Pain revised – learning from anomalies

1 Introduction

In his book “The Laws of Medicine” Siddhartha Mukherjee claims that we from ordinary patients learn the rules of medicine, which are very helpful in our clinical work. But it is from clinical anomalies we can discover the fundamental laws of medicine [1]. Therefore, meticulously written anecdotes and cases that contradict our current understanding and explanations should be scrutinized thoroughly and with an open mind. This article is such an attempt in the field of chronic pain medicine. It is triggered by case reports of relief from chronic pain and opioid dependence in conjunction with acute, time-limited amnesia [2], [3], [4].

2 Degeneracy

The majority of clinicians and researchers agree that the human brains do not have a pain center or even a uniquely dedicated pain network [5]. The activated brain regions during a pain experience are context sensitive, meaning that the same regions are activated during certain non-painful stimuli as well. In an evolutionary perspective this is rational. Essential life preserving functions (like pain) should not be controlled from one specific area, since this will make the system too vulnerable and the human species less sustainable. Besides, having dedicated brain regions for all essential functions will make our cognitive capacity much less than it is, and our species less adaptive.

This is more generally known as degeneracy. Degeneracy is a fundamental biological phenomenon in the animal kingdom, including neural networks [6]. Degeneracy in biological systems means that different elements, pathways or networks can produce the same outcome. This makes the biological systems ability to maintain homeostasis more robust and stable in a challenging and changing environment. An illuminating example of this in pain is that several salient sensory stimuli can invoke the same fMRI-response in the brain representing a “pain circuit” [5].

But if something is vital (i.e. essential for homeostasis and survival), like pain sensation, humans most likely have evolved a system that is not easily destroyed (i.e. born without pain sensation). Inspired by this, humans construct airplanes so that they only need one engine to fly, but having two makes it very unlikely that they both will fail simultaneously or on the same flight. Another aspect is that a perfectly stable system is also rigid, and thus not inherently able to learn. Therefore, degeneracy might be an important feature of the learning brain and neural plasticity. This is because we are not talking about instability in the brain, more like flexibility. When a system, like our central nervous system, show maximal adaptability to process neural inputs expediently they are functioning close to a critical point (i.e. criticality) [7]. This criticality is useful for a flexible and learning species, where adaptability is one of its foremost hallmarks. For instance, will criticality be important for a well-functioning resting state network, while executing specific tasks suppresses the flexibility in the system [8], [9]. Therefore, criticality seems crucial for a good cognitive learning environment, which is somewhat reduced in chronic pain patients [10]. These aspects are important to remember when the treatment plan is outlined.

3 Memories and habits

The plasticity of the human brain is unique in the animal kingdom. It is likely that our enormous learning capacity has given us the opportunity to develop our civilizations, not our opposable thumbs. Let us therefore review an ordinary day in a chronic pain patient from a learning and memory perspective. Every day the patient wakes up and expects another painful day. Based on previous days’ experience certain tasks and movements are expected to cause pain. And every day the patient experiences that the expectations are fulfilled. Even with occasional pain-free movements the overall experience is the same. So, we have a cycle: expectation; performance; and confirmation of expectation that is repeated several times every day. This is the same template that has been used in schools for centuries for memorization. Thus, every day in this patient’s life is an ongoing repetition of automatic pain experiences strengthening memory of painful associations. The pain has unwillingly become a habit. This is a downside to brain plasticity (although in sum smaller than the benefits).

4 Shape shifting pain – the difference between acute and chronic pain

As already mentioned, in an acute pain setting there is a distinct – although not specific for pain – network activity in the brain. But when the pain condition has transitioned from an acute phase to a chronic phase a few months later (if the transition is gradual or without transition is so far unknown), so has the correlated pattern of network activity. The pain still often is experienced in the exact same way, but the pattern is now in an emotion-related network [11], [12]. Even though these studies concern acute, subacute and chronic low back pain it is reasonable to postulate that these findings hold for chronic pain conditions in general.

Thus, it seems that chronic pain can continue without any peripheral substrate for the pain experience. This is further supported by the existence of deafferentation, hypnosis, and nocebo induced pain experiences. In other words, the chronic pain can be, and most often is, self-perpetuating. This argument is also backed by the fact that there hardly is any condition that categorically transitions into a chronic pain condition. For instance, only a minority of nerve injuries develops into neuropathic pain; there is a discrepancy between degenerative findings in osteoarthritis and pain symptoms; and after amputations not all patients develop a chronic phantom limb pain.

An important consequence of this usual lack of peripheral input as cause for chronic pain experiences is that pharmaceutical treatments in principle will only be symptom relieving. Another aspect is that many of the drugs used in chronic pain treatment today target peripheral factors and will thus not succeed. The phase transition of chronic pain to emotion-related circuitry will also partly explain why benzodiazepines is experienced as pain relieving, and that opioids’ affective component is what many chronic pain patients experience the benefit of, and not the more peripheral effects. And since acute and chronic pains are experienced similarly, so will the drugs’ relieving effects and thus patients will likely confuse the affective effect with the peripheral and acute pain-relieving effects.

5 Therapeutic overarching principles

The major clinical implication of this article is that chronic pain treatment will be most effective if it consists of three parts. The first part is presenting the patient with an explanatory model for why they have chronic pain and how this interlock with the proposed treatment plan outlined later in the consultation. Our brains are automatic prediction machines about what the nearest future will look like [13]. This inherently evolved survival mechanism propels us to always construct a self-narrative so our surroundings makes sense to ourselves. This self-narrative is in continuous development, and is essential to our chosen actions. Therefore, an explanatory model is an essential premise for the two next parts of the treatment plan to work. But, remember that it is paramount that the patients are able to internalize and understand your explanatory model. If they do not, you have failed as a clinician before you even started your clinical obligation to the patient.

The second part provides the patient with some sort of a symptomatic pain-relieving treatment component. That might be drugs (the most common approach; includes too often omitting part three and stopping the treatment after part two has been (un)successfully completed), cognitive behavioral therapy, exercise, hypnosis, virtual reality, (computer) games, sham treatment, meditation, placebo treatment, or something completely different. Some patients might after understanding the implications of part one choose to opt out of part two and go straight for part three. The content of part two is partly due to clinicians’ knowledge/skills, partly patients’ preferences, and partly cost-benefit assessments (including monetary aspects, but also adverse effects, risks on personal and societal levels, and ethical aspects). In other words, we are looking for what works for this patient in this setting to an acceptable cost, and not necessarily for evidence-based effectiveness. This part will enable the patient to be less restrained and limited from the pain condition when working on the third part, rehabilitating to the patients individualized functional goals. Many clinicians forget that part two is only a transient treatment. You give the treatment for as long as it is necessary (i.e. until the actions in part three is firmly established as a new automated behavior).

The third part is the most active part of the treatment since it is aimed at replacing the habit of pain with something less intrusive in the patients’ lives. If we can change the patient’s experiences, we can ease (or even sometimes cure) the pain. The content of this part of the treatment is to a large extent determined by the treatment goals that are jointly defined by the patient and the clinician. Defining treatment goals is essential if one is to find meaningful tasks for patients’ pain rehabilitation. But the task need to be something the patient actively does, an action, since it is too hard to achieve change without preceding action. This part is often the most challenging part of chronic pain treatment and is often forgotten or omitted, for reasons we can only speculate about, but lack of knowledge may be one important part.

6 Concluding remarks

This article has shown how time restricted amnesia can improve or even eradicate an underlying chronic pain condition and eliminate the patient’s dependence on daily opioid consumption. This outline has fundamental implications for the clinical practice of chronic pain medicine. Elaborating on the details of the underlying mechanisms of chronic pain conditions and extensive treatment details are beyond the scope of this article, but will be part of three later articles.