There is some logic to having acute pain. It acts as a signal for withdrawal from danger or damage; it enforces rest after injury or during illness; and it can be used in pain vs pleasure calculations of which signals are needed to avert future damage or incite beneficial behaviors. Chronic pain, on the other hand, seems to have no purpose. In fact, the more we learn about pain processes, the clearer it becomes that chronic pain differs from acute pain in ways not previously appreciated. It may be felt similarly in that it is perceived in an anatomical location, often after an acute injury or event. It is easy to assume that chronic pain is merely acute pain that has not gone away, and reflects unresolved peripheral damage. Yet, recent scientific study has revealed processes in the nervous system, and particularly the brain, which account for chronic pain, and are distinct from acute pain processes. A seemingly paradoxical role for the endogenous opioid system in the development of chronic pain is brought to light. What follows is that the actions of exogenous opioids (opioid medications) differ vastly between acute and chronic pain.
2. Understanding pain as a disorder of the nervous system
We can categorize pain as nociceptive (transmitted by nociceptors), neuropathic (due to damaged nerves), or inflammatory (produced by inflammatory mediators). In each case, we perceive of a process occurring in the periphery that incites pain and which could be amenable to reversal as a means of reducing the pain. This is the concept of pain that many clinicians and patients cling to, partly because pain always feels as if it is in the periphery, and partly because of the hope that peripheral causes of pain can be treated. Although it is true that indeed, many pain conditions do have reversible peripheral causes, it is becoming increasingly clear that the most refractory, perplexing, prolonged, and treatment-resistance pain conditions may not.3 This realization, which is now supported by copious scientific evidence, should alter the way we approach the management of difficult pain problems.
Much chronic pain is successfully managed with either primary disease control (eg, anti-inflammatory treatment of arthritis) or targeted analgesics (eg, anticonvulsants or antidepressants for neuropathic pain). Regardless, pain will persist in some individuals and not in others. Persistent painful stimulation induces sensitization that can be counteracted by endogenous inhibitory control. For many individuals, a balance develops between sensitization and inhibition so that chronic pain, even if pain generators are present, does not become a persistent and overwhelming problem. Those individuals in whom chronic pain does become a persistent and overwhelming problem could be especially prone to sensitization, lacking in endogenous inhibitory control, or both.
2.1. Propensity to sensitization
Stimulation of nociceptors can trigger a reversible increase in excitability and synaptic efficacy in pain pathways throughout the nervous system, a phenomenon termed “central sensitization.” Such induction of excitability shifts the sensitivity of the nervous system so that painful stimulation becomes more painful (hyperalgesia), and normally non-noxious stimulation becomes noxious (allodynia). The exact molecular mechanisms for central sensitization remain obscure,6,22,49,90,94 but it becomes increasingly clear from clinical studies that for a range of pain states, which includes fibromyalgia, osteoarthritis, temporomandibular joint disorders, generalized musculoskeletal pain, low back pain, visceral pain, and postsurgical pain, a propensity to central sensitization plays an important role in the development of pain.124 In affected individuals, normally nonpainful or minimally painful activity incites pain that is severe enough for affected individuals to seek medical help.102,124 Although central sensitization is reversible, the increase in pain sensitivity induced in these individuals on a chronic basis makes their central sensitization de facto a chronic state of the nervous system.
2.2. Deficiency in endogenous inhibition
Since it was first inferred by researchers in the 1950s,18,68,119 descending inhibition of pain and its mechanisms are now well established.17,19,58,59 Pain processing pathways in the brain are widespread and contribute to a “multisensory salience network” (embracing both nociceptive and non-nociceptive input) that is involved in estimating the saliency or relevance of its input. The network processes stimuli that alert the organism to danger, or incite reward to reinforce behaviors that are advantageous to survival.6,30,45,69 Thus, the network, with its connections within reward and limbic systems, serves to determine what is perceived (pain or pleasure) according to survival values. It is perhaps no surprise that the endogenous opioid system plays a key role in these functions, in the balancing of pain and reward, and in the affective dimension of pain.72,86
Building on the idea that perceived pain is less a simple reflection of nociceptive input than a complex product of calculations of the motivational value of pain, one can begin to see the importance of the brain in determining what is perceived as pain. Because the brain is capable of processing nociceptive input so that no pain is perceived (and may do this in normal individuals, despite the existence of peripheral pain generators), is chronic pain then a disease of the brain? In fact, accumulating evidence from functional magnetic resonance imaging studies suggests that the brain undergoes extensive change in chronic pain states and differs markedly from the brain with prolonged acute pain.4,6,31,110 The conscious perception of pain depends on the conversion of nociception to perception in the mesolimbic system. As chronic pain develops, learning-based synaptic reorganization causes the thresholds for conversion from nociception to perception to shift.3,5,8,47 Such learning-based synaptic reorganization is similar to that occurring in the development addiction.91,115,116 The model that has been proposed on the basis of functional magnetic resonance imaging studies is one where chronic pain is primarily a neurological disorder, nociceptive input is less important, and brain properties are the primary determinants of risk of chronic pain.4,6,7,32,110–112 Underlying this model is the assumption that genetic or environmental factors embedded in the limbic system account for differences between individuals in the way pain is processed.7 Chronic pain is thereby seen as a learned state and a maladaptive neuropathological disease largely independent of nociceptive input (Table 1).
3. Stress, endogenous opioid dysfunction, and chronic pain
Stress responses exist to maintain homeostasis and improve survival. Stress responses may occur through attempts to balance punishment and reward within the pain salience network, as previously described.19,58,59,86 They may also serve to balance stress hormone–induced arousal and avoidance behaviors, with antiarousal mechanisms, many of which are opioid mediated.82,88,99,100,113 Corticotrophin-releasing factor (CRF) is a brain neuromodulator that coordinates autonomic, behavioral, and cognitive responses to stress. By its effects in the locus coeruleus, a noradrenergic brain stem nucleus that mediates physiological responses to stress and pain, this hormone helps increase arousal and attention. Endogenous opioids are also active in the locus coeruleus, having the opposite effects to CRF, and are important for helping the organism recover after the stressor disappears. The counteraction between CRF and endogenous opioids works well to balance arousal and antiarousal during acute stress. However, with repeated stress, particularly early social rejection or abuse, opioid tone increases and becomes dominant. This increased opioid tone means that individuals who have been subjected to repeated stress may develop something similar to tolerance to exogenous opioids. It is proposed that chronic stress thus induces a state of endogenous opioid-induced tolerance and dependence similar to chronic exposure to opioids where tolerance to opioid analgesics is increased, and attempts to avoid withdrawal may result in opioid overuse.42,65,113,122 This is effectively a state of continuous withdrawal, which could contribute to the development of pain through withdrawal hyperalgesia. High-opioid tone also produces a state of reward deficiency or anhedonia—a reduced capacity to experience pleasure or indeed to experience the reward and salience associated with pain relief. Such reward deficiency would be similar to that well described in substance abusers.97,108 This could contribute to the vulnerability of affected individuals to develop comorbid pain, high-dose opioid use, opioid abuse, depression, anxiety, and post-traumatic stress disorder.6,20,38,42,66,70,71,73,120
High tonic levels of endogenous opioids also downregulate μ-opioid receptors on γ-aminobutyric acid inhibitory neurons that normally keep antinociceptive neurons switched off. Dysregulation of the endogenous opioid system leads to less excitation of antinociceptive brain regions by incoming noxious stimulation, which becomes manifest as hyperalgesia and allodynia. Thus, the patient with generalized pain lacks valuable pain inhibition.95 This helps explain both the lack of efficacy of exogenous opioids and the efficacy of the opioid antagonist naltrexone for generalized pain conditions such as fibromyalgia.84,125
4. The brain on opioids
This discussion will be centered on the brain effects of long-term opioid use when opioids are used for the treatment of pain. Short-term or occasional opioid use may result in early brain changes, but what is of greater interest here is the changes that arise with longer-term use. Brain changes that arise in persons addicted to opioids have been increasingly well elucidated.23,44,114 Although there is inevitable overlap in brain changes between use for pain and addiction, the focus here will be on brain changes arising from use for pain.
4.1. Central sensitization
It is believed that a propensity to develop central sensitization underlies many chronic pain conditions, especially the conditions we currently call centralized pain conditions, which include fibromyalgia, musculoskeletal pain, chronic low back pain with no pathoanatomic basis, jaw pain, headache, irritable bowel syndrome, and pelvic pain. Neither the molecular changes producing sensitization, nor the underlying genetic and environmental factors, are fully understood. Nevertheless, recent scientific exploration has revealed many similarities between sensitization arising from noxious stimulation, and those arising from opioid administration. This raises the question whether despite their ability to provide symptom relief, opioids could in some circumstances augment the sensitization in centralized pain states, or any pain state where repeated or continuous noxious stimulation is occurring.
For practical purposes, and for clinicians using opioids to treat pain, opioid tolerance is the need to increase opioid dose to achieve the same level of analgesia. However, that clinical end point is produced not only by changes at the opioid receptor level, but can also be produced by activation of pronociceptive systems by opioids.2,41,76,101 Multiple cellular events are involved in the pronociceptive adaptive response produced by opioid exposure, and most of them are common to the pronociceptive processes involved in the development and maintenance of chronic pain.27,33,48,87,90,101,103 Existing data strongly support long-term neuronal changes caused by opioid exposure, even short-term exposure. This suggests that pain vulnerability may be facilitated by opioid use.
In addition to such neuronal changes, there is now abundant evident that opioids can produce neuroinflammatory responses in both the peripheral and central nervous system. Microglia-to-neuron signaling is known to play a key role in opioid-induced tolerance and hyperalgesia, at least in part due to the release of proinflammatory cytokines and chemokines.67,80,83,123 Proinflammatory cytokines are believed to play a role in the generation and enhancement of chronic muscle pain, including fibromyalgia.102 Both chronic pain and chronic opioids engage similar neuroimmune mechanisms in the brain and spinal cord, which contribute to pain and negative affect. Moreover, both chronic pain and chronic opioids promote neuroinflammation in limbic brain structures contributing to negative affective states, which may increase the propensity to opioid misuse in patients with chronic pain.22,109
It seems that long-term opioid-induced pronociceptive activity may persist long after cessation of opioid administration (latent pain sensitization).40,61,90 This is consistent with the idea that opioids produce long-term alterations in pain sensitization, which facilitate the initiation and maintenance of the chronic pain state. Data support the critical role of microglia not only in opioid-induced hyperalgesia and tolerance, but also in long-term pain sensitization observed after brief exposure to opioid. Opioids may also trigger epigenetic mechanisms that produce hyperalgesia and tolerance.93 Whether through cellular processes such as receptor trafficking, intracellular signaling, N-methyl-D-aspartate neurotransmission or epigenetic changes, opioid-induced neuroinflammation, or latent pain sensitization, opioid-induced tolerance and hyperalgesia must be seen as potentially irreversible phenomena.
4.2. Tolerance, dependence, and continuous withdrawal
Although many factors contribute to the development of persistent pain, it seems that the most important of these is dysfunction of endogenous inhibition of pain, in turn largely mediated by endogenous opioids.102 This fact is highlighted when considering that regardless of peripheral generation of pain, be it nociceptive, neuropathic, or inflammatory, the pain that is actually perceived is determined by central processes in the brain. Healthy individuals can often suppress nociceptive input; for patients with chronic pain, inability to achieve such suppression may underlie their propensity to progress to the chronic pain state. Many of the processes underlying failed pain inhibition have already been discussed. What follows is a discussion of the ways in which the brain adapts to chronic opioid administration, and the ways in which these adaptations may impair natural pain inhibition.
Opioid tolerance and dependence have been described in detail elsewhere.9,12 What is important in the present context is the relationship between tolerance and dependence. Tolerance may be a receptor phenomenon (nonassociative) or a psychological phenomenon (associative).53,104,117 The latter means that independent of changes in receptor function brought about by continuous exposure to opioid drugs, psychological factors such as anxiety, exposure to stress, or changes in circumstance, can result in an increase (or in some cases, a decrease) in tolerance. Any increase in tolerance that is not compensated for with a dose escalation will result in withdrawal, an unpleasant experience comprising physical symptoms (nausea, abdominal cramps, piloerection, dilated pupils, agitation, and tachycardia), anhedonia, and importantly, hyperalgesia. Dependence, and the symptoms of withdrawal, are powerful drivers of opioid seeking for all persons using opioids continuously, not only people who have developed opioid use disorder.23,51 Tolerance, dependence, and opioid seeking in turn drive up opioid doses. Ultimately, patients taking opioids for pain can enter a state whereby no dose is enough, in other words, pain persists despite repeated dose escalation (Fig. 1).
It is clear that people dependent on opioids do not simply experience diminished opioid effects because of tolerance. The idea that opioid dependency could be a state of continuous withdrawal is suggested when intermittent emergence of mild withdrawal symptoms is seen in opioid-dependent patients, despite stable dosing. This dysfunction could be explained by the fact that these patients are experiencing drug-opposite effects as long as drug administration continues. Moreover, this dysfunction could extend to their mood and ability to function socially.12,122 In this case, continuous withdrawal is a drug effect, but it could exacerbate the continuous withdrawal that might occur if a patient has increased opioid tone as a consequence of repeated stress described previously.20,113,122
The importance of continuous withdrawal is brought into focus by the clinical presentation of patients doing badly with opioid therapy of chronic pain. They report high levels of pain, despite high doses of opioid. Yet, they cannot be convinced that the opioid is not helping because if they try to reduce their dose, the pain worsens, likely because of withdrawal, but interpreted as needing opioid. Furthermore, in multiple studies, and according to anecdotal experience, people who successfully stop their opioid treatment report no change in pain, sometimes even an improvement, only a “lifting of the cloud” and “return of the old personality.”
4.3. Disruption of normal rewards and social functions
Although this article does not set out to describe the brain changes that arise with addiction, the risk that opioid treatment of pain could lead to opioid addiction (more properly termed “opioid use disorder”) cannot be ignored. It probably does not need to state that addiction is a miserable state that seriously impairs the affected individual's ability to function in society, to have normal social relations, and to work. In the natural state, endogenous opioid systems balance punishment (perceived pain) and reward (perceived pleasure) in pain and reward centers in the brain, which are closely aligned. Pain relief is rewarding; damaged reward is painful. Chronic pain and addiction are both learned states and represent dysfunction of the normal adaptations that regulate survival behaviors including adjustments in pain levels, feeding, socialization, and sex (Table 1). A likely majority of individuals do not become addicted when using opioids for the treatment of chronic pain. Assessment of addiction rates for opioid-treated chronic pain has proven difficult because there is little consensus on addiction definitions and terminology in the case of analgesic use, with the result that recent estimates vary widely according to the definitions used, but also according to the type of study and the population under study.21,78,118 It would seem from population data that at least 75% of those taking opioids for the treatment of chronic pain do not become addicted. At the same time, it must be acknowledged that there are several factors that suggest a higher risk of addiction for opioid-treated chronic pain patients than for the general population.1,12,38,42,43,56,66,77,97 Patients with chronic pain, especially those with centralized pain states, tend to have psychiatric comorbidities common to both chronic pain and addiction. As already described, patients with centralized pain may have high-opioid tone with continuous withdrawal, as well as reward deficiencies, all of which put them at risk of craving opioids.36,37,64,85,89,96,98,105,121 These factors are compounded by being on opioids because exogenous opioids exacerbate continuous withdrawal, and overwhelm natural endogenous opioid functioning to the extent that the opioid drug is necessary to achieve pain relief and other rewards.
Although the development of addiction may not be inevitable for patients with chronic pain taking opioids, the development of dependence is inevitable for all persons taking opioids continuously and long term.13 Many of the neuroadaptations that arise with continuous opioid use occur with dependence as well as with addiction, except the secondary learning that leads to synaptic reorganization and permanent brain changes, which will differ between dependence and addiction because behaviorally, relief seeking differs markedly from drug seeking.44,51–53 The main difference between dependence and addiction is the lack of craving and compulsive use in the former (although craving and compulsive use may actually emerge in apparently nonaddicted patients if their opioid treatment is stopped abruptly). In other respects, however, dependence, and the neuroadaptations underlying it, is similar to addiction and a possible precursor to addiction.9,13 Dependence is manifest as withdrawal, and possibly continuous withdrawal, which drives opioid seeking. Dependence on opioids is also associated with reward deficiencies. Just as for the addicted person, normal endogenous opioid functions are overwhelmed by the opioid drug, and it becomes more difficult to muster natural pain relief and rewards, so increasing the likelihood of needing opioids. What has become increasingly clear from U.S. opioid epidemic is that there is a high incidence of social dysfunction and work disability attributable to opioid use that is higher than the incidence of addiction.26,57 We are learning that these deleterious effects on essential human functions are associated not just with addiction and pain, but with continuous long-term opioid use itself.
Caution in using or prescribing opioids long term has existed for centuries. Such caution has been based on the association of long-term opioid use with addiction. In the 20th century, it was suggested that the existence of pain protected against addiction, and that fear of addiction was unwarranted when treating chronic pain. A consequence of this change in thinking was that opioid treatment of chronic pain became much more commonplace in many countries, particularly in the United States. This expansion of opioid prescribing did not have entirely happy results, and in fact in the United States, it led to an epidemic of prescription opioid abuse. The reasons for the U.S. prescription opioid epidemic are many and complex, and were not fully explored in this article, other than to note that some but not all the abuse and death arises from diverted opioid and not from patients with pain. What is of interest here is the analgesic efficacy and safety of long-term opioid treatment. This article has explored new knowledge about how chronic pain develops, and how exogenous opioids, despite being largely effective for symptom relief, can actually worsen the underlying pain processes. Much has been learned from the outcomes data that have arisen out of widespread prescribing of opioids for chronic pain over the past few decades; and much has been learned about how that clinical experience informs, and is informed by, what is being revealed in the laboratory. Understanding how chronic pain differs from short-lived pain is a critical first step towards understanding that opioid treatment can be highly effective and relatively safe for the treatment of severe short-lived pain, yet when it is used to treat chronic pain, it can have limited efficacy, significant safety concerns, and poor outcomes.
Early evidence in the 1980s and 1990s supporting efficacy and safety for chronic opioid therapy consisted of randomized controlled trials plus some observational studies. Both types of studies were conducted over limited time spans, recruited select populations, and used dose restrictions.10,11 These studies were largely positive and largely supportive of chronic opioid treatment. It was not until later that population studies began to give rise to concern about the efficacy and safety of chronic opioid therapy.28,29 The first long-term (12 months) pragmatic randomized trial of chronic opioid therapy published this year finds worse pain and adverse effects for opioid-treated patients with low back pain, hip, and knee arthritis compared with non–opioid-treated matched controls.55 An important lesson learned from the population studies is that problematic opioid use, including loss of control over use, opioid use disorder, accidental overdose, suicide, and analgesic failure, is more likely to arise in individuals with psychiatric comorbidities.24,36,37,64,85,89,97,98,105,121 There are also individuals who are likely to escalate to high doses, which increases these risks. This link between high-dose usage, poor outcomes, and multiple pain comorbidities has been termed “adverse selection.”106 It seems that the patients who eventually have difficulty in controlling their opioid use and end up on high and risky opioid doses (often made more dangerous by concomitant use of other central nervous system depressants) are a self-selected group of patients with preexisting risk. We have tended to assume that it is the high doses that are risky, but it is equally possible that it is underlying risk factors and the behaviors that are risky.14
Chronic pain is not the same as acute or short-lived pain, and a key factor in the development of chronic pain, or risk of chronic pain, is stress. This is particularly true of chronic refractory, nonresponsive pain. Stress increases vulnerability to a host of stress-induced illnesses, including chronic pain, and the disruption of normal endogenous opioid function is a key factor in the long-term effects of stress. Because endogenous opioids play a central role in social functioning for humans,12,15,16,25,34,35,46,54,60,62,74,75,79,81,107 not only does social rejection and other abuse frequently underlie chronic pain and associated disorders, the resulting disruption of endogenous opioid function then perpetuates the risk. The idea that opioid tone is increased in these high-risk individuals suggests that they hunger for exogenous opioids, often get relief only from exogenous opioids, yet have inherent high risk of developing an opioid use disorder. Unfortunately, when these high-risk individuals become dependent on opioids, which they inevitably do if they take opioids continuously and long term, one result is that their social functioning deteriorates even further.26,57
What begins to emerge from population data and an improved understanding of chronic pain is that high-risk individuals may account for the majority of the poor outcomes and the alarming statistics that have forced a reexamination of chronic opioid treatment. It is unfortunate that we do not have any way of measuring how many, and which, people use opioids safely and with good effect, but anecdotal reports still suggest that there are long-term opioid treatment successes. Reluctance to abandon chronic opioid treatment altogether is based on these successes, and on the hope that a combination of pharmacological, genetic, and molecular research will produce better and safer solutions. One promising avenue of research is based on the idea of biased ligands that can target analgesic pathways (the Gi/o signaling proteins) and spare adverse effects pathways (the ß-arrestin signaling proteins).50,63,92 A separate line of research involves the role of buprenorphine and other kappa antagonists, which have already proven useful in the treatment of chronic pain comorbidities (depression and addiction), as well as pain itself.39,65,66 Regardless, present knowledge suggests that traditional opioids have serious safety concerns and limited long-term efficacy for the majority of those who were selected for chronic treatment before present-day concerns were raised. Understanding exogenous opioid risks and the factors that contribute to them will go a long way towards optimizing both pain treatment and the role of exogenous opioids.
Conflict of interest statement
The author has no conflict of interest to declare.
Much of the groundwork for this article was completed in collaboration with Mark D. Sullivan, University of Washington, Seattle, WA, United States. No technical support was needed. No financial support was given.
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