Chronic pain
Chronic pain is defined as pain lasting or recurring for 3 months or longer.1 It can be a primary condition or can occur in the context of a disease.2 It is estimated that about one in five adults worldwide experience pain that is moderate or severe in its intensity and lasts 3 months or more;3 however, estimates vary and may be higher. In the UK, reviews of chronic pain suggest that between one-third and one-half of the population experience chronic pain.4 Some populations are more likely to experience chronic pain: older adults, women, people not in employment due to ill health and disability and people with comorbidities. Social circumstances are particularly influential; people in low socioeconomic circumstances are not only more likely to experience chronic pain, but also report higher levels of severity and disability.5 Thus, chronic pain disproportionately affects the poor, facilitating social isolation and increasing all-cause morbidity6 and mortality.7,8 Almost one-third (30%) of people living with burdensome chronic pain struggle with productive engagement in society. Policy-makers have called for action.9
The impact of chronic pain is similar across conditions, despite the different aetiologies. Globally, chronic pain accounts for the highest number of years lived with disability, and affects individuals’ daily lives, society and healthcare services.10,11 Chronic pain accounts for up to one in five general practice consultations each year in Europe, Africa and Asia.12–14 Chronic pain is also one of the global leading causes for sickness absence and people being unable to work.15,16
There are many different treatments aimed at reducing and managing chronic pain, including analgesic medication, physiotherapy, self-management guidance, exercise, psychological therapy, antidepressants, pain management clinics and surgery. The use of these depends upon the pain condition, severity of pain, individual characteristics, availability of services and national policy and guidelines. NHS England has called for better understanding of the risk of analgesic medication for pain conditions, especially when prescribed long-term. Although there are several non-pharmacological treatments aimed at living well with pain, for patients, the need to reduce pain remains a top priority.
Successful treatment of chronic pain can result in significant improvements in quality of life, including anxiety and depression.3,17,18
A systematic review identified that for people with fibromyalgia, reductions in pain intensity of 50% or more are associated with self-reports of sleep, fatigue and depression reverting back to normative values.3 Therefore, efficacious treatment of the pain condition is essential for improvement of both pain and mood, in addition to potential improvements in sleep, physical function and quality of life. In addition, for many people, engaging effectively with physical exercise depends on reducing daily pain. Thus, effective reduction of pain remains an important aspect of treatment.
Pharmacological approaches directly target pain and are the main treatment available to first-line clinicians when faced with chronic disabling pain. Despite this, upon scrutiny of the evidence, a majority of common medicines have been removed from guideline recommendations for treatment of most chronic pain conditions, including paracetamol, non-steroidal anti-inflammatory drugs, opioids and synthetic cannabis.8–10
Antidepressants and chronic pain
What are they, and how might they work?
Antidepressants are medicines developed and used primarily for the treatment of clinical depression. A network meta-analysis (NMA) of the 21 most common antidepressants has shown that they are efficacious in the treatment of acute major depression, particularly severe depression.19
Antidepressants are grouped into different classes based on their chemical structure and presumed mechanism of action. The most common classes are as follows:
tricyclic antidepressants (TCAs): amitriptyline, desipramine, imipramine, nortriptyline and others
selective serotonin reuptake inhibitors (SSRIs): citalopram, sertraline, fluoxetine and others
serotonin norepinephrine reuptake inhibitors (SNRIs): duloxetine, levomilnacipran, milnacipran, venlafaxine
Antidepressants were originally developed to treat depression. Most antidepressants work by targeting monoamine neurotransmitters associated with mood and emotion and their receptors in the nervous system. These receptors, such as 5-hydroxytryptamine receptors, are activated by many neurotransmitters including serotonin, dopamine, adrenaline and noradrenaline.20 Antidepressants prevent the neurotransmitters from being absorbed into neurons, which prolongs their activity in synapses. While the process by which antidepressants relieve depression is not fully understood, recent theories focus on neurochemical changes and neuroplasticity.20
Changes in the pain response systems travelling to and from the brainstem and involving the noradrenergic neurotransmitters have been theorised to explain the analgesic properties of antidepressants, and their proposed ability to reduce pain. By increasing the amount of serotonin and noradrenaline in the nervous system, pain signals are hypothesised to be blocked at the peripheral, spinal and supraspinal levels, reducing perceived pain, particularly in neuropathic pain.21,22
In addition, the locus coeruleus in the brain may have an analgesic effect on perceived pain.23 Signals from this part of the brain are sent when the body reacts to a stimulus, such as pain, and noradrenaline is released into the dorsal horn in the spine to block receptors. Animal studies have shown that when pain signals are continuously received, as is the case in chronic pain, this analgesic response lessens over time, and noradrenaline is then not released.23,24 However, when antidepressants are given, the analgesic response from the locus coeruleus is restored.23,25
Guidelines for antidepressants in the treatment of chronic pain
Antidepressants are one of the few remaining recommended pharmacological interventions for chronic pain, although, to date, the evidence has not allowed the nuance of ranking the prioritisation. Where consideration of the quality of the supporting evidence is reported, it is often unclear.26 Across guidelines from the USA,27 Canada28 and Japan,29 TCAs (e.g. amitriptyline, nortriptyline) and SNRIs (e.g. duloxetine, milnacipran) are the most common classes recommended. In the UK, the National Institute for Health and Care Excellence (NICE) has produced different sets of recommendations for different pain types: chronic primary pain,30 neuropathic pain,31 low back pain and sciatica32 and osteoarthritis.33 For chronic primary pain, amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine and sertraline are recommended equally. For neuropathic pain, amitriptyline or duloxetine are recommended. For low back pain and sciatica, the guidelines explicitly advise against use of SNRIs, SSRIs and TCAs; and for osteoarthritis, antidepressants are omitted entirely. The lack of concordance across guidelines can be confusing for clinicians, especially as many patients present with several types of pain concurrently. Furthermore, some of these recommendations are made based on very low-quality evidence. For example, in the chronic primary pain guidelines,9 citalopram is recommended based upon one trial with 42 participants,34 sertraline from one crossover trial with 14 participants,35 and paroxetine from one trial with 46 participants.36 These small trials are of very low scientific rigour and are not a reliable evidence base. This is especially alarming given that within the context of the guidelines, antidepressants are the only pharmacological intervention recommended. Although the NICE guidelines for treatment of chronic low back pain published in 2016 recommend not prescribing antidepressants (regardless of mood), NICE guidelines for people with depression and chronic health problems recommend antidepressants in cases of mild depression and physical health problems. No advice exists to help practitioners resolve the contradiction between the two sets of advice.
Antidepressants in practice
Prescriptions of antidepressants are relatively common in patients with chronic pain internationally; for example, 12.3% of people with chronic low back pain in Portugal report taking antidepressants for pain relief.37,38
In the UK, amitriptyline has long been the most commonly prescribed antidepressant for chronic pain. Amitriptyline was widely used to treat depression from the 1960s, but has restricted use now due to the risk of taking a lethal overdose. Its use is also characterised by side effects such as dizziness, dry mouth, constipation and weight gain; side effects are more common with higher dosages. Although amitriptyline is only licensed for the treatment of depression and neuropathic pain, it is commonly prescribed ‘off licence’ at a lower dose to treat any chronic pain. TCAs (of which the most common is amitriptyline) are the 19th most common prescription in primary care, accounting for 1.6% of all prescriptions.39 Open-source prescribing data recorded over 14.5 million prescriptions for amitriptyline in 2021.40 It is reasonable to believe that a majority of these prescriptions were for pain: amitriptyline is not recommended to treat depression,41 and chronic pain is the most common indicator for antidepressant prescription in older adults.42 A multinational comparison of antidepressant use in older adults found that TCAs were the most common class in the UK prescribed for chronic pain, at 55%. In comparison, SNRI prescriptions were very low (1.5%).41 Indeed, there were 3.4 million duloxetine prescriptions in 2021, less than one-quarter of the number of amitriptyline prescriptions.
Antidepressants and safety
There are also risks in the prescription of antidepressants. Adverse events such as dizziness, headache, nausea, ejaculation disorder, weight loss, tremor, sweating and insomnia have been found by randomised controlled trials (RCTs) to be more common in people taking antidepressants compared with those taking placebo.43,44 Studies assessing the safety of antidepressants across a range of adverse outcomes in older people45,46 and in people aged 20–64 years47,48 have shown increased risks of falls and fractures associated with most antidepressants, and differences between antidepressants in risks of all-cause mortality, stroke and self-harm or suicide. Antidepressants also increase the risk of onset of seizures,49 while the potential for gastrointestinal bleeding with SSRIs is widely recognised.50 Long-term use of antidepressants for pain syndromes is therefore expected to be associated with harms at the population level.
The evidence on the efficacy and safety of antidepressants
At the start of this study, there was no evidence comparing classes of antidepressants to each other in the management of chronic pain, as identified by the recent NICE guidelines.51 There have been several systematic reviews for specific conditions (detailed below). Therefore, in the absence of any one RCT comparing the efficacy and safety of all antidepressants for chronic pain, a NMA was considered a priority to assess the relative effectiveness of each antidepressant, by dose.
Previous Cochrane Reviews investigated the efficacy of specific antidepressants in improving pain in specific conditions. A summary of their findings indicates that there is no high-quality evidence to support or refute the use of amitriptyline, milnacipran, nortriptyline, venlafaxine, desipramine or imipramine for management of neuropathic pain,52–57 principally because trials are few and those that exist have small numbers of participants and typically have high risks of bias. The lack of evidence for some antidepressants stands in stark contradiction to guideline recommendations. For example, amitriptyline is recommended as a first-line treatment for neuropathic pain in primary care in guidelines for the UK, Canada and the International Association for the Study of Pain (IASP).31,58–60
For fibromyalgia, Cochrane Reviews of antidepressants show that there is no unbiased evidence that amitriptyline, desvenlafaxine, venlafaxine or SSRIs are superior to placebo.61,62 There is low-quality evidence that duloxetine and milnacipran have some benefit in improving Patient Global Impression of Change (PGIC) scores and providing an improvement in pain relief of 30% or more, but no clinical benefit over placebo for improvement in pain relief of 50% or more, health-related quality of life or fatigue.62 Similarly for mirtazapine, there is evidence for improvement in pain relief of 30% or more, and reduction of mean pain intensity and sleep problems, but this evidence is of low to medium quality, and there is no benefit for improvement in pain relief of 50% or more, PGIC, 20% improvement of health-related quality of life, reduction of fatigue or reduction in negative mood.63
Only one Cochrane Review has investigated the use of antidepressants for low back pain, and it found no clear evidence to support the use of any antidepressants.64 A more recent systematic review supports these conclusions.65 However, when analysed using the ‘baseline observation carried forward’ (BOCF) imputation method for missing data, pooled individual patient data analyses of RCTs have shown duloxetine and etoricoxib to be effective in reducing pain for pain conditions including chronic low back pain.3,63,66 These distributions were bimodal: participants generally responded very well or very poorly, with few in between.3
The current systematic review and NMA allowed us to compare, for the first time, all antidepressants across all chronic pain conditions (bar headache), and identify whether certain classes or doses of antidepressants are useful in the management of pain and mood for people with chronic pain, and for certain chronic pain conditions. As antidepressants are also associated with a number of side effects, the review allowed the comparison of the proportion of adverse events occurring with the use of different antidepressants (including different classes of antidepressants, different types of antidepressants, and different dose regimens) within populations living with chronic pain.
The relationship between pain and low mood
Although antidepressants are typically prescribed as analgesics for chronic pain patients, there is a strong possibility that if effective, they may also be effective at improving patient mood. The prevalence of depression in patients with chronic low back pain has been estimated as three to four times greater than that among the general population.67,68 Distress and depression have been found to predict the transition to persistent pain states in several reviews.60,69,70 It is clearly important to provide treatment that improves mood and quality of life in people living with pain. The most common intervention for patients with pain who also present with low mood is the prescription of antidepressant drugs, based on the assumption that these are effective in improving both pain and mood. Patients will often be told by clinicians that these drugs may help in a number of ways: they may have a direct effect on pain reduction, they may help by improving muscle relaxation, they can improve sleep, and they may help by improving mood. Which of these are of most benefit to the patient, if any, and in which patient group has not been established.
People suffering from depression and people living with chronic pain often report similar symptoms, such as low mood, lack of energy, difficulty making decisions and loss of pleasure from activities. Despite this, there appear to be some important differences between the two groups, which might imply that they require distinct interventions. For example, the content of depressive thoughts and the antecedents of feelings of sadness experienced by people in chronic pain may differ to those experienced by people with depression but without pain.71 It is important to identify differences in pain-related distress (i.e. individuals with chronic pain experiencing low mood because of their pain) and clinical depression, which may reflect on the prevalence statistics reported above. The distinction between pain-related distress and depression is particularly important as primary care practitioners are often given contradictory guidance: they are encouraged to better detect depression,72,73 while avoiding overmedicalisation of distress and thus overtreatment.74,75 This is important as antidepressants can be prescribed for the management of both pain and mood (e.g. clinical depression) in people with chronic pain. This review aimed to clarify this guidance as, unlike previous reviews in this area, we intended to investigate whether there were differences dependent upon whether the antidepressants were prescribed primarily to treat mood or pain.
Patient and public involvement
We always involve our patient and public network in our research from conception and through the full cycle of research. For this study, in the first instance we met with five people (three females, two males) from our Research User Group at Royal Holloway, University of London, who had experience of chronic musculoskeletal pain and of NHS care for their condition. We discussed whether studying mood in chronic pain would have value, and whether we should know if antidepressants are effective. The group endorsed the general aim of the study strongly, and considered that the design was appropriate. The participants advised that they would personally never take antidepressants, although they had all been offered these at some time for pain or distress. We followed this with a second meeting with seven members of the Research User Group at Keele University. The group informed us that the study of low mood in people with chronic pain was very important, and that they considered the widespread use of antidepressants to be harmful. They wanted to know whether the cost of side effects associated with taking antidepressants outweighed any benefits associated with improving pain or mood. They saw this project as a possible first step in the development of a new, more effective intervention. For a description of the patient and public involvement (PPI) post review, see Chapter 7.
