Pain “chronification”: what is the problem with this model?

“Historically, pain has been arbitrarily divided into acute and chronic with the belief that different mechanisms were involved in the development of each. Recent research, however, indicates that we should see the two as a continuum of the same underlying process. In the past ten years our understanding of how acute post-operative pain becomes chronic has increased with the elucidation of the physiological mechanisms underpinning central and peripheral nervous system processing of pain and the identification of risk factors, including demographic, psychosocial, genetic, and medical factors.” [1]. That focus identifies the problem of persistent post-operative pain as a major healthcare issue, despite that only about 10% of post-surgical pain patients have severe problems [2]. Admittedly, this is a significant number but a small proportion of those with chronic pain, 19% in all of Europe and 30% in Norway [3]. Neil et al. [1] posit that the continuum begins with an acute event, an operation–but hints at something else to be discussed later in this essay.

This statement by Neil et al. identifies a process that the literature describes as “chronification” whereby acute pain becomes chronic. The word “chronification” does not exist in either the Oxford English dictionary or the Merriam-Webster dictionary. The earliest references to the word come from German discussions of acute low back pain evolving into chronic low back pain [4, 5]. A recent panel of the Pain Change Advisory Board defined the term as follows; “Pain chronification describes the process of transient pain progressing into persistent pain; pain processing changes as a result of an imbalance between pain amplification and pain inhibition; genetic, environmental and biopsychosocial factors determine the risk, the degree, and time-course of chronification.” [6]. The term “chronification” has taken on a life of its own and now is identified as the cause of unexplained chronic pain under the biomedical model. For many, it is also the explanation for the development of every type of chronic pain. “All chronic pain begins at some discrete point in time.” Badiola [7]. Thus, according to Badiola, all chronic pain begins as acute pain.

Let us go back to some basics. Acute pain is defined by the International Association for the Study of Pain (IASP) as follows: “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.” [8].

Chronic pain is also defined by IASP and is as follows: “Pain that persists past the healing phase following an injury.” [9].

The second definition implies that “chronification” is the primary cause of chronic pain, i.e., chronic pain is a transition from acute pain. The thinking that all chronic pain has acute pain as the origin is also used in our explanation, especially for patients, of the difference between acute and chronic pain. That clarification states that acute pain is an essential function of the nervous system. It is a warning of “actual or potential tissue damage”, to paraphrase the definition from the IASP taxonomy. On the other hand, chronic pain is stated to be a malfunction of the nervous system that gives false information about the state of the body and produces a reaction as if an acute and possibly life-threatening event is ongoing. It is as if the mechanism (or mechanisms) causing acute pain becomes fixed in some way and that the usual regression of pain that accompanies the healing process has not happened. We are stuck with this idea and all the research, and there is plenty, on acute post-operative pain transitioning to chronic pain (CPOP) has only served to emphasize this.

But is this the case out in the real world? A very common, primarily nociceptive, chronic pain problem is osteoarthritis. There is little data to support that this begins as an acute event except in some instances that evolve after an acute joint injury. The same can be said of a very common chronic neuropathic pain problem, diabetic polyneuropathy. Again, this usually starts as a gradual peripheral sensory change with pain appearing as a later phenomenon but without a definite starting “event”. In some cases, pain also appears gradually as the first sign of the development of neuropathy.

In a recent study, HUNT pain examination [10], 551 individuals from two adjacent counties in central Norway were interviewed and examined. Of these, 399 reported “moderate” to “severe” to “very severe” chronic pain when asked in an interview “How much bodily pain have you had over the past week – none, very mild, mild, moderate, severe, very severe?” The high proportion of those with chronic pain relates to the study being enriched, i.e. having a pain cohort and a random control cohort. All were asked about how their pain began, and the responses are revealing: 1.0% after surgery, 21.8% acutely with or without some other initiating event and 76.5% stated that their pain just began gradually (2% could not specify). Thus, a total of 22.8% with a significant chronic pain problem could possibly fit within the “chronification” profile to explain their complaints. Many of the subjects also had difficulty in recalling how long they had had chronic pain. It seems that our focus on the acute to chronic transition, although very important when looking at surgery or trauma as the initiating event, ignores the fact that a significant percentage of those with chronic pain cannot identify what seems like an acute starting point and more importantly, some acute pain event (Table 1).

A majority of these subjects were diagnosed with “chronic primary pain” according to the new International Classification of Diseases-11 (ICD-11) criteria [11] which imply that no pathological (bio) cause could be identified. A recent review of the new pathophysiological mechanism, nociplastic pain [12], often given as the mechanism in “chronic primary pain”, in addition to nociceptive and neuropathic pain phenotypes, describes the onset as often “de novo”, without any initiating event. Their description of nociplastic pain goes on to state: “However, the causal relationship between a patient-reported inciting event and a chronic pain condition is often unclear, because many patients identify precipitating events that do not have a pathoanatomical basis.” This statement casts doubt even on the validity of some “chronification” scenarios.

“All chronic pain begins at some discrete point in time” again, according to Badiola [7]. The implication in the Badiola article is that all chronic pain begins as acute pain. This statement brings up another very important point in light of the animal research on “chronification” of pain which attempts to identify the process (or processes) that explains the phenomenon in humans. When does a pain problem become chronic? And what is “chronic” for a rat or a mouse or any other animal used in pain research? To address the first question, “chronic” for humans is variously defined as “pain after healing has occurred”, “three months after surgery or an injury”, “six months after surgery or an injury” by IASP and others. The difficulty with this, on one hand, is that some “chronic” pain problems such as rheumatoid arthritis or Crohn’s disease show evidence of ongoing inflammation, an acute process that waxes and wanes but we still refer to the associated pain as “chronic”. It is certainly difficult to try to explain to these individuals that there is a malfunction in the nervous system that is giving them false signals when we have biomarkers proving that their current heightened pain is due to an increase in disease activity. On the other hand, what about the significant proportion of others with non-specific chronic pain that recall that their pain just began gradually?

A recent literature search in PubMed using the search words “chronic pain, rats, mice” resulted in 1,508 references. The 393 most recent were reviewed. Of these, animal experiments, which discuss the acute to chronic process in various models accounted for 165. An article that reviews this research states: “The long-term maintenance of chronic pain involves late-onset central sensitization, so named because the changes involved in its development can take hours to occur.” [13].

In those 165 animal studies (rats, mice) there was a range of time to transition from acute to chronic pain from one day to six weeks although a majority of the times described fell into the 7–14 day window.

If we look at the large literature on the transition from acute to chronic pain in animals that supposes to explain mechanisms, we have a problem. It is difficult to understand that the process leading from acute to “chronic pain” in a rat at 14 days is the same process in a 50 year’s old man with chronic low back pain that has been present for 20 years but without any initiating event. And that man recalls that it possibly just started as an occasional “tired back” related to his work as a bricklayer.

We need to modify our thinking in a few ways. It is possible that chronic pain is not just an acute pain process gone awry. There may be some connection, but it need not be a direct cause – effect relationship. We need to be careful how we use the “chronification” explanation of a change from acute pain to chronic pain for patients like the 50 years old brick-layer who would be mystified since he cannot remember any acute event and doesn’t fit the model. Or the 30 years old pain researcher (a colleague) recently diagnosed with fibromyalgia who cannot say exactly when her various loci became painful or when occasional pain became constant pain. We must also be cautious in accepting the many suggested animal explanations for the acute to chronic transition since they assume that this process is rapid and that perhaps days are appropriate for the change from acute pain to chronic pain.

To step back from this debate, a major problem is the focus of an article by Quintner et al. [14]. The healthcare system has a rigidity that persists in the mind-body dualism concept. There is a focus on pathological processes that can be explained by dissecting the body, including the nervous system, by anatomical, biochemical, radiological and even more sophisticated ways. We must identify a physical cause for pathology that is assumed to exist. There is an attempt to use these investigations mechanistically to explain the abstract concept of pain. Engel’s biopsychosocial model from psychiatry [15] was eagerly accepted by those interested in pain research and treatment to expand ideas and explain some of the issues raised by Melzack and Wall’s gate theory [16]. Quinter et al. postulate that the biopsychosocial model perpetuates mind-body dualism by compartmentalizing the issues to mind, body and environment although their interactions and the newer studies using Magnetic Resonance Imagery (fMRI) and Positron Emission Tomography (PET) would seem to break down the separation. The focus is still a biological one as a unifying mechanism.

Another, model, not well stated by Quinter et al. is the clinical concept of disease as a continuum with a starting point and a progression of signs and symptoms. It has been proposed that pain should be classified as a “disease in its own right” [17]. It is quite easy for this to be the focus for explaining the phenomenon of chronic pain using a disease model and possibly avoiding the “chronification” explanation.

Although Badiola’s statement that “all chronic pain begins at some discrete point in time” seems inherently logical and that the “discrete point in time” implies that acute pain is the starting point, this is not the subjects’ experience in the HUNT pain study. Is this a problem with those subjects’ memory; that they do not recall the initiating event since it is often in the distant past? Some evidence that memory in pain subjects in the HUNT pain study is reliable comes from research on recall vs. report from the same population as the statistics above on pain onset [18].

Our problem, as Quintner et al. point out, is that we focus on chronic pain as a biological event, even the psychosocial aspects, trying to explain it as a dysfunctional state of the nervous system brought on by acute injury when peripheral tissue pathology cannot account for nociceptive/neuropathic input. The idea that pain can arise spontaneously without tissue injury is a difficult concept. However, we have no real problem with accepting that various forms of headache, especially “tension-type” have a functional basis where no identifiable pathology is evident. For a majority of those chronic headache sufferers, the problem is like that of the bricklayer with low back pain. They had intermittent mild headache that has gradually evolved to chronic daily headache but, for most, without an initiating event and with only a vague idea of when the headache symptoms became problematic. Similarly, for many with fibromyalgia syndrome. Our biological explanation then often falls back on “central sensitization” a spinal process originally identified acutely in anesthetized animals and now taken out of context to explain the enigma of chronic pain when we have no better explanation [19]. Thus, chronic pain as “central sensitization” is considered a biological problem, a central nervous system disease. We are back to Descartes and mind/body dualism.

The newer concept of a different chronic pain mechanism, “nociplastic pain,” attempts to explain some non-nociceptive, non-neuropathic pain states [20]. As mentioned previously, this concept accepts that the process can arise spontaneously in many, i.e., fibromyalgia, without an identifiable starting point or initiating cause in many cases.

In an interesting article by Herta Flor summarizing her recent plenary lecture at the IASP biannual conference in Japan discussing the acute to chronic process, she alludes to “yellow flags” [21]. These are psychological and behavioral traits that predict those who will progress to chronic pain after an acute episode. Data that Flor also quotes come from fMRI and Conditioned Pain Modulation (CPM) studies that identify predictors that can point us in new directions [22, 23]. Certain alterations from normal in the brain before or after an acute pain problem, low back pain in one case, can predict individuals who will later have chronic pain. Perhaps an acute pain incident comes when the nervous system processes that we associate with chronic pain are already present, a latent chronic pain state, that is activated by the acute incident. The nervous system, at many levels, has been primed by genetics, psychosocial conditions, previous pain experiences and other aspects that fit the “yellow flag” definition. This can also explain the case of those who develop chronic pain without any known initiating event. The process evolves from latent to active as a gradual progression of the plastic central processes. The concept of a latent chronic pain state that is activated could explain why the complicated “preventive” treatments, usually polypharmacy, to control inter- and post-operative pain are unsuccessful in preventing “chronification” [24, 25]. If the latent to active concept is correct, the mechanism(s) are rather advanced at the time of surgery and it takes little to tip the system over from latent to chronic pain. This is analogous to closing the barn door after the horse has bolted.

Thus, the process can be viewed not as a transition from acute to chronic pain but the transition from a latent chronic pain state to an active chronic pain state. This theoretical framework suggests a rethinking of our concepts and definition of chronic pain. Neil and McCrae’s statement that there is a pain continuum from acute to chronic pain may only be partially correct [1]. Acute and chronic pain may be only points on a longer continuum that is a part of the plastic processes of the central nervous system throughout life and also with a genetic predisposition. In some individuals, this continuum may also go on to recovery, or partial recovery where pain ceases to be a problem. This has been shown in several demographic studies on pain, including HUNT pain [26]. We just need to find the correct treatments to reverse the direction of the continuum and early intervention before pain is the issue is imperative.

In conclusion, there are many questions about the validity of the “chronification” theory explaining that all chronic pain is due to a transition from acute pain. Since more evidence is accumulating about predisposing factors that predict the development of chronic pain, a change in our thinking is indicated. Also, the holy grail of finding a prevention for “chronification” by a variety of acute pain treatments perhaps should be forgotten. We need to focus on interventions for those predisposing factors, both early to decrease the chances for an evolution to chronic pain, at the time of an acute pain event such as surgery and as a focus in the treatment once a chronic pain state is present.