norepinephrine with fewer side effects than TCA’s and SRI’s. In an animal model of neuropathic pain, venlafaxine reversed hyperalgesia as well prevented its development (Lang et al. 1996). Nefazodone possesses both the actions of analgesia and potentiation of opioid analgesia in the mouse hotplate assay (Pick et al. 1992). Other antidepressants that inhibit serotonin reuptake and block certain serotonin receptor subtypes such as mirtazapine will need to be studied in the treatment of pain (Galer 1995).
|Generic Name (Brand)||Daily Dose||Primary Mechanism|
|Heterocyclic Tertiary Amine (TCA’s)|
|Mixed NE and 5-HT reuptake inhibition|
|Heterocyclic Secondary Amine (TCA’s)|
|NE>5-HT reuptake inhibition|
|Selective Serotonin Reuptake Inhibitors (SSRI’s)|
|5-HT>>NE reuptake inhibition|
|Venlafaxine (Effexor)||75-450 mg||5-HT>NE>>DA reuptake inhibition|
|5-HT2 receptor blockade>5-HT reuptake inhibition|
|Bupropion (Wellbutrin)||100-450 mg||DA>NE reuptake inhibition|
|Mirtazepine (Remeron)||15-90 mg||Alpha2-NE and 5-HT2 presynaptic agonist
5-HT2/3 receptor blockade
Chronic pain is an intrapersonal experience not a specific diagnosis. Patients with chronic pain should receive treatment for underlying medical conditions, and should be evaluated for anxiety and distress. Major depression is a common psychiatric comorbidity of chronic pain, is associated with severe consequences, and is very responsive to treatment. In addition to being a primary treatment for depression, antidepressants are effective in the treatment of many chronic pain syndromes such as neuropathic disorders. The complexity of chronic pain requires an extensive knowledge of the potential actions of many pharmacological agents. The physician should always think about the innovative application of medications regardless of how they are traditionally classified.
JU, Von Seggern R: Cost considerations in headache treatment. Part 1: Prophylactic migraine treatment.
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