Secondary Logo

Share this article on:

The brain on opioids

Ballantyne, Jane C.

doi: 10.1097/j.pain.0000000000001270
Biennial Review of Pain
Global Year 2018

Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, United States

Address: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Box 356540, Seattle, WA 98195-6560, United States. Tel.: (206) 543 2568; fax: (206) 543 2958. E-mail address: (J.C. Ballantyne).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received February 09, 2018

Received in revised form April 24, 2018

Accepted April 25, 2018

Back to Top | Article Outline

1. Introduction

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.

Back to Top | Article Outline

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.

Back to Top | Article Outline

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.

Back to Top | Article Outline

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).

Table 1

Table 1

Back to Top | Article Outline

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

Back to Top | Article Outline

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.

Back to Top | Article Outline

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.

Back to Top | Article Outline

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).

Figure 1

Figure 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.”

Back to Top | Article Outline

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.

Back to Top | Article Outline

5. Summary

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.

Back to Top | Article Outline

Conflict of interest statement

The author has no conflict of interest to declare.

Back to Top | Article Outline


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.

Back to Top | Article Outline


[1]. Amari E, Rehm J, Goldner E, Fischer B. Nonmedical prescription opioid use and mental health and pain comorbidities: a narrative review. Can J Psychiatry 2011;56:495–502.
[2]. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–87.
[3]. Apkarian AV, Baliki MN, Geha PY. Towards a theory of chronic pain. Prog Neurobiol 2009;87:81–97.
[4]. Apkarian AV, Hashmi JA, Baliki MN. Pain and the brain: specificity and plasticity of the brain in clinical chronic pain. PAIN 2011;152(3 suppl):S49–64.
[5]. Apkarian AV. Pain perception in relation to emotional learning. Curr Opin Neurobiol 2008;18:464–8.
[6]. Baliki MN, Apkarian AV. Nociception, pain, negative moods, and behavior selection. Neuron 2015;87:474–91.
[7]. Baliki MN, Geha PY, Fields HL, Apkarian AV. Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron 2010;66:149–60.
[8]. Baliki MN, Petre B, Torbey S, Herrmann KM, Huang L, Schnitzer TJ, Fields HL, Apkarian AV. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci 2012;15:1117–9.
[9]. Ballantyne JC, LaForge SL. Opioid dependence and addiction in opioid treated pain patients. PAIN 2007;129:235–55.
[10]. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003;349:1943–53.
[11]. Ballantyne JC, Shin NS. Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain 2008;24:469–78.
[12]. Ballantyne JC, Sullivan MD. Discovery of endogenous opioid systems: what it has meant for the clinician's understanding of pain and its treatment. PAIN 2017;158:2290–300.
[13]. Ballantyne JC, Sullivan MD, Kolodny A. Opioid dependence vs addiction: a distinction without a difference? Arch Intern Med 2012;172:1342–3.
[14]. Ballantyne JC. Opioids for the treatment of chronic pain: mistakes made, lessons learned, and future directions. Anesth Analg 2017;125:1769–78.
[15]. Bandelow B, Wedekind D. Possible role of a dysregulation of the endogenous opioid system in antisocial personality disorder. Hum Psychopharmacol 2015;30:393–415.
[16]. Bandelow B, Schmahl C, Falkai P, Wedekind D. Borderline personality disorder: a dysregulation of the endogenous opioid system? Psychol Rev 2010;117:623–36.
[17]. Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 1984;7:309–38.
[18]. Beecher HK. The measurement of pain. Prototype for the quantitative study of subjective responses. Pharmacol Rev 1956;9:59–209.
[19]. Borsook D, Edwards R, Elman I, Becerra L, Levine J. Pain and analgesia: the value of salience circuits. Prog Neurobiol 2013;104:93–105.
[20]. Borsook D. Opioidergic tone and pain susceptibility: interactions between reward systems and opioid receptors. PAIN 2017;158:185–6.
[21]. Boscarino JA, Rukstalis MR, Hoffman SN, Han JJ, Erlich PM, Ross S, Gerhard GS, Stewart WF. Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4 diagnostic criteria. J Addict Dis 2011;30:185–94.
[22]. Cahill CM, Taylor AM. Neuroinflammation-a co-occurring phenomenon linking chronic pain and opioid dependence. Curr Opin Behav Sci 2017;13:171–7.
[23]. Cami J, Farre M. Drug addiction. N Engl J Med 2003;349:975–86.
[24]. Campbell G, Nielsen S, Bruno R, Lintzeris N, Cohen M, Hall W, Larance B, Mattick RP, Degenhardt L. The Pain and Opioids IN Treatment study: characteristics of a cohort using opioids to manage chronic non-cancer pain. PAIN 2015;156:231–42.
[25]. Carr DB. Endogenous opioids' primary role: harmonizing individual, kin/cohort, and societal behaviors. Pain Med 2017;18:201–3.
[26]. Case A, Deaton A. Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century. Proc Natl Acad Sci U S A 2015;112:15078–83.
[27]. Celerier E, Laulin J, Larcher A, Le Moal M, Simonnet G. Evidence for opiate-activated NMDA processes masking opiate analgesia in rats. Brain Res 1999;847:18–25.
[28]. Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, Dana T, Bougatsos C, Deyo RA. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 2015;162:276–86.
[29]. Contextual evidence review for the CDC guideline for prescribing opioids for chronic pain—United States, 2016. CDC Stacks, Public Health Publications, 2016. Available at: Accessed 12 July, 2018.
[30]. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002;3:655–66.
[31]. Davis KD, Moayedi M. Central mechanisms of pain revealed through functional and structural MRI. J Neuroimmune Pharmacol 2013;8:518–34.
[32]. Davis KD, Seminowicz DA. Insights for clinicians from brain imaging studies of pain. Clin J Pain 2017;33:291–4.
[33]. De Kock M, Lavand'homme P, Waterloos H. “Balanced analgesia” in the perioperative period: is there a place for ketamine? PAIN 2001;92:373–80.
[34]. Dunbar RI, Teasdale B, Thompson J, Budelmann F, Duncan S, van Emde Boas E, Maguire L. Emotional arousal when watching drama increases pain threshold and social bonding. R Soc Open Sci 2016;3:160288.
[35]. Dunbar RI. Bridging the bonding gap: the transition from primates to humans. Philos Trans R Soc Lond B Biol Sci 2012;367:1837–46.
[36]. Edlund MJ, Steffick D, Hudson T, Harris KM, Sullivan M. Risk factors for clinically recognized opioid abuse and dependence among veterans using opioids for chronic non-cancer pain. PAIN 2007;129:355–62.
[37]. Edlund MJ, Martin BC, Fan MY, Braden JB, Devries A, Sullivan MD. An analysis of heavy utilizers of opioids for chronic noncancer pain in the TROUP study. J Pain Symptom Manage 2010;40:279–89.
[38]. Elman I, Borsook D. Common brain mechanisms of chronic pain and addiction. Neuron 2016;89:11–36.
[39]. Emrich HM, Vogt P, Herz A, Kissling W. Antidepressant effects of buprenorphine. Lancet 1982;2:709.
[40]. Grace PM, Strand KA, Galer EL, Urban DJ, Wang X, Baratta MV, Fabisiak TJ, Anderson ND, Cheng K, Greene LI, Berkelhammer D, Zhang Y, Ellis AL, Yin HH, Campeau S, Rice KC, Roth BL, Maier SF, Watkins LR. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 2016;113:E3441–E3450.
[41]. Hayhurst CJ, Durieux ME. Differential opioid tolerance and opioid-induced hyperalgesia: a clinical reality. Anesthesiology 2016;124:483–8.
[42]. Hipolito L, Wilson-Poe A, Campos-Jurado Y, Zhong E, Gonzalez-Romero J, Virag L, Whittington R, Comer SD, Carlton SM, Walker BM, Bruchas MR, Moron JA. Inflammatory pain promotes increased opioid self-administration: role of dysregulated ventral tegmental area mu opioid receptors. J Neurosci 2015;35:12217–31.
[43]. Hojsted J, Ekholm O, Kurita GP, Juel K, Sjogren P. Addictive behaviors related to opioid use for chronic pain: a population-based study. PAIN 2013;154:2677–83.
[44]. Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 2006;29:565–98.
[45]. Iannetti GD, Salomons TV, Moayedi M, Mouraux A, Davis KD. Beyond metaphor: contrasting mechanisms of social and physical pain. Trends Cogn Sci 2013;17:371–8.
[46]. Insel TR. Is social attachment an addictive disorder? Physiol Behav 2003;79:351–7.
[47]. Johansen JP, Fields HL. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat Neurosci 2004;7:398–403.
[48]. Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005;103:147–55.
[49]. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001;413:203–10.
[50]. Kieffer BL, Gaveriauz-Rugg C. Exploring the opioid system by gene knockout. Prog Neurobiol 2002;66:285–306.
[51]. Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science 1997;278:52–8.
[52]. Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropharm 2001;24:97–129.
[53]. Koob GF, Maldonado R, Stinus L. Neural substrates of opiate withdrawal. Trends Neurosci 1992;15:186–91.
[54]. Krahe C, Springer A, Weinman JA, Fotopoulou A. The social modulation of pain: others as predictive signals of salience—a systematic review. Front Hum Neurosci 2013;7:386.
[55]. Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, Kroenke K, Bair MJ, Noorbaloochi S. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA 2018;319:872–82.
[56]. Kreek MJ, Vocci FJ. History and current status of opioid maintenance treatments: blending conference session. J Subst Abuse Treat 2002;23:93–105.
[57]. Krueger AB. Where have all the workers gone? An inquiry into the decline of the US labor force participation rate. Brookings Papers on Economic Activity, BPEA Conference Drafts, September 7–8, 2017.
[58]. Kucyi A, Davis KD. The neural code for pain: from single-cell electrophysiology to the dynamic pain connectome. Neuroscientist 2016. pii: 1073858416667716. [Epub ahead of print].
[59]. Legrain V, Iannetti GD, Plaghki L, Mouraux A. The pain matrix reloaded: a salience detection system for the body. Prog Neurobiol 2011;93:111–24.
[60]. Liebowitz MR. Chemistry of love. Boston: Little Brown, 1983.
[61]. Loram LC, Grace PM, Strand KA, Taylor FR, Ellis A, Berkelhammer D, Bowlin M, Skarda B, Maier SF, Watkins LR. Prior exposure to repeated morphine potentiates mechanical allodynia induced by peripheral inflammation and neuropathy. Brain Behav Immun 2012;26:1256–64.
[62]. Machin AJ, Dunbar RI. The brain opioid theory of social attachment: a review of the evidence. Behaviour 2011;148:985–1025.
[63]. Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hubner H, Huang XP, Sassano MF, Giguere PM, Lober S, Da D, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK. Structure-based discovery of opioid analgesics with reduced side effects. Nature 2016;537:185–90.
[64]. Martin BC, Fan MY, Edlund MJ, Devries A, Braden JB, Sullivan MD. Long-term chronic opioid therapy discontinuation rates from the TROUP study. J Gen Intern Med 2011;26:1450–7.
[65]. Massaly N, Moron JA, Al-Hasani R. A trigger for opioid misuse: chronic pain and stress dysregulate the mesolimbic pathway and kappa opioid system. Front Neurosci 2016;10:480.
[66]. Massaly N, Ream A, Hipolito L, Wilson-Poe A, Walker B, Bruchas M, Moron-Concepcion J. (323) Kappa opioid receptors in the nucleus accumbens mediate pain-induced decrease in motivated behavior. J Pain 2016;17:S56.
[67]. Melik Parsadaniantz S, Rivat C, Rostene W, Reaux-Le Goazigo A. Opioid and chemokine receptor crosstalk: a promising target for pain therapy? Nat Rev Neurosci 2015;16:69–78.
[68]. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150:971–9.
[69]. Moseley GL, Butler DS. Fifteen years of explaining pain: the past, present and future. J Pain 2015;16:807–13.
[70]. Narita M, Kishimoto Y, Ise Y, Yajima Y, Misawa K, Suzuki T. Direct evidence for the involvement of the mesolimbic kappa-opioid system in the morphine-induced rewarding effect under an inflammatory pain-like state. Neuropsychopharmacology 2005;30:111–8.
[71]. Narita M, Kaneko C, Miyoshi K, Nagumo Y, Kuzumaki N, Nakajima M, Nanjo K, Matsuzawa K, Yamazaki M, Suzuki T. Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala. Neuropsychopharmacology 2006;31:739–50.
[72]. Navratilova E, Atcherley CW, Porreca F. Brain circuits encoding reward from pain relief. Trends Neurosci 2015;38:741–50.
[73]. Nees F, Becker S, Millenet S, Banaschewski T, Poustka L, Bokde A, Bromberg U, Buchel C, Conrod PJ, Desrivieres S, Frouin V, Gallinat J, Garavan H, Heinz A, Ittermann B, Martinot JL, Papadopoulos Orfanos D, Paus T, Smolka MN, Walter H, Whelan R, Schumann G, Flor H, consortium I. Brain substrates of reward processing and the mu-opioid receptor: a pathway into pain? PAIN 2017;158:212–19.
[74]. Nummenmaa L, Manninen S, Tuominen L, Hirvonen J, Kalliokoski KK, Nuutila P, Jaaskelainen IP, Hari R, Dunbar RI, Sams M. Adult attachment style is associated with cerebral mu-opioid receptor availability in humans. Hum Brain Mapp 2015;36:3621–8.
[75]. Nummenmaa L, Tuominen L, Dunbar R, Hirvonen J, Manninen S, Arponen E, Machin A, Hari R, Jaaskelainen IP, Sams M. Social touch modulates endogenous mu-opioid system activity in humans. Neuroimage 2016;138:242–7.
[76]. Ossipov MH, Lai J, King T, Vanderah TW, Porreca F. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers 2005;80:319–24.
[77]. Pain management and the opioid epidemic: balancing societal and individual benefits and risks of prescription opioid use. Washington: The National Academies Press, 2017. Available at: Accessed 12 July, 2018.
[78]. Palmer RE, Carrell DS, Cronkite D, Saunders K, Gross DE, Masters E, Donevan S, Hylan TR, Von Kroff M. The prevalence of problem opioid use in patients receiving chronic opioid therapy: computer-assisted review of electronic health record clinical notes. PAIN 2015;156:1208–14.
[79]. Panksepp J. Affective neuroscience. New York: Oxford University Press, 1999.
[80]. Patel JP, Sengupta R, Bardi G, Khan MZ, Mullen-Przeworski A, Meucci O. Modulation of neuronal CXCR4 by the micro-opioid agonist DAMGO. J Neurovirol 2006;12:492–500.
[81]. Pearce E, Launay J, Dunbar RI. The ice-breaker effect: singing mediates fast social bonding. R Soc Open Sci 2015;2:150221.
[82]. Pearce E, Wlodarski R, Machin A, Dunbar RIM. Variation in the beta-endorphin, oxytocin, and dopamine receptor genes is associated with different dimensions of human sociality. Proc Natl Acad Sci U S A 2017;114:5300–5.
[83]. Pello OM, Martinez-Munoz L, Parrillas V, Serrano A, Rodriguez-Frade JM, Toro MJ, Lucas P, Monterrubio M, Martinez AC, Mellado M. Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation. Eur J Immunol 2008;38:537–49.
[84]. Peng X, Robinson RL, Mease P, Kroenke K, Williams DA, Chen Y, Faries D, Wohlreich M, McCarberg B, Hann D. Long-term evaluation of opioid treatment in fibromyalgia. Clin J Pain 2015;31:7–13.
[85]. Phifer J, Skelton K, Weiss T, Schwartz AC, Wingo A, Gillespie CF, Sands LA, Sayyar S, Bradley B, Jovanovic T, Ressler KJ. Pain symptomatology and pain medication use in civilian PTSD. PAIN 2011;152:2233–40.
[86]. Porreca F, Navratilova E. Reward, motivation, and emotion of pain and its relief. PAIN 2017;158(suppl 1):S43–S49.
[87]. Remerand F, Le Tendre C, Baud A, Couvret C, Pourrat X, Favard L, Laffon M, Fusciardi J. The early and delayed analgesic effects of ketamine after total hip arthroplasty: a prospective, randomized, controlled, double-blind study. Anesth Analg 2009;109:1963–71.
[88]. Ribeiro SC, Kennedy SE, Smith YR, Stohler CS, Zubieta JK. Interface of physical and emotional stress regulation through the endogenous opioid system and mu-opioid receptors. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1264–80.
[89]. Richardson LP, Russo JE, Katon W, McCarty CA, Devries A, Edlund MJ, Martin BC, Sullivan M. Mental health disorders and long-term opioid use among adolescents and young adults with chronic pain. J Adolesc Health 2012;50:553–8.
[90]. Rivat C, Ballantyne JC. The dark side of opioids in pain management: basic science explains clinical observation. Pain Rep 2016;1:e570.
[91]. Robinson TE, Berridge KC. Addiction. Annu Rev Psychol 2003;54:25–53.
[92]. Rominger DH, Cowan CL, Gowen-MacDonald W, Violin JD. Biased ligands: pathway validation for novel GPCR therapeutics. Curr Opin Pharmacol 2014;16:108–15.
[93]. Sahbaie P, Liang DY, Shi XY, Sun Y, Clark JD. Epigenetic regulation of spinal cord gene expression contributes to enhanced postoperative pain and analgesic tolerance subsequent to continuous opioid exposure. Mol Pain 2016:12.
[94]. Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002(5 suppl):1062–7.
[95]. Schrepf A, Harper DE, Harte SE, Wang H, Ichesco E, Hampson JP, Zubieta JK, Clauw DJ, Harris RE. Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study. PAIN 2016;157:2217–25.
[96]. Schwartz AC, Bradley R, Penza KM, Sexton M, Jay D, Haggard PJ, Garlow SJ, Ressler KJ. Pain medication use among patients with posttraumatic stress disorder. Psychosomatics 2006;47:136–42.
[97]. Schwartz N, Temkin P, Jurado S, Lim BK, Heifets BD, Polepalli JS, Malenka RC. Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science 2014;345:535–42.
[98]. Seal KH, Shi Y, Cohen G, Maguen S, Krebs EE, Neylan TC. Association of mental health disorders with prescription opioids and high-risk opioid use in US veterans of Iraq and Afghanistan. JAMA 2012;307:940–7.
[99]. Shippenberg TS, Millan MJ, Mucha RF, Herz A. Involvement of beta-endorphin and mu-opioid receptors in mediating the aversive effect of lithium in the rat. Eur J Pharmacol 1988;154:135–44.
[100]. Shippenberg TS, Herz A, Nikolarakis K. Prolonged inflammatory pain modifies corticotropin-releasing factor-induced opioid peptide release in the hypothalamus. Brain Res 1991;563:209–14.
[101]. Simonnet G, Rivat C. Opioid-induced hyperalgesia: abnormal or normal pain? Neuroreport 2003;14:1–7.
[102]. Sluka KA, Clauw DJ. Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience 2016;338:114–29.
[103]. Solomon RL. The opponent-process theory of acquired motivation: the costs of pleasure and the benefits of pain. Am Psychol 1980;35:691–712.
[104]. South SM, Smith MT. Analgesic tolerance to opioids. Pain clinical updates. IASP Press 2001;9:1–4.
[105]. Sullivan MD, Edlund MJ, Zhang L, Unutzer J, Wells KB. Association between mental health disorders, problem drug use, and regular prescription opioid use. Arch Intern Med 2006;166:2087–93.
[106]. Sullivan M. Clarifying opioid misuse and abuse. PAIN 2013;154:2239–40.
[107]. Tarr B, Launay J, Dunbar RI. Silent disco: dancing in synchrony leads to elevated pain thresholds and social closeness. Evol Hum Behav 2016;37:343–9.
[108]. Taylor AM, Becker S, Schweinhardt P, Cahill C. Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction. PAIN 2016;157:1194–8.
[109]. Taylor AM, Mehrabani S, Liu S, Taylor AJ, Cahill CM. Topography of microglial activation in sensory- and affect-related brain regions in chronic pain. J Neurosci Res 2017;95:1330–5.
[110]. Tracey I, Bushnell MC. How neuroimaging studies have challenged us to rethink: is chronic pain a disease? J Pain 2009;10:1113–20.
[111]. Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron 2007;55:377–91.
[112]. Vachon-Presseau E, Tetreault P, Petre B, Huang L, Berger SE, Torbey S, Baria AT, Mansour AR, Hashmi JA, Griffith JW, Comasco E, Schnitzer TJ, Baliki MN, Apkarian AV. Corticolimbic anatomical characteristics predetermine risk for chronic pain. Brain 2016;139:1958–70.
[113]. Valentino RJ, Van Bockstaele E. Endogenous opioids: the downside of opposing stress. Neurobiol Stress 2015;1:23–32.
[114]. Volkow ND, McLellan AT. Opioid abuse in chronic pain–misconceptions and mitigation strategies. N Engl J Med 2016;374:1253–63.
[115]. Volkow ND, Fowler JS, Wang GJ. The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies. Neuropharmacology 2004;47(suppl 1):3–13.
[116]. Volkow ND, Wang GJ, Fowler JS, Tomasi D, Telang F, Baler R. Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain's control circuit. Bioessays 2010;32:748–55.
[117]. von Zastrow MA. Cell biologist's perspective on physiological adaptation to opiate drugs. Neuropharmacology 2004;47(suppl 1):286–92.
[118]. Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. PAIN 2015;156:569–76.
[119]. Wall PD. The laminar organization of dorsal horn and effects of descending impulses. J Physiol 1967;188:403–23.
[120]. Watson D. Rethinking the mood and anxiety disorders: a quantitative hierarchical model for DSM-V. J Abnorm Psychol 2005;114:522–36.
[121]. Weisner CM, Campbell CI, Ray GT, Saunders K, Merrill JO, Banta-Green C, Sullivan MD, Silverberg MJ, Mertens JR, Boudreau D, Von Korff M. Trends in prescribed opioid therapy for non-cancer pain for individuals with prior substance use disorders. PAIN 2009;145:287–93.
[122]. White JM. Pleasure into pain: the consequences of long-term opioid use. Addict Behav 2004;29:1311–24.
[123]. Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA. CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain Behav Immun 2011;25:565–73.
[124]. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. PAIN 2011;152(3 suppl):S2–S15.
[125]. Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum 2013;65:529–38.
© 2018 International Association for the Study of Pain