When pain gets stuck: the evolution of pain chronification and treatment resistance

Abstract

It is well-recognized that, despite similar pain characteristics, some people with chronic pain recover, whereas others do not. In this review, we discuss possible contributions and interactions of biological, social, and psychological perturbations that underlie the evolution of treatment-resistant chronic pain. Behavior and brain are intimately implicated in the production and maintenance of perception. Our understandings of potential mechanisms that produce or exacerbate persistent pain remain relatively unclear. We provide an overview of these interactions and how differences in relative contribution of dimensions such as stress, age, genetics, environment, and immune responsivity may produce different risk profiles for disease development, pain severity, and chronicity. We propose the concept of "stickiness" as a soubriquet for capturing the multiple influences on the persistence of pain and pain behavior, and their stubborn resistance to therapeutic intervention. We then focus on the neurobiology of reward and aversion to address how alterations in synaptic complexity, neural networks, and systems (eg, opioidergic and dopaminergic) may contribute to pain stickiness. Finally, we propose an integration of the neurobiological with what is known about environmental and social demands on pain behavior and explore treatment approaches based on the nature of the individual's vulnerability to or protection from allostatic load.

Figure 1:. Chronic Pain Syndromes that get ‘Stuck’.

In Figure 1, we represent the idea of pain evolving and persisting, remaining static, or worsening. Back Pain: Back pain may start as an acute process and get better or it may worsen and chronify. Eighty percent of adults will have back pain at some point, and most resolve. Twenty percent however go on to have chronic pain for more than a year. Risk factors, like many but not all pain conditions that relate to disease resilience in back pain include age, fitness, pregnancy, weight, genetics, anxiety/depression [1]. In its ‘stuck’ form, it is difficult to treat and the ongoing pain and disability continue to contribute to the allostatic load of the condition and its treatment resistance. Post-Surgical Pain: Surgery may produce damage to nerves resulting in neuropathic pain and occurs in 15–50% of patients [144] [174] [30]. Risk factors include genetic [286], pre-operative pain [108], acute post-operative pain [35], psychosocial factors such as catastrophizing [126]; surgical stress [30] and potentially perioperative treatments including intraoperative opioids that may induces post-operative hyperalgesia [146] [281] [98]. It may be more common after certain surgeries (e.g., surgery for failed back; limb amputation, mastectomy) and some surgeries may have a higher incidence because of the location of the surgery relative to certain nerves (e.g., intercostal n., intervertebral n., ilio-hypogastric n., divisions of the sciatic n.). Taken together, these multifactorial processes may contribute individually or in various combinations to a chronic pain syndrome that may be persistent and severe. Thalamic Stroke: Few pain syndromes are as severe and persistent as the pain following thalamic (usually right sided) stroke [25] that involves the spinothalamic tract. It affects some 8% of stroke patients [5]. While the onset may be days to months after the stroke [34], it represents a forme fruste of a ‘stuck’ pain syndrome and as shown in the figure the pain intensity with onset may be progressive but usually ramps up to a very severe level. The syndrome has no socioeconomic variability, age, or sex predisposition. Other syndromes that result in severe and persistent pain also produce damage the spinothalamic tract and include spinal cord injury [179]. The figure shows a timeline vs. intensity that summarizes the process in which patients may not have pain or have relatively rapid onset, in most cases, of this severe central pain syndrome. Migraine: Migraine is an example of a pain syndrome (that is intermittent (acute episodic migraine) that can increase in frequency and chronify [168] [143]. In the acute episodic form (≥ 14 headache days a month; International Headache Society Definition: [245], the pain and associated symptoms of the pre-, peri- and post- ictal event are acute and subside completely. In chronic migraine the pain persists (≤ 14 headache days a month; International Headache Society Definition: [245]. Some 6–8 million American suffer from chronic migraine [178]. Migraine chronification may be considered to be due to increasing allostatic load [32] and medication overuse [19], increased frequency of headache, menstrual cycle amongst other things contribute to the maladaptive changes in the transition from acute episodic migraine to chronic migraine. Interestingly some data supports a reversal of the chronic state with the withdrawal of certain stressors such as opioid medication [234]. The figure shows two forms of migraine – acute intermittent migraines (multiple attacks) are present. In the acute form there is an intermitted attack that recedes, usually with hours but may last up to 72 hours. In the chronic form pain is present most of the time. Pain+Anxiety: The notion that psychological processes (e.g., fear, avoidance, anhedonia) can affect chronic pain either as a predictor [208] because of a particular constitutional makeup or as an exacerbator of the pain condition [253] is depicted in the figure. Treatment: Treatment for chronic pain is a double-edged sword in that drugs are frequently given for a long period of time without an understanding of their long-term effects on neural or other systems. In chronic pain, the field has embraced the notion of such concepts as ‘opioid induced hyperalgesia’ that may reflect the induction of aberrant neural systems to produce increased ongoing pain [46] and perhaps increased resistance to treatment [18]. Indeed chronic opioids alter morphological and functional measures in patients without pain [267]. Similarly and perhaps more notable, are the effects of medications including specific anti-migraine drugs called triptans, on migraine progression (increased frequency) and chronification (transformed from acute episodic to chronic) [18] [167]. Key:   Represents the onset/event of the pain and the point from which it may improve or get worse.   Represents when pain is severe and resilient to treatment and/or chronifying.   Is time from the Onset/Event   Is a scale of increasing or decreasing Pain as it relates to the level of Resilience.

Figure 2:. Top:Multiple interactions – Disease (Pain), Effectors (Stress, Genetic etc.) and Downstream Modulation (Epigenetic changes).

The term “epigenesis” as used here refers to potential changes that may contribute to altered cellular/neuronal function via non-genetic influences on gene expression (see Text). Bottom: Weighting of Interactions has a different effect on Pain Left Panel: Increased pain due to an altered immune responsivity due to aging: In this example Age and Immune response are abnormal. In some cases the altered immunity is protective. For example, in young (neonatal) animals and children, the propensity to develop neuropathic pain after surgery may be diminished, based on processes that include altered T lymphocyte responses, but is a major contributor to neuropathic pain adults [53]. Middle Panel: Environmental factors may exacerbate psychological factors leading to great pain: Parental-child and other relationships may contribute to processes such as fear-avoidance exacerbation of pain [270]. Right Panel: Decreased pain based on Genetic Profile: In humans [156] and rat strains [235] [155], differences in chronic pain have been reported based on altered genetic backgrounds or gene alleles that may be protective. The converse is thus also true that the genetic background may lead to the phenotypic expression of chronic pain and have different risk profiles for severity and progression/chronicity.

Figure 3:. Synaptic Connections, Neural Assemblies and Neural Networks

Synaptic Complexity:The figure summarizes the complexity of normal (red) and abnormal (purple) neuronal dendrites. Altered synaptic connections take place in the pathways (functional or structural connectivity) in pain chronification in sensory [261], thalamus [159], somatosensory cortex [100], and in emotional pathways (e.g., nucleus accumbens [88]). Neural Assemblies: Neural assemblies represent populations of cells within a structure that usually function in a coordinated or synchronized/temporal manner. Such assemblies usually act in a similar to produce a specific action or function in a manner based on past ‘experience’ or memory. The concept is that the assembly is interdependent and cohesive as a result of the pattern of synaptic connections. As such assemblies may falter when synaptic processes are diminished. Neurons within assemblies may activate or inhibit in a cohesive manner, other members of the assembly. Brain regions where these assemblies have been studied include the hippocampus [121] [181]. Neural Networks: Neural networks are dependent on connectivity. When there are alterations in this connectivity, presumably originating at the level of synaptic changes, these networks are altered. Neural networks can be measured using fMRI and represented as resting state networks. A correlation with anatomic changes has been shown using the same methods, supporting the notion of altered gray matter changes underlying changes in connectivity [37]. In chronic pain these are disrupted. For example, in painful diabetic neuropathy [43], chronic back pain [11], fibromyalgia [145], and complex regional pain syndrome [15].

Figure 4:. integrative Treatments

A: Drivers of Change: The figure conceptualizes the notion of how ongoing pain load may be modified by innate and external processes – Allostatic Load [184] (see B, below). The latter may become maladaptive when the process of responsiveness to stress/pain fails. These changes are manifest as alterations of brain structure and function that in its ‘terminal’ formulation is stuck and very difficult to treat. Multiple treatment options (A – E) are noted in the Measures and Treatments (detailed in B below). The current approaches are defined under Rational Medicine where all forms of treatment are or should be based on randomized control trials wherever possible. More aggressive treatments represent a failure to reverse pain chronification. Ideally specific, highly effective treatments, with tolerable or minimal side effects will become available. Markers of pain chronification have not reached a “Biomarker Status” include clinical [223], treatment resistance [148] [73], psychological measures [80] [276], physiological measures (e.g., measures of altered descending modulation [204] [248]) and brain measures [27] [266]. B: Treatment Approaches: Treatment is based on the nature of the individual’s resistance/resilience that is modified by a number of allostatic phenomena that include: (I) Biological State - pain process, genetic constitution, epigenetic modifications, general health all contribute to the biological state of an individual; (II) Psychological State - Multiple psychological processes contribute to increased risk for pain chronification including fear of pain [238] or catastrophizing [212]; anxiety and depression [260] and prior pain [125] or trauma, including torture [275]; (III) Physiological State - Although robust clinical trials are still needed a number of physiological processes that may contribute to either enhancing or making the condition worse including sleep hygiene [95], exercise [105], and diet [180]; (IV) Socio-Economic State: - Pain may be made worse by socioeconomic stressors such as work status, family, income, and educational standing [217]. A summary of premorbid, pain initiation, and post morbid approaches have been reviewed in the context of the wounded warrior [106].