Depression and Pain

Abstract

Only recently have the association between depressive disorders and the presentation of painful physical symptoms gained attention. This article reviews the symptoms, assessment, and diagnoses of pain associated with depression. This article also reviews pharmacological treatment options.

Introduction

In any given year, major depression affects 9.5 percent of Americans,¹ and is the leading cause of disability in the US.² Common and chronic in nature, it affects people of all ages, races, and socioeconomic status. It is associated with significant impairment in work productivity, role function, and quality of life (QOL). Frequently, painful physical symptoms accompany depression and may add to a decreased QOL.³

Independent of a depressive disorder, chronic pain is also a well known cause of morbidity. Recurrent or persistent pain is estimated to occur in about 45 percent of the general population.⁴ Chronic pain is one of the most common reasons for seeking medical care and is associated with the need for medical attention at a rate almost five times that of the general population.^4,5

Only recently has the association between depressive disorders and the presentation of painful physical symptoms gained attention. The current view moves beyond physical sensation, understanding pain to be a symptom modulated by mental, emotional, and sensory mechanisms and including both sensory and emotional components.⁶ The presence of painful symptoms not only affects economic productivity but also leads to worsening health-related quality of life (HRQOL).⁷ As a result, there has been a new emphasis on social and psychiatric approaches toward its treatment in addition to pharmacological interventions.

Economic Burden of Depression and Pain

Depressed workers report significantly more health-related loss of productive time (LPT) than those without depression due to absenteeism and reduced work performance. In absolute amounts, depressed workers cost the US economy losses in excess of $30.94 billion compared to nondepressed workers.⁸ In addition, $61.2 billion of the total annual lost productivity in the US can be attributed to pain alone.⁹ Results of the American Productivity Survey found that individuals with major depression presenting with physical symptoms (pain, weakness, or fatigue) reported the most LPT compared to those without pain. In the same study,⁸ less than a third of the depressed workers reported receiving a prescription drug for depression or anxiety in the previous 12 months, and there was a high prevalence of partially treated depression among the work force.

Quality of Life Among Patients with Depression and Pain

Data from the World Health Organization indicates that over 75 percent of patients with depression in primary care settings complain of pain-related symptoms, such as headache, stomach pain, neck and back pain, or diffuse unspecified pain.¹⁰ Worldwide, 22 percent of all primary care patients experience persistent pain and are four times more likely to have depression or anxiety than patients who are pain-free. If the pain is diffuse, the depression risk is even higher and QOL is poorer. In addition, increased pain intensity predicts increased severity of depressive symptoms and worsening QOL.^11,12 Survey data from the Behavioral Risk Factor Surveillance System also shows a strong relationship between mental health impairment and reduced health-related QOL.¹³

Moreover, patients with serious physical illness who have comorbid pain and depression have poorer outcomes. A study of new neurology patients found that depression and pain often persist for extended periods of time, having long-term negative effects on health status, and those patients with comorbid depression and pain had the greatest utilization of healthcare services and the greatest health impairment.¹⁴ Other research has shown that women recovering from hysterectomies had 3 to 5 times the odds of ongoing QOL impairment if they had experienced pain and depression.¹⁵

CoMorbid Pain/Depression and Suicide

Patients with depression and chronic pain are more likely to commit suicide than patients with depression or pain alone or have pain with out depression.^16,17 Survey data from the Hispanic Health and Nutritional Center for Health Services showed that the lifetime prevalence of suicidality, both ideations and attempts, was 2 to 3 times more in patients with chronic pain.¹⁸

Depression and Pain Associations in Psychopathology

There is growing clinical and biological evidence of the close association between pain and depression. In a multinational study¹⁹ of depressed adults with chronic pain, the prevalence of pain increased linearly with age, headache being the most common chronic pain symptom reported. Subjects with major depression were four times more likely to report chronic pain. More than a quarter of subjects with at least one of three key depressive symptoms also had at least one chronic pain condition. The more depressive the reported symptoms were, the stronger the association between pain and depression. Patients with backaches and headaches had the highest odds of having major depression. It was also noted that having a chronic painful condition elongated the duration of depressive symptoms compared to patients without painful conditions.¹⁹

Similarly, a study of depressed inpatients found that 92 percent had pain complaints at admission, with 76 percent reporting multiple pain complaints.²⁰ Pain complaints were related to depressive and anxiety symptoms, but not to age, suicide attempts, or depression severity. These complaints decreased in the first 10 days of hospitalization, as did depression scores.

Neurobiological Explanations of Pain and Depression Comorbidity

Pain and depression are often comorbid, explained by the association between the central and peripheral neural pathways affected in depression. Descending serotonergic and noradrenergic pathways originate from the same neurons as the central pathway (raphe nucleus and locus ceruleus).²¹ When these pathways are disrupted in depression, causing emotional and vegetative symptoms, the descending inhibitory pathways may be affected as well. The modulation of pain through these descending pathways is disrupted and pain sensations are allowed to ascend to the brain. Sensations from various organs are not suppressed and are interpreted by the body as pain. This explanation accounts for the fact that pain in many depressed patients has no detectable pathology.

The above theory may also explain why antidepressants modulating both NE and 5-HT are more effective in pain management than those that have only NE or 5-HT properties.²² The importance of 5-HT and NE in modulation of pain is also demonstrated in chronic pain patients without an affective component. In “functional somatic syndromes,”²³ such as fibromyalgia and irritable bowel syndrome, dual action antidepressants have been effective in treating painful symptoms.^17,24

Diagnosis of MDD in Chronic Pain Patients

Currently, diagnostic options are the following: 1) inclusion of somatic complaints towards the diagnosis of MDD, except when they are clearly and fully accounted for by a general medical condition (DSM-IV); 2) inclusion of all criteria towards diagnosis of MDD when assessing medically ill patients regardless of physical illness confounding, as the risk of untreated depression outweighs over-treated depression;²⁸ or 3) alternate diagnosing criteria in which there is substitution of somatic symptoms with nonsomatic symptoms. Inclusive and substitute criteria are likely to reduce false negatives in assessing depression in chronic pain patients.²⁹

There is no clear consensus about the measurement of depression in chronic pain. Standard depression measures include the following: Beck Depression Inventory (BDI); Montgomery-Asberg Depression Rating Scale (MADRS); Center for Epidemiological Studies-Depression Scale (CES-D); Hamilton Rating Scale for Depression (HRSD); and Inventory for Depressive Symptomatology (IDS). Failure to modify the standard assessment procedures for depression in a medical population probably increases false positive symptoms as somatic complaints, fatigue, sleep disturbance, and weight loss/gain are common in both depression and chronic pain.^25,26 As disability and somatic preoccupation are inherent in patients with chronic pain, this could lead to misinterpretation of Beck Depression Inventory (BDI) scores, the most common scale used. For example, it is noted that chronic pain patients tend to endorse items related to performance difficulty and physiological manifestations more often than items reflecting negative attitudes and suicidality.²⁷

Symptoms likely to be reported by both depressed and non-depressed patients with chronic pain include weight loss, sleep disruption, and work inhibition.²⁷ The study authors recommend exclusion of these items, scoring 18 rather than 21 items on the BDI, to significantly improve its diagnostic abilities. The presence of depressive symptoms is more likely if the patient with chronic pain scores a 10 or more on an 18-item BDI scale.

In another study,³ the authors concluded that removal of somatic items from the Center for Epidemiological Studies- Depression (CES-D) Scale led to a 13-percent increase in specificity but a very small increase in sensitivity. It was concluded that a cut-off score of 19 would be more sensitive in diagnosing depression patients with somatic complaints like chronic pain, increasing specificity by 12 percent.

Assessment of Pain Symptoms

There are a number of measures used to assess various aspects of pain. Some of these instruments address quantitative components, such as location, intensity, and duration [McGill Pain Questionnaire (MPQ); Visual Analog Scale (VAS)]. Other assessments reflect individual adaptation to chronic pain, including level of functioning (West Haven-Yale Multidimensional Pain Inventory [WHYMPI];³¹ Oswestry Disability Scale;³² and Survey of Pain Attitudes [SOPA]).

The Role of Antidepressants in Depression and Pain

Within the spinal cord both NA and 5 HT receptors are known to produce analgesia.³³ It has been proposed that antidepressants interact directly and indirectly with endogenous opioids to produce analgesia.³⁴ Significant interactions accounting for analgesic actions of antidepressants include alpha-adenoreceptors, histamine, cholinergic muscarinic, and nicotinic receptors, and adenosine and NMDA receptors.

Antidepressants have been shown to have analgesic properties in the presence or absence of depression. The presence of depression requires higher medication doses. Onset of action in chronic painful conditions is much earlier (one week) compared to treatment response in depression.³⁵ Although pain and depression have a similar neuronal basis, these conditions are distinct entities that should be addressed separately.

Tricyclic Antidepressants

Study results from 41 controlled trials indicate that tricyclic antidepressants (TCAs), such as amitriptyline, desipramine, imipramine, clomipramine, and doxepine, have analgesic effects.³⁶ TCAs have been shown to be effective against chronic painful conditions, such as post-herpetic neuralgia and diabetic neuropathy,^37,38 tension headaches,³⁹ migraine,⁴⁰ arthritic pain, and chronic back pain.⁴¹

Selective Serotonin Reuptake Inhibitors (SSRIs)

On the other hand, SSRIs have not been shown to be very effective in relieving pain symptoms.³⁶ Two smaller studies have shown paroxetine⁴² and citalopram⁴³ to be better than placebo. Fluoxetine⁴⁴ and sertraline⁴⁵ have not been found to have any analgesic effect in most studies.

Traizolopyridines

Of the four known placebo-controlled trials evaluating the use of traizolopyridines (trazodone), only one has supported some analgesic affect.⁴⁶ Other studies have failed to show any effect on chronic back pain or rheumatoid arthritis.^47,48 A trial comparing amitriptyline and trazodone found similar efficacy in relieving pain.⁴⁹

Bupropion

A randomized, double-blind, placebo-controlled, crossover study⁵⁰ of buproprion SR showed significant pain relief beginning at Week 2 of treatment. A significant decrease in the impact of pain on QOL was observed in those patients receiving bupropion SR compared with placebo. In an open-label study of bupropion SR in patients with neuropathic pain, pain relief was shown to be statistically significant after 4 weeks of treatment.⁵¹ Most patients were not depressed, and analgesia was observed to occur without change in depression ratings in most patients who responded.⁵⁰

Venlafaxine

Venlafaxine, because of its dual effect on neurotransmitters, has shown promise in the treatment of pain. Entsuah, et al.,⁵² in a pooled analysis of 31 randomized, double-blind, clinical studies, found that venlafaxine was superior to SSRIs in causing full remission of somatic complaints. Double-blind placebo-controlled studies have shown venlafaxine to be effective in the treatment of diabetic neuropathic pain,^53,54 and neuropathic pain secondary to breast cancer.⁵⁵

Compared to amitriptyline, patients that were switched to venlafaxine showed equivalent pain relief with considerably less side effects.³⁵ In a comparator trial of venlafaxine and imipramine, the two antidepressants were qualitatively and quantitatively similar after four weeks of treatment for painful neuropathy.⁵⁴ Patients in an eight-week, open-label study of venlafaxine in the treatment of fibromyalgia⁵⁷ experienced 50-percent or greater symptom reduction. In another open-label trial,⁵⁸ inpatients with fibromyalgia and comorbid depression showed significant reduction in mean pain and disability. However, there was no correlation between the relief of depression and anxiety with the effects on pain caused by fibromyalgia.

Duloxetine

Goldstein, et al.,⁵⁹ evaluated the effectiveness of duloxetine (40mg, 60mg, 80mg) compared to placebo and paroxetine in treatment of major depression and its associated poinful symptoms. Assessing overall pain, headache, back pain, and shoulder pain, time in pain while awake, and how pain interfered with daily activities, the authors found that across groups, for overall pain severity, 80mg of duloxetine showed significant correlation with improvement of HAM-D scores. The effect of duloxetine treatment was much greater among patients with a high Somatic Symptom Inventory (SSI) score (>2.2). Also, for overall pain severity the reduction in scores on the Visual Analogue Scale from baseline was significantly greater within each of the subgroups compared to placebo. This change was not affected by patient's age, gender, or race. The beneficial effect on pain was robust and confirmed by several measures, such as repeated measure analysis, analysis of mean changes in scores and the analysis of the AUC (area under the curve).⁵⁹

Milnacipran

Milnacipran is a dual action antidepressant that inhibits the reuptake of both noradrenaline and serotonin. It also binds to NMDA receptors.⁶⁰ In a double-blind randomized, placebo-controlled, multicenter study comparing two dosing regimens with placebo in patients with fibromyalgia, the twice-daily dose of milnacipran was significantly more effective compared to once daily dose. From weekly scores, 37 percent of twice-daily milnacipran treated patients reported at least a 50-percent reduction in pain intensity compared with 14 percent of placebo-treated patients. Over 70 percent of patients receiving either of the two regimens of milnacipran showed improvement in global impression of change scores compared to 38 percent of patients on placebo. Significant improvement was seen in domains like ‘physical functioning' and ‘feel good' in both the milnacipran groups. Other open-label studies and case reports have shown milnacipran to be effective in the treatment of fibromyalgia.^61,62

Role of ECT in depressed patients in chronic pain

There is some research into the beneficial effects of electroconvulsive therapy (ECT) in the treatment of depression with chronic pain.^63–65 In a case series of 21 depressed patients with chronic pain, Bloomstein, et al.,⁶⁶ found significant improvement in pain with associated improvement in affective symptoms using ECT as a treatment modality. Schreiber, et al.,⁶⁷ found that improvement of pain threshold flowed closely with patterns of improvement of affective states. This improvement of pain threshold was evident after the sixth ECT treatment. Pain tolerance, however, showed a delayed pattern reaching statistical significance after the end of treatment (end of 12 ECT treatments). The authors suggest that the beneficial effect of ECT could be secondary to stimulation of deep brain structures like basal ganglia, thalamus, alternation of cerebral blood flow and permeability of the blood brain barrier, modulation of beta adrenergic receptors, and change in muscarinic, cholinergic, and dopaminergic systems.

Recommendations for Treating Depression with Chronic Pain

Since depression frequently presents with vague aches and pains or with predominantly physical symptoms, treatment of these symptoms requires a thorough evaluation both at the onset of treatment and during the routine monitoring of the full dimension of the depressive syndrome. With the recent emphasis on sustained remission as the treatment goal for depression, a lack of focus on the associated symptoms of depression, like anxiety and painful physical complaints, leaves patients vulnerable to incomplete remission and associated risks for morbidity and mortality. Thus, the initial treatment approach should focus on the core symptoms as well as physical symptoms, with antidepressant medications likely to improve symptoms in all domains of the syndrome.

It is recommended that pain and depression (as evidenced by sleep disturbance, loss of energy, chronic fatigue, and persistent worrisome thoughts)⁶⁸ be treated as separate and independent entities. Initially, an empirical trial of antidepressants is recommended for at least four weeks. If there is less than a 20-percent reduction in depressive symptoms, a switch to another antidepressant or the addition of an augmentation agent would be recommended. If there is a 20-percent or greater reduction of symptoms, the antidepressant should be continued for an additional 4 to 6 more weeks until the expected maximal benefits are achieved between 12 to 16 weeks. The addition of goal-directed, depression-focused psychotherapy is recommended if response to the initial monotherapy is incomplete. Patients with a preference for psychotherapy could start the treatment with a depression-focused psychotherapy and monitor symptoms in the manner described above. A continuation and maintenance of antidepressant and/or therapy is always recommended along with aggressive treatment of residual symptoms and increased social support.⁶⁸