QUOTE
The Pain-Depression Conundrum: Bridging the Body and Mind
Author: Rollin M. Gallagher, MD, MPH
Medical Writer: Sophia Cariati, MA
Complete author affiliations and disclosures are at the end of this article.
Release Date: October 2, 2002;
Medscape clinical upate based on session presented at the 21st Annual Scientific Meeting of the American Pain Society.
Introduction
Pain and depression seem to go hand in hand. What person with intractable pain would not, understandably, be depressed? Yet the relationship of these conditions is complex and unpredictable. Indeed, people in pain are not invariably depressed, although approximately one third of patients with pain do experience comorbid depression. By contrast, three fourths of those with depression will present with physical symptoms, including pain.
Certainly, individuals with pain-related disorders are at risk for depression.[1-6] In fact, some research suggests that pain can be the best indicator of depression, especially among the elderly.[7] A number of studies also suggest that depression can augment the impairment associated with pain. In a 24-month study of 228 elderly patients with depression or pain living in retirement communities,[8] Mossey and colleagues[9] evaluated the severity of depression and pain and their impact on functional activity. Initially, almost 50% of the patients who did not suffer depression reported limitations associated with their pain. Over the course of 2 years, however, people who began experiencing depressive symptoms also began reporting more impairment associated with the pain. In addition, high levels of depression were consistently associated with high levels of pain-associated impairment, and in the presence of pain, even low levels of depression were associated with increased healthcare utilization.[10]
The relationship between pain and depression clearly is complex and still emerging. Recent research shows that serotonin and norepinephrine may modulate pain as well as mood. Understanding the shared pathophysiology of these phenomena will help clinicians to manage both conditions and ultimately help their patients to achieve remission. This Clinical Update will detail the epidemiologic, neurobiologic, and pharmacologic correlates of pain and depression.
Pain and Depression in Primary Care
Painful or uncomfortable physical symptoms are among the most common reasons individuals seek medical care. In a recent study, 107 HMO participants were asked to record all symptoms they experienced during a given 3-week period.[11] The results revealed that each person experienced at least 1 symptom, including backache, headache, or stomach pain, every 3-4 days. Yet patients reported less than 6% of these problems to a physician.
When and why, then, do people bring their aches and pains to the doctor? Evidence suggests that people seek out medical care when symptoms become worrisome, interfere with their daily lives, or are disabling. In addition, studies show that when depression, anxiety, panic, or other psychiatric conditions are present, symptoms are more likely to reach this threshold.[12-17] In fact, persons who seek healthcare for fatigue, migraine headaches, and gastrointestinal complaints experience more stressful life events, more distress, and are more likely to have an anxiety or depressive disorder than are those who do not seek care.[18,19]
Several studies of irritable bowel syndrome (IBS) poignantly demonstrate the role of psychiatric disorders in healthcare-seeking behavior for corporeal aches and pains. Drossman and colleagues[14-16] studied 72 patients with IBS who sought medical care, 82 persons with IBS who had not sought medical care, and 84 healthy subjects. They found that patients with IBS who seek care and those with IBS who do not seek care experience the same symptoms. However, IBS patients who seek help from a physician are significantly more likely to have psychiatric disorders, abnormal personality patterns, and more life stress.
In fact, evidence suggests that half of all high medical care users are psychologically distressed. What specific psychiatric disorders are most common among this group? According to a study by Katon and colleagues,[12] 40% have depressive disorders, 22% have generalized anxiety disorder, 20% have somatization disorders, 12% have panic disorder, and 5% are alcohol abusers.
Statistics on the relationship between specific common physical symptoms and psychiatric disorders in primary care patients illustrate the pervasiveness of this comorbidity. Kroenke and colleagues[17] found that the presence of any physical symptom increased the likelihood of a diagnosis of a mood or anxiety disorder by as much as 3-fold. Furthermore, 34% of patients with joint or limb pain, 38% of patients with back pain, 40% of patients with headache, 46% of patients with chest pain, and 43% of patients with abdominal pain also had a mood disorder.
While psychological problems may be prevalent among high healthcare users, what specific symptoms prompt most patients to seek out medical care? Physical symptoms account for half of all primary care physician visits.[20] And while physical symptoms restrict the activities of Americans an average of 9.7 days annually, most of these physical manifestations are never explained by a disease or injury (Figures 1, 2).
fig1
Figure 1. Medical symptoms associated with current major depression.
fig2
Figure 2. Medical symptoms associated with lifetime major depression.
Kroenke,[21] a leading researcher of symptoms in patient samples, reviewed the records of 1000 patients over 3 years to examine the incidence, evaluations performed, and outcome of symptoms commonly reported in primary care. At some point during the study period, approximately 9% of patients had presented with chronic pain, 8% with fatigue, and 5% with dizziness, headache, edema, low back pain, dysphoria, insomnia, and abdominal pain. Despite the high incidence of symptoms, only 16% of new physical symptoms reported were ever linked to physical injury or disease-related pathology.
The Links Between Physical and Psychological Complaints
Whether explained or unexplained, the number and severity of symptoms have been shown to rise with number and severity of psychological complaints.[22-24] Patients with anxiety or depressive disorders are more apt to complain of multiple symptoms.[23] Likewise, as the number of physical symptoms increases so does the risk of experiencing anxiety and depression. Evidence further suggests that stressful life events, psychological distress, and depressive and anxiety disorders are associated with a range of medical symptoms with no identified pathology.[25]
In a study of 500 primary care adult patients, Kroenke[22] found a number of independent predictors of mental disorders. These included recent stress, 6 or more physical symptoms, higher reported severity of symptoms, lower self-rating of overall health, age younger than 50 years, and physician perception of the encounter as difficult. In addition, patients with depressive or anxiety disorders were more likely to experience unmet expectations after the visit (20% vs 8%, P < .001) and to report persistent psychiatric symptoms 3 months after the initial visit, compared with those without such disorders. Thus, this subgroup of patients may warrant closer psychiatric evaluation.
Barriers to Recognizing Depression in Primary Care
Despite its pervasiveness in the primary care setting, depression goes undetected in the majority of cases. Studies have found that 50% of patients who experience major depression are not diagnosed by their primary care physicians.[26,27] Several factors are thought to contribute to this phenomenon, including time and cost restrictions. In addition, 50% to 80% of patients with depression initially present with a physical symptom.[28] These individuals are significantly less likely to receive an accurate psychiatric diagnosis than are those who tell their physician they're feeling "down." Medical school curricula that teach students to rule out physical disease before considering mental disorders may also contribute to these missed diagnoses. Because of the frequency of depression and anxiety in medically ill populations, relative to the rare conditions students are taught to look for, this is akin to the proverbial problem of teaching the students "to look for zebras (medical disorders) in a herd of horses." Thus, high rates of unnecessary tests are ordered, driving up the cost of care, increasing the chance of a spurious positive finding and the risk of prolonging the illness, with secondary consequences for the patient.
Since most Americans receive their only mental health care in the primary care setting, improving recognition rates of depression in primary care has important public health implications.[29] In fact, citing the ability to reduce clinical morbidity, the United States Preventive Services Task Force recently recommended depression screening for all adults in primary care settings.[30-32]
International studies confirm that the relationship between somatic symptoms and depression is not a uniquely Western phenomenon. Simon and colleagues[33] analyzed World Health Organization data to examine this phenomenon in more than 5400 patients at 15 primary care centers in 14 countries. As is the case in the United States, approximately 10% of these patients were diagnosed with major depression. Forty-five percent to 95% of depressed patients reported only somatic symptoms. Half reported multiple unexplained symptoms and 11% denied psychological symptoms of depression when questioned. Purely somatic presentation was more common in patients who lacked an ongoing relationship with their doctor, perhaps because of the issues of trust and stigmatization of depression.
Chronic Pain and Depression
Does chronic pain cause the depression or does depression cause the pain? Current evidence supports both relationships.[34-39] Research shows that patients with persistent or chronic pain are at risk for developing an anxiety or depressive disorder.[40-42] A recent analysis[34] of data from the World Health Organization, found that 22% of primary care patients complained of persistent pain, which was defined as experiencing at least 6 months of pain plus disability because of the pain and/or receipt of medical care for the pain. Those with persistent pain were 4 times more likely to have an anxiety or depressive disorder than were pain-free individuals.
A host of other psychological and social factors may also be involved in the development of chronic pain.[34,37] Gureje and colleagues[34] analyzed data from the World Health Organization to examine persistent pain in more than 3000 primary care patients around the world. Researchers found that 49% of patients who experienced persistent pain at baseline continued to have persistent pain 12 months later. The best independent predictor of persistent pain was the number of pain sites. Psychiatric disorder, poor self-rated overall health, and occupational related disability were also found to be independently associated with chronic pain. Furthermore, persistent pain at baseline predicted the onset of a psychological disorder with the same strength that a baseline psychological disorder predicted the onset of persistent pain.
In their review of the epidemiology of pain and depression in primary care, Von Korff and Simon[43] made 4 broad generalizations. They are as follows:
* Pain is as strongly associated with anxiety as with depressive disorders;
* The number of pain sites (diffuseness of pain) and the extent to which pain interferes in daily life are the characteristics that most strongly predict depression;
* Certain psychological symptoms of depression, including low energy, sleep disturbances, and worry, are common among pain patients whereas guilt and loneliness are not; and
* Psychological distress and disability often surface and resolve early during the course of a pain disorder that evolves into a chronic condition.
Based upon their findings, these researchers hypothesized that pain and psychological illness have reciprocal psychological and behavioral effects. They proposed 2 theories about the mechanisms underlying the pain-depression comorbidity: (1) some individuals are genetically susceptible to both physical and psychological symptoms and a state in which psychological distress amplifies unpleasant physical sensations; (2) the physical and psychological stress of pain may induce or aggravate psychological distress.
Other, more recent models of the relationship between pain and mood blend the evidence from studies of neurobiological and biobehavioral concepts such as sensitization, conditioning, and kindling to explain the comorbidity of pain and depression.[44]
The Neurochemical Connection Between Pain and Depression
Pain is a complex, intricate neurochemical process involving neurotransmitter and other molecules acting in both peripheral and central pain signaling pathways. Similarly, multiple neurotransmitters are involved in most neurologic and neuropsychiatric disorders including depression. Thus, several neurochemicals seem to be involved in the overlapping of the phenomena of pain and depression. Serotonin (or 5-HT) and norepinephrine have emerged as 2 neurotransmitters that appear to be involved in both pain and depression.
Serotonin and Norepinephrine in Depression
Serotonin and norepinephrine are present in virtually every organ system in the body. Furthermore, research suggests that serotonergic and noradrenergic neurons interact. Specifically, serotonergic neurons have been shown to exert an inhibitory effect on noradrenergic neurons.[45-50] Among other structures, norepinephrine and serotonin pathways are present in the prefrontal cortex and the limbic system, areas known to be involved in mood disorders, including depression.
Initially, investigations into the mechanisms of action of antidepressants focused on altering monoamine levels through the inhibition of amine reuptake via monoamine oxidase inhibitors (MAOIs).[45] Then physicians began using tricyclic antidepressants (TCAs), which were thought to work over time to enhance the levels of norepinephrine and serotonin[46,47] by blocking the reuptake of these neurotransmitters. During the past 10 years, the action of antidepressants has become even more specific with the use of selective serotonin reuptake inhibitors (SSRIs) and noradrenaline reuptake inhibitors (NRIs).[48-50]
Most research has failed to show a significant difference in the efficacy of these 2 drug classes for the treatment of depression.[48] A body of evidence suggests that some patients with depression will respond better to selective inhibition of norepinephrine while others seem to do better with SSRIs.[51] Other research has shown that depressed patients who are unresponsive to both SSRIs and TCAs may improve with a combination of the 2 classes of medications.[52]
Studies involving precursor amino acids have consistently supported the hypothesis that serotonin and norepinephrine are independently involved in the biology of depression. An elegant series of treatment studies by Delgado and colleagues[53-55] may have provided the first mechanistic proof that serotonin and norepinephrine might be implicated in distinct symptoms common to mood disorders. The investigators designed the studies around a depletion strategy. The synthesis of serotonin requires the precursor molecule tryptophan, whereas the production of dopamine and norepinephrine requires the precursor molecule tyrosine. Thus, depletion of these molecules results in a drop in levels of the associated neurotransmitters (Figure 3).
fig3
Figure 3. Schematic representation of neurotransmitter loss related to tryptophan and tyrosine depletion.
Delgado studied 3 different groups of patients: (1) depressed individuals who responded predominantly to SSRIs; (2) depressed individuals who responded best to NRIs such as desipramine; and (3) healthy subjects. Patients in all 3 groups were depleted of serotonin via tryptophan depletion. Then, after a washout period, all patients were depleted of norepinephrine via tyrosine depletion.
In more than half of SSRI responders, tryptophan depletion led to the resurgence of the depressive symptoms originally present before SSRI treatment (Figure 4). When these patients underwent tyrosine depletion, there was no return of symptoms. Conversely, less than 7% of NRI responders who underwent tryptophan depletion relapsed. The majority of NRI responders who underwent tyrosine depletion, however, experienced a return of depressive symptoms. Patients in the control groups were unaffected by either tryptophan or tyrosine depletion. These results suggest that in different groups of patients, under certain conditions, serotonin and norepinephrine may exert independent effects on mood disorders.
fig4
Figure 4. Graphic depiction of response of patients to depletion of serotonin or norepinephrine.
Thus, agents that work to concurrently inhibit the reuptake of both serotonin and norepinephrine might be expected to effectively treat depression in a wider population of patients. Serotonin-noradrenaline reuptake inhibitors (SNRIs) or dual serotonin-norepinephrine reuptake inhibitors, including venlafaxine and duloxetine, have been developed as the end result of this hypothesis.[56-58] While all SNRIs inhibit both serotonin and norepinephrine reuptake, research indicates that some of the newer agents may be more selective for these neurotransmitters than others.[59]
Norepinephrine and Serotonin in Pain Pathways
In addition to innervating the limbic and prefrontal regions of the brain, noradrenergic and serotonergic neurons are also involved in a well-described pain-modulating circuit that includes the amygdala, periaqueductal gray (PAG), dorsolateral pontine tegmentum (DLPT), and rostroventral medulla (RVM).[55-60] According to this model, cells in the PAG project primarily to RVM cells that in turn act on the spinal dorsal horn. When activated, RVM neurons inhibit pain sensory processing, presumably by inhibiting the dorsal horn cells that are receiving pain information. Through descending projections, this circuit controls spinal pain-signaling mechanisms as well as dorsal horn pain transmission and is an endogenous mechanism of pain relief. In multiple studies in rodents, Fields and colleagues[61-65] have shown that serotonin and norepinephrine are important neurotransmitters in this pain-modulating circuit (Figures 5, 6).
fig5
Figure 5. The relationship of serotonin and norepinephrine pathways to neural centers for pain and depression.
fig6
Figure 6. Links between pain transmission neurons (blue) and serotonin (red) and norepinephrine (yellow) pathways.
All pain is not created equal, however. Sharp, stabbing pain and dull aching pain involve different neural pathways.[66,67] Under normal circumstances, an acute pain will be transmitted to the brain and will then be resolved in part due to the endogenous pain-modulating system. In persistent pain, however, resolution does not take place. Instead, plastic changes take place in the neural pathways involved in transmitting acute pain.
Several other animal studies further support the important role of norepinephrine and serotonin in the process of pain modulation. Molecules that block the synthesis of norepinephrine and serotonin -- alpha-adrenoceptor and 5-hydroxytryptamine (5-HT; serotonin) antagonists -- have been shown to inhibit antidepressant-mediated pain relief in mice.[68-71] In related research, depletion of central noradrenergic and serotonergic systems has been shown to block antidepressant-mediated pain relief in mice.[72,73]
Norepinephrine and serotonin are likewise important for the functioning of the endogenous pain-suppressing descending projections described originally by Fields and Basbaum.[74] Normally, as part of a negative feedback loop, the output of the pain-transmission neurons helps activate the pain-suppression system. The PAG, DLPT, and RVM are the key regions of the brain involved in this descending pain modulation. Research shows that lesions made to these areas of the brain block pain relief associated with the antidepressant clomipramine.[75] Furthermore, within the spinal cord itself, activation of noradrenergic and serotonergic receptors also produces pain relief.[76,77]
Norepinephrine and Serotonin in Persistent Pain
Persistent pain is characterized by greater sensitivity to pain, lowered thresholds to painful stimuli, and also episodes of spontaneous pain. Individuals with persistent pain are often hyperresponsive to normally painful stimuli and may also experience pain in response to stimuli that are not normally painful. Many of these symptoms seem to be the result of plastic changes -- sensitization and desensitization -- taking place in the central nervous system.[78,79]
Animal models of persistent pain provide further evidence for the involvement of serotonin and norepinephrine in the modulation and analgesia of chronic pain states. In one of these models, injecting formalin into the hind paw of the rat induces sensitization.[80-83] This causes characteristic 2-step behavior: Approximately 5 minutes after the injection, the rat intensely licks the hind paw; a quiescent period follows this, and then a period of exaggerated licking behavior ensues. This second round of licking is caused by central nervous sensitization.
Sawynok and colleagues[80,81] have demonstrated that antidepressants can provide pain relief in this mouse model of persistent pain. In one study, amitriptyline, a nonselective noradrenaline and serotonin reuptake inhibitor produced pain relief in the formalin test.[80] In another, the investigators examined the effects of desipramine, a selective NRI, and fluoxetine, an SSRI, on behavior during the formalin test.[81] They found a dose-related reduction in biting and licking behaviors when desipramine and fluoxetine were coadministered with the formalin.
Human Studies
How does this information translate to humans? Clinical trials have shown that antidepressants acting through both noradrenergic and serotonergic receptors provide effective pain relief in the clinical setting.[84-86] O'Malley and colleagues[84] conducted a meta-analysis of 94 placebo-controlled trials involving 6595 patients treated with antidepressants for unexplained physical symptoms. Most studies examined the use of TCAs, SSRIs, or multiple agents for the treatment of the following syndromes: headache, fibromyalgia, functional gastrointestinal syndromes, idiopathic pain, tinnitus, and chronic fatigue. This meta-analysis found a significant benefit from antidepressants yet there was no differential effect across the classes of antidepressants.
A meta-analysis on the treatment of fibromyalgia with antidepressants produced similar results. O'Malley and colleagues[85] examined the findings of 13 randomized, placebo-controlled trials involving TCAs, SSRIs, and S-adenosylmethionine. Patients taking antidepressants were 4 times more likely to report overall improvement than were those who received placebo. Patients who took antidepressants reported moderate improvements in individual symptoms like sleep, fatigue, pain, and well-being. However, examination of studies of chronic pain caused by neuropathic mechanisms (eg, postherpetic neuralgia, diabetic neuropathy, radiculopathy) reveals that medications with dual reuptake inhibition, such as TCAs and venlafaxine, are effective, whereas SSRIs are not.[87,88]
In 1994, Max[87] reported his analysis of 15 clinical trials using antidepressant drugs to treat patients with postherpetic neuralgia or diabetic neuropathy. He found the dual noradrenaline/serotonin (NA/5-HT) reuptake inhibitor amitriptyline to be effective (ie, most or all of the pain was abolished or the patient rated pain relief as moderate or better) in 4 of 5 placebo-controlled crossover studies of patients with postherpetic neuralgia. One study also found desipramine (a specific NRI) to be effective. By contrast, the specific 5-HT reuptake blocker zimeldine was "completely without effect." In 4 of these trials, patients with postherpetic neuralgia who were not depressed showed a similarly impressive response to amitriptyline or desipramine.
In this analysis, Max also found that studies of patients with diabetic neuropathy demonstrated amitriptyline and desipramine to be effective, but not the 5-HT reuptake inhibitor fluoxetine. However, 2 other 5-HT reuptake inhibitors, paroxetine and citalopram, did prove more effective than placebo, though less effective than imipramine. Max encouraged more study of the (at the time) newer 5-HT reuptake inhibitors, postulating that, although only weakly antinociceptive, these drugs would augment the action of the NRIs.
Six years later, Fishbain and colleagues[88] analyzed 22 animal studies and 5 human studies that compared the analgesic effects of dual NA/5-HT reuptake inhibitor antidepressants, selective NA antidepressants, and selective 5-HT antidepressants in various experimental models of acute, chronic, and neuropathic pain. They found that, overall, the dual NA/5-HT reuptake inhibitor antidepressants were more effective than the selective NA antidepressants, which were, in turn, more effective than the selective 5-HT antidepressants. However, these investigators emphasized the need for more head-to-head comparisons among these antidepressants in well-defined animal and human experimental models.
Managing Comorbid Pain and Depression
Despite response rates to antidepressants that reach above 70%,[86] only an estimated 30% of patients with clinical depression actually receive antidepressant therapy. However, a recent study on trends in outpatient treatment found that the percentage of individuals receiving treatment for depression rose from 0.73 per 100 persons in 1987 to 2.33 in 1997 (P < .001).[89] Furthermore, among patients being treated, antidepressant use increased from 37% to 74% (P < .001). Unfortunately, the proportion who received psychotherapy declined from 71.1% to 60.2% (P =.006). Thus, while there is clearly a long way to go, better-tolerated antidepressants, greater efforts in public education, and the growth of managed care have directed more depressed individuals towards medication.
Comorbid pain and depression may be more difficult to treat than depression alone. Treating only one or the other may prevent the patient from ever achieving remission. As discussed, pain may perpetuate the depression and depression may perpetuate the pain. Thus, clinicians need to be aware of all of the comorbidities of pain and depression and use an integrated approach to treatment, including medical, physical, and behavioral therapies.[89-91] Pain, sleep disturbances, depression, and other physical, behavioral, or psychosocial factors all must be addressed to maximize chances of success.
Because ongoing, untreated pain leads to structural changes in the central nervous system and this, in turn, augments the risk of persistent pain, physicians should have a low threshold for referral, consultation, and treatment for patients with comorbid pain and depression.[92] Untreated depression and pain can lead to dire psychosocial consequences, including job loss, substance abuse, and suicide.[93]
In the phenomenon of comorbid pain and depression, what comes first? There are a number of hypotheses, which all seem to be partly correct: chronic pain is a symptom of masked depression, the stress of chronic pain causes depression, and the stress of depression causes pain. There does, however, seem to be at least one other important factor: genetics. Studies of patients with chronic myofascial face pain suggest that major depression that has its onset before or soon after the onset of the pain tends to be familial and primary.[40] On the other hand, major depression that surfaces after chronic pain tends to be nonfamilial and secondary.[91]
The Challenges of Treating Depression
Depression carries a high potential for relapse and chronicity.[94,95] Thus, achieving remission and preventing relapse are equally important treatment goals. Physicians must be aware of the impact of the stigma of pain and depression. Often patients want to discontinue the medications they view as a symbol of personal weakness. So to improve adherence, it is important to remind these individuals that they have an illness with a chemical basis. The following interventions have been found to be useful adjuncts in the successful management of depression[96]:
* Case management involving active patient follow-up;
* Adherence monitoring;
* Symptom tracking; and
* Changing treatment if it is found unsuitable.
Despite advances in treatment with antidepressants, only one third of patients actually achieve remission, defined as at least a 50% reduction of total scores in the Hamilton Rating Scale for Depression (HAM-D).[97-100] The remaining groups of patients are only partially responsive or are nonresponsive to antidepressants. This subset of patients has a greater risk of relapse and recurrence compared with those who remain symptom-free. In fact, the risk of relapse after a single depressive episode is 50%, and becomes between 50% and 90% after 2 episodes; after 3 episodes the risk of recurrence is greater than 90%.[101] Up to one third of depressions are chronic in nature.[102]
There are 7 broad classes of antidepressants, all of which have been shown to effectively treat depression and reduce the risk of relapse and recurrence.[103] These groups, classified according to mechanism of action are as follows:
* Mixed and neuroreceptor antagonists plus sodium fast channel inhibitors (amitriptyline, doxepin, imipramine)
* Norepinephrine selective reuptake inhibitors (desipramine, nortriptyline)
* SSRIs (citalopram, fluoxetine, paroxetine, sertraline)
* Dual serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine)
* Serotonin-2A (5-HT2A) receptor blockers and weak serotonin reuptake inhibitors (nefazodone)
* Serotonin (5-HT2A and 5-HT2C) and norepinephrine alpha2-receptor blockers (mirtazapine)
* Dopamine and norepinephrine reuptake inhibitors (bupropion)
Tackling Pain and Depression
How does one choose the best antidepressant for the patient with comorbid pain and depression? The issues of efficacy, remission rates, dosing, adherence, and cost are all important factors that must be considered together (Figure 7).[92] For example, if you give a very expensive antidepressant to a patient who can't afford it, he is likely going to discontinue the drug, leading to relapse and a recurrence of the depression. Instead, looking at remission rates and cost together will help the clinician determine the best value for cost-sensitive patients. Dosing simplicity is also important as it promotes adherence.
fig7
Figure 7. Algorithm for management of patients with chronic pain.
Start With SSRIs
Due to the good efficacy rates and dosing simplicity, many patients with pain and depression receive SSRIs as initial treatment.[92] As soon as antidepressants are started, it is important to follow the patient closely for a response. Patients, family, and physicians all become impatient quickly. If after a couple of weeks the patient is not responding to the recommended dose, titrate it upwards.
It is also important to confirm that the patient is in fact taking the medication.[89] Don't ever assume a patient is taking the drug as prescribed. Many have preset notions about the dangers and social implications of receiving antidepressants. Educating patients and their families (if possible and appropriate) about the benefits of the drug and the risk of relapse will help promote adherence. Furthermore, perpetuating factors such as stress, pain, and substance abuse must be addressed for successful outcomes.[92]
When SSRIs Fail
If a patient is not responding to SSRIs, another category of antidepressants with a mixed mechanism of action should be tried.[92] There is some evidence to suggest that dual-action antidepressants with both noradrenergic and serotonergic activity may actually have increased efficacy in treating depression remission.[104-106] Thase and colleagues[105] conducted a meta-analysis of 8 randomized, double-blind trials to compare remission rates for depression during treatment with SSRIs vs venlafaxine, a dual reuptake inhibitor at high doses. Forty-five percent of patients achieved remission on venlafaxine vs 35% of those taking SSRIs (P < .001); 25% of patients who were randomized to receive placebo achieved remission.
Animal and human studies suggest that antidepressants with combined noradrenergic and serotonergic activity also provide superior pain relief compared with pain relievers that selectively act on either neurotransmitter alone.[86,107-109] In theory, these medications have the potential to help ameliorate symptoms of neuropathic pain and depression at the same time through their dual action. A recent study by Detke and colleagues[86] examined the effects of duloxetine hydrochloride, a dual reuptake inhibitor of serotonin and norepinephrine, for the treatment of major depressive disorder and associated physical symptoms. In this multicenter, double-blind trial, 245 adult patients with major depressive disorder were randomly assigned to receive placebo or duloxetine for 9 weeks. Researchers used the 17-item Hamilton Rating Scale for Depression (HAM-D-17) to evaluate symptoms of depression; visual analog scales to assess painful physical symptoms; and the Clinical Global Impressions-Severity scale, the Patient Global Impressions-Improvement scale, and the Quality of Life in Depression Scale to evaluate quality of life.
Duloxetine proved significantly more effective than placebo (P < .001) in reducing depression scores beginning at week 2. The probability of remission in the duloxetine group was estimated at 44%, compared with an estimate of 16% for those in the placebo group. In addition, duloxetine significantly reduced painful physical symptoms when compared with placebo. Nausea, dry mouth, and somnolence were the most common adverse events. While these results are encouraging, more clinical trials are needed to better understand the role of these medications in the treatment of pain and depression.
TCAs have also been shown to be effective analgesics, particularly for neuropathic pain.[110] Tricyclics potentiate serotonin and norepinephrine in descending pain pathways and have consistently been shown to be effective pain relievers.[111,112] Urinary retention, hypertension, and arrhythmias are all potential toxicities associated with these drugs. The toxicity and side effect profile thus limit their usefulness in clinical practice. Data on the effectiveness of SSRIs for pain relief are less consistent. Results of some studies show significant analgesia, while others reveal no benefit over placebo.[113-116] However, in studies of discrete neuropathic conditions that control for the presence of depression, SSRIs have not been shown to be effective, whereas TCAs have.[110] Thus, while SSRIs are safer and better tolerated than TCAs, their efficacy in pain relief remains questionable.
Psychotherapy for Comorbid Pain and Depression
Psychotherapy and behavioral modification, either alone or in combination with medication, has been shown to be an effective and important part of the successful treatment of comorbid pain and depression.[90-92,117-123] While poor insurance company reimbursement and the perceived stigma of psychotherapy can be barriers to patient participation, physicians should encourage psychotherapy and cognitive behavioral therapy to all patients suffering from pain and depression. Some studies have found that the combination of medical and psychotherapeutic treatments provides better results than medication alone.[120-123]
In addition, physicians should take a psychotherapeutic attitude toward these patients in the clinical setting. With this approach, clinicians can help empower patients. For example, by giving patients a diary in which to record changes in their pain, patients can begin to measure and perhaps objectify their pain. Physicians should also help patients identify others who can be part of a support network for the patient.
Physicians should expect their patients to actively participate in their treatment. Pain blocks, medications activity restrictions, massage, and manipulation are all passive treatments. Encourage and set goals for patients to actively participate in strategies, such as:
* Keeping a pain medication diary;
* Self-education about pain through books, expert, peer-reviewed Web sites (eg, www.painconnection.org), and community groups;
* Starting a graduated exercise program;
* Participating in occupational therapy;
* Trying yoga;
* Stretching; and
* Using relaxation techniques, biofeedback, and hypnosis.
Conclusion
Pain and depression are widespread public health problems resulting in substantial morbidity and mortality, not to mention staggering economic costs. In the primary care setting, up to 46% of patients presenting with one physical symptom also have a psychiatric disorder. And the risk of psychiatric comorbidity only increases with the numbers of physical symptoms.
While the relationship between pain and depression continues to emerge, studies suggest that aggressive treatment of both symptoms can improve patient satisfaction and outcomes and reduce healthcare utilization. Thus, when a patient presents with physical symptoms and potential symptoms of depression, physicians in doubt should treat the depression also. The negative effects of nontreatment on patient outcomes outweigh the side effects and risks of treatment. Early, aggressive management of both symptoms strives to prevent central reorganization or plastic changes in the central nervous system. Antidepressant therapy and psychotherapy combined with close follow-up are central to the successful treatment of these comorbidities.References
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Source:-
Author
Rollin M. Gallagher, MD, MPH
Professor of Psychiatry, Anesthesiology, and Public Health and Director of Pain Medicine, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania; Director, Pain Medicine and Comprehensive Rehabilitation Center, Graduate Hospital, Philadelphia, Pennsylvania
Disclosure:
Rollin M. Gallagher, MD, MPH, has disclosed that he has served as advisor or consultant to Lilly, Janssen, Purdue, and Endo Pharmaceuticals.
Writer
Sophia Cariati, MA
Freelance Health & Science Writer, New York, NY.
Disclosure: Sophia Cariati has no significant financial interests to disclose.
Editor
Priscilla Scherer, RN
Editor, Medscape Neurology & Neurosurgery
The Pain & Depression Conundrum, Bridging the Body and Mind |
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Sep 5 2006, 11:53 PM
