Chronic pain and depression

Chronic pain and depression A Surah MBChB FRCA MRCS G Baranidharan PG Dip (Anaes) FRCA FFPMRCA S Morley BSc (Hons) MPhil (Clinical Psychology) PhD FBP...
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Chronic pain and depression A Surah MBChB FRCA MRCS G Baranidharan PG Dip (Anaes) FRCA FFPMRCA S Morley BSc (Hons) MPhil (Clinical Psychology) PhD FBPsS

Key points Chronic pain and depression are common causes of morbidity. Coexistence of the two conditions is underestimated and poorly understood. When the two conditions are comorbid, outcomes are worse. Serotonin and norepinephrine are thought to play a key role in the association, but the exact mechanism is unclear. Management can be difficult and a multi-disciplinary approach is vital.

A Surah MBChB FRCA MRCS Specialist Registrar in Anaesthesia Leeds Teaching Hospitals NHS Trust D Ward, Seacroft Hospital Leeds LS14 6UH UK G Baranidharan PG Dip (Anaes) FRCA FFPMRCA Consultant in Anaesthesia and Pain Medicine Leeds Pain and Neuromodulation Centre Leeds Teaching Hospitals NHS Trust D Ward, Seacroft Hospital Leeds LS14 6UH UK Tel: þ44 113 2063128 Fax: þ44 113 2063144 E-mail: [email protected] (for correspondence) S Morley BSc (Hons) MPhil (Clinical Psychology) PhD FBPsS Professor of Clinical Psychology Room 1.13 Charles Thackrah Building University of Leeds Leeds LS2 9LJ UK


Chronic pain and depression Depression and chronic pain are becoming increasingly common and important causes of morbidity in the Western world. Pain is the most common complaint in outpatient clinics; with back pain alone accounting for up to 20% of the UK’s health expenditure.1 Depression is the third most common reason for consultation with a GP and the most common mood complaint. The prevalence of chronic pain is variably estimated at 8–60% depending on the definition of chronic pain used.2 In the UK, 6% of the adult population per year will experience a depressive episode and one-third of the population will at some point experience a depressed mood that interferes with their daily activities. The prevalence of depression in the primary care setting is between 5% and 10%. The conditions are very closely linked, but the association is complicated and is often underestimated. Between 40% and 60% of patients with chronic pain have depression, and due to the association, the term ‘pain–depression dyad’ has been coined.3 When the two conditions coexist, they are more difficult to treat and outcomes are worse than when occurring in isolation.4 Both conditions require expert input from chronic pain specialists and psychiatrists to effectively manage the conditions, but as the coexistence of the two conditions is underestimated/unrecognized, appropriate treatment is not always achieved/administered.

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are a number of different pain syndromes, ranging from neuropathic pain to inflammatory pain. (iii) Depression: Depression refers to a range of mental disorders where symptoms persist for longer than 2 weeks. It is a condition with a cluster of symptoms not all of which occur in every case. The key features are a persistent low mood, absence of positive affect (loss of interest and enjoyment in ordinary things and experiences), and a range of associated emotional, cognitive, physical, and behavioural symptoms. Depression is usually defined and classified in severity according to one of the two classification systems. DSM-IV (Diagnostic and Statistic Manual of Mental Disorders) involves five or more symptoms being present during the same 2 week period (Table 1).5 One of the symptoms must be depressed mood or loss of interest or pleasure. The ICD 10 (International Classification of Diseases) involves three key symptoms and a further seven other symptoms. Depression is then graded according to severity (Table 2).6 (iv) Chronic pain and depression: It is well established that there is an association between chronic pain and depression. What is unclear is the strength and mechanism of this association. Undiagnosed and untreated chronic pain and depression can exacerbate the other condition, leading to a cycle of worsening pain and depression.

Definitions (i) Pain: As described by the International Association for the Study of Pain (IASP) ‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. (ii) Chronic pain: A continuous, long-term pain of more than 12 weeks or after the time that healing would have been thought to have occurred in pain after trauma or surgery. There

Diagnostic difficulties The association between chronic pain and depression is complex. Each condition can occur independently, but pain and depression may develop secondarily to each other or may coexist. This makes diagnosis of the coexisting conditions difficult. The existence of chronic pain is a risk factor for the development of depression. Also,

doi:10.1093/bjaceaccp/mkt046 Advance Access publication 8 October, 2013 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 14 Number 2 2014 & The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]

Chronic pain and depression

Table 1 Depression DSM IV classification Key symptoms † Persistent sadness or low mood † Marked loss of interests or pleasure At least one of these, most days, most of the time for at least 2 weeks If any of above present, ask about associated symptoms † Disturbed sleep (decreased or increased compared with usual) decreased or increased appetite and/or weight † Fatigue or loss of energy † Agitation or slowing of movements † Poor concentration or indecisiveness † Feelings of worthlessness, excessive or inappropriate guilt, suicidal thoughts or acts Severity is determined by the number of symptoms present † Subthreshold depressive symptoms: fewer than five symptoms of depression † Mild depression: few, if any, symptoms in excess of the five required to make the diagnosis, and symptoms result in only minor functional impairment † Moderate depression: symptoms or functional impairment are between ‘mild’ and ‘severe’. † Severe depression: most symptoms, and the symptoms markedly interfere with functioning. Can occur with or without psychotic symptoms

Table 2 Depression ICD10 classification Key symptoms At least one of these must be present for most days for at least 2 weeks † Persistent sadness or low mood; and/or † Loss of interests or pleasure † Fatigue or low energy If any of the above symptoms are present then ask about associated symptoms † Disturbed sleep † Poor concentration or indecisiveness † Low self-confidence † Poor or increased appetite † Suicidal thoughts or acts † Agitation or slowing of movements † Guilt or self-blame The 10 symptoms then define the degree of depression and management is based on the particular degree † Not depressed—fewer than four symptoms † Mild depression—four symptoms † Moderate depression—five to six symptoms † Severe depression—seven or more symptoms, with or without psychotic symptoms Symptoms should be present for at least 2 weeks and every symptom should be present for most of every day

Hypotheses: ‘chicken or egg’ A common question in the association between chronic pain and depression is whether depression precedes or follows chronic pain. A number of theories have been proposed.7

Antecedent hypothesis In the antecedent hypothesis, depression precedes the development of chronic pain. Depression can increase pain sensitivity and lower pain thresholds evoking pain. Approximately half of all depressed patients have pain, and it can often be a presenting symptom.

Consequence hypothesis In the consequence hypothesis, depression occurs as a result of chronic pain. The presence of chronic pain can worsen mood, with the subsequent development of depression. This is particularly the case if chronic pain produces an incapacitating physical condition with a reduction in physical and social activities. This can result in isolation, a loss of worth, and other psychological symptoms that are features of depression. In essence, the patient adopts the sick role and behaviours of chronic invalidism, with depression being part of a maladaptive response to pain.8

Scar hypothesis The scar hypothesis implies that there is a genetic predisposition to the development of depression. An early minor episode lays the foundations for more extensive episodes of depression in later life. Adverse events that would not normally trigger depression might become more likely to do so. In circumstances of some stress, such as pain or a physical illness, these individuals would become depressed.

Cognitive behavioural hypothesis There are psychological mediators involved in the relationship between chronic pain and depression and this can be thought of as a variant of the consequence hypothesis. These mediators, such as life interference and decreased self-control, mediate the relationship.

Pathogenetic hypothesis physical illness can produce symptoms of depression. Chronic pain patients develop many of the somatic and vegetative symptoms that form diagnostic criteria for depression according to DSM-IV and ICD 10. This overlap of symptoms can lead to varying prevalence of chronic pain and depression. The relative contribution and effect of each illness on the patient can be difficult to determine, making management challenging. Psychiatrists and chronic pain specialists may lack the skills to recognize and manage symptoms, which fall outside of their areas of expertise.


The pathogenetic hypothesis suggests that chronic pain and depression share common pathological changes. These are most likely to be in the form of a neurochemical association, which is discussed below. In these final two hypotheses, there are common biobehavioural mechanisms in the aetiology of pain and depression. A simple cause and effect does not explain the relationship between the two conditions. The fact that numerous theories exist highlights the issue that the strength of the association between the two conditions is unclear, and that no hypothesis is a ‘Best fit’. Many of the studies that have explored this association have also been cross-sectional studies, with only a few prospective studies

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Chronic pain and depression

being performed. This has meant it is difficult to ascertain which condition occurred first or whether they occurred concomitantly.

Biological models There are potential models utilizing biological pathways that can be used to explain the association of chronic pain and depression. These models may represent the main underlying mechanism for all the hypotheses described above that are involved in the ‘pain– depression dyad’. Further research is needed to clarify these models. These biological models can be either neuroanatomical or neurochemical.

Neuroanatomical basis Depression and pain are neuroanatomically linked, which may be key to the association. Parts of the brain involved in processing of emotions are also involved with pain processing and modulation. This overlap of areas involved in processing mood and pain may be a site for pathological changes that can result in the development of both conditions. Emotions are processed in the hypothalamus, the amygdala, and the anterior cingulate gyrus. These areas relay signals to the periaqueductal grey matter and the ventromedial medulla, which have a role in pain modulation. The anterior cingulate gyrus in particular may have a key role in depression and pain, as structural and functional changes have been demonstrated in this area in both conditions.9

Neurochemical basis Depression and chronic pain also share commonality with various neurotransmitters and receptors involved in the conditions. The two main transmitters are serotonin and norepinephrine (Table 3).

Depression There is an increasing body of evidence that in depression there is a reduction in pre-synaptic serotonin (5-HT) release with a compensatory increase in post-synaptic receptors. Studies have shown reduced

levels of serotonin and 5-hydroxyindoleacetic acid (5-HIAA—a metabolite of 5-HT) in post-mortem brain tissue of depressed patients. All drugs that selectively inhibit serotonin reuptake are effective in the treatment of depression.10 The evidence supporting the role of norepinephrine in depression is also extensive with reduction in concentrations in cerebrospinal fluid (CSF), and its metabolites in plasma and urine. There are altered neuroendocrine responses to noradrenergic challenges. Studies performed on post-mortem brain tissue from depressed patients have shown b-adrenergic receptor up-regulation and increased density. This is most likely secondary to reduced synaptic levels of norepinephrine. All antidepressant treatments, including electroconvulsive therapy, increase synaptic norepinephrine levels by blocking re-uptake, highlighting its importance in depression.11

Chronic pain Pain signals are modulated at various levels by descending neurones involving various neurotransmitters such as serotonin, norepinephrine, and endogenous opioids. In normal circumstances, this descending modulation serves to filter out extraneous signals, allowing the passage of normal and important signals. Electrical stimulation of these pathways produces a deep analgesia by inhibiting the passage of painful stimuli. However, in both chronic pain and depression, neurochemical alterations can affect this inhibition, resulting in disruption of ‘Filtering’ and the passage of abnormal signals. Depletion of serotonin levels results in increased painful responses to electrical stimuli in rats, and a functional noradrenergic system is necessary for this descending modulation. Pain can also cause an increased turnover of serotonin, with a net reduction in pre-synaptic serotonin release. This would lead to a reduction in the activity of the descending pain control pathways, and result in more pain. This reduction in pre-synaptic serotonin release could cause the development of depression as outlined above. The effectiveness of antidepressants in the treatment of both conditions supports this theory.

Table 3 Neurochemical changes in depression Serotonin (5-HT) Reduced 5-HT and 5-HIAA in post-mortem brain Reduced CSF 5-HIAA Increased density 5-HT binding sites in the brain and platelets Reduced pre-synaptic 5-HT release Drugs preventing 5-HT reuptake effective in treatment Reduced 5-HT synthesis produces relapse in treated patients Norepinephrine Reduced concentrations of norepinephrine in CSF Reduced metabolites in plasma and urine Altered neuroendocrine responses to noradrenergic challenges Reduced synaptic norepinephrine levels b-Adrenergic receptor up-regulation and increased density Antidepressant treatments increase synaptic norepinephrine levels by blocking re-uptake

Management The management of both conditions when they coexist can be challenging, and a multi-disciplinary approach is vital. Anaesthetists and psychiatrists will be comfortable managing parts of the condition relevant to their area of expertise. Depression in isolation can be managed by psychiatry services. However, depression with chronic pain is best managed in the pain clinic with input from psychiatric services, which commonly involves clinical psychologists. Screening patients with chronic pain issues for signs of depression may allow more prompt and successful treatment. Management can be broken down into non-pharmacological, pharmacological, and interventional.

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Non-pharmacological Psychotherapy Although analgesic agents can reduce pain, they rarely provide complete relief. With continued use, reduced efficacy can become evident and there is also the risk of side-effects. Psychotherapy can be used in conjunction with analgesic agents to allow patients to more effectively manage their pain. The most common forms of psychotherapy are outlined below. It is often the mainstay in managing depression and pain.

Cognitive behavioural therapy This involves managing thought processes and patterns with the aim of restructuring them to enable patients to better manage their pain. The theory behind cognitive behavioural therapy (CBT) is that by changing dysfunctional emotions, maladaptive behaviours, and cognitive processes, a change in affect and mood can be facilitated. An example of cognitive behavioural therapy would be altering problematic thoughts such as ‘I will always be in pain’ to ‘I can manage my pain’. CBT has six phases:12 (i) (ii) (iii) (iv) (v) (vi)

assessment, reconceptualization, skills acquisition, skills consolidation and application training, generalization and maintenance, post-treatment assessment follow-up.

Assessment identifies the degree of psychosocial impairment and the most appropriate course of action. The reconceptualization phase contributes the majority of the cognitive aspect of cognitive behavioural therapy. This seeks to help patients to challenge and question the rationality of maladaptive thoughts. In the skills acquisition phase, the therapist teaches patients how to deal with obstacles in their day-to-day lives, and how to avoid falling into the pattern of automatic thoughts. In the skills consolidation and application training phase, patients are given homework in an attempt to help them reinforce the skills that they have acquired during the skill acquisition phase, one of the hallmark methods in CBT. In the generalization and maintenance phase, the therapist and patient discuss the future, and how the patients are going to cope once they have left treatment. Finally, patients participate in the post-treatment assessments and follow-up phase in order for the therapist to monitor and evaluate patients’ application of CBT skills to their lives.

Hypnosis, relaxation, and guided imagery Hypnosis utilizes a trance-like state to suggest to patients that their pain is manageable or will improve. Relaxation therapy involves techniques such as progressive muscle relaxation and deep breathing, which may offset some of the physiological markers of pain. In guided imagery, the patient is taught to imagine a pleasant, comfortable setting in great detail. By focusing on this setting, patients are


distracted from their pain, allowing an improvement in their symptoms to occur.

Biofeedback Biofeedback can be used to help patients control their physiological state associated with their pain. Pain and stress can cause an involuntary physiological response in the form of muscle tension, increased heart rate, increased arterial pressure, and an increased respiratory rate. When this response is controlled and modified, an improvement in symptoms can be seen. Multiple studies on biofeedback and depression have found that this therapy can have significant positive effects. Different types of biofeedback are used to monitor different body systems, then various techniques are used to help the patient control the physiological response. Techniques utilized by biofeedback include: † deep breathing, † progressive muscle relaxation—alternatively tightening and then relaxing different muscle groups, † guided imagery—concentrating on a specific image to focus the mind, † mindfulness meditation—focusing thoughts and letting go of negative emotions.

Acupuncture Acupuncture can be used to improve pain. It is thought to release endogenous opioids and also stimulate descending inhibition of pain pathways via norepinephrine and serotonin.

Exercise Exercise can play an important role due to its beneficial effects on both chronic pain and mood. It can also take various forms from stretching, strengthening, and aerobic exercise to Tai Chi. Recent Cochrane reviews have shown a moderate effect on patients with fibromyalgia, and a small to moderate effect on depression.4 Regular exercise is also recommended as an adjunct in treatment of depression. The reasons for the beneficial effects are multi-factorial. Regular physical activity can cause physiological changes with increased levels of endorphins and monoamines, while also reducing cortisol levels. This can improve the mood of patients. The process of exercising can also act as a distraction from negative thoughts due to their condition and result in an improvement in function, management of symptoms, and quality of life.

Pharmacological The pharmacological management of chronic pain and depression in isolation is well established and documented in other literature. A number of drugs that are used to treat depression can also be used as analgesics in an altered dose. Appropriate choice of agents to cover both conditions avoids the issue of polypharmacy, reduces side-effects, and improves compliance with treatment. In-depth

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pharmacology is beyond the scope of this article. Pharmacological management involves the use of antidepressants, mood stabilizers, and anticonvulsants and analgesic agents.

Antidepressants Tricyclic antidepressants (TCAs) work by increasing synaptic cleft monoamine levels, in particular serotonin and norepinephrine. They have a well-documented role in the treatment of neuropathic pain and depression. Serotonin and norepinephrine reuptake inhibitors (SNRIs) have a similar mechanism of action as TCAs and have been used in the treatment of chronic pain. SNRIs have less anticholinergic, antihistaminic, and adrenergic side-effects than TCAs and are also relatively safer in overdose. Selective serotonin reuptake inhibitors (SSRIs) due to their lack of effect on norepinephrine are thought not to have independent analgesic properties. Their use in chronic pain has had varied results.

Summary The coexistence of depression and chronic pain is important to appreciate in the successful and appropriate management of both conditions. The underlying mechanism for the association remains unclear with a number of potential explanations. Successful management involves expert input from a multi-disciplinary team.

Declaration of interest None declared.

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Mood stabilizers and anticonvulsants Anticonvulsants work via varied mechanisms, but all essentially decrease excitation in neurones, which provides the theoretic underpinning of their analgesic effects. Their use in the treatment of chronic pain is widespread. Drugs such as pregabalin and gabapentin can cause depression as a side-effect in their early treatment phase, which should be carefully monitored.

5. National Collaborating Centre for Acute Care. NHS National Institute for Clinical Excellence Clinical Guideline 90: Depression in adults. Available from 6. Gruenberg AM, Goldstein RD, Pincus HA. Classification of depression: research and diagnostic criteria: DSM-IV and ICD-10. In: Licinio J, Wong M, eds. Biology of Depression. From Novel Insights to Therapeutic Strategies. Weinheim: Wiley-WCM, 2005 7. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic painassociated depression: antecedent or consequence of chronic pain? A review. Clin J Pain 1997; 13: 116–37


8. Von Korff M, Simon G. The relationship between pain and depression. Br J Psychiatry 1996; 168: 101– 8

The use of analgesics as per the WHO analgesic ladder can lead to an improvement in pain and consequently depression.

9. Nicolson SE, Caplan JP, Williams DE, Stern TE. Comorbid pain, depression, and anxiety: multifaceted pathology allows for multifaceted treatment. Harv Rev Psychiatry 2009; 17: 407– 20 10. Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994; 40: 288– 95

Interventional Interventional treatments can be considered on carefully selected patients with pain and depression. They can take the form of nerve blocks, spinal cord stimulators, or surgery. Interventions can help avoid using pharmacological agents with side-effects. A multidisciplinary team (MDT) should carefully select the patients to avoid further deterioration in depression secondary to treatment failure.

11. Baker GB, Greenshaw AJ. Effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system. Cell Molec Neurobiol 1989; 9: 1– 44 12. Turk DC, Flor H. The cognitive-behavioral approach to pain management. In: McMahon SB, Koltzenburg M, eds. Wall and Melzack’s Textbook of Pain, 5th Edn. London: Elsevier Churchill Livingstone, 2006

Please see multiple choice questions 29–32.

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