Pain persistence and the pain modulatory system – an evolutionary mismatch perspective

Millions of years ago humans lived as simple hunter-gatherers in small tribal bands. Since then societal and other environmental circumstances have changed and this change has dramatically accelerated in the last centuries. In contrast, evolution with the mechanism of selection over generations is a rather slow process in organisms with a long generation time and has difficulties to keep pace with fast environmental and societal changes. It is thus conceivable that many biological processes in humans are not fully adapted to the challenges of current environments [10] and this disparity between biological processes that are not fully adapted and the challenges of the current environment can lead to a mismatch [23].

Obesity is a classic example of such an evolutionary mismatch and has doubled in less than a century, posing major health risks to many societies [3]. The evolutionary mismatch results from the fact that our organisms have been shaped by evolution to ingest high caloric food whenever available to store energy for subsequent periods with less or no food supply. This dilemma can be ameliorated by adopting a life style which is aligned with mechanisms shaped by evolution, for instance by emulating food scarcity (i.e. diet) and higher energy expenditure (i.e. exercise) [22].

A similar evolutionary mismatch has been suggested with respect to chronic pain [44] (but see [38] for an alternative evolutionary process, with some forms of chronic pain suggested to involve mechanisms under positive selection during evolution). In our human ancestors, prolonged recuperative behavior after injuries could severely threaten survival. Therefore, a resumption of activity including foraging and movement required to evade predators was survival relevant, despite ongoing pain. For the organism, this can be seen as a “decision” for a behavior that has the highest value for survival. This is not a conscious decision and is the basis of the motivation-decision model by Fields [14]. Central to this model is that a “decision” for survival relevant activity is accompanied by activation of the descending pain modulatory system (DPMS). It is this system that reduces acute pain in extreme situations and allows the organism to pursue survival relevant activity even in the presence of severe injuries. However, human development has changed our environment at a fast pace and societal and health care systems now allow prolonged inactivity after injury without negative consequences regarding survival (i.e. starvation). It is thus possible for the organism to decide against activity and chose prolonged recuperative inactivity. This “decision” against survival relevant activity also entails less DPMS involvement. In the following I suggest that this reduced activation of the DPMS during the acute phase after an injury might be problematic, as the DPMS cannot exert its preventive effect on pain persistence [9]. Conceptually, this notion represents an extension of the motivation-decision model including the trajectory from acute to chronic pain and provides the missing neurobiological mechanism for an evolutionary mismatch hypothesis related to chronic pain [44].

According to Wall [36] the time after an injury can be divided into the immediate, acute and chronic phase. In the immediate phase after a predator attack, an ancient hunter, who has been injured, can minimize additional injuries by defensive action e.g. in the form of escape. This behavior still applies today, for example if we are attacked by a dog. Even if we were bitten, we need to escape in the immediate phase.

However, in the acute phase [36] the circumstances are quite different for us compared to the ancient hunter. In our case, a wound will be taken care of and all activity such as moving the affected limb can be reduced to maximally avoid pain. This is different for the ancient hunter who usually does not have the opportunity to rest, but has to continue to pursue survival relevant activities such as foraging, despite pain [39,44]. This is made possible by the DPMS, which can inhibit pain by modulating neuronal activity at various stages of the central nervous system from the spinal cord to the cortex [2,17,27,37]. This system originates in cortical areas, including the anterior cingulate cortex (ACC) and anterior insula (AI), and projects —via subcortical regions such as the amygdala and the hypothalamus— to the periaqueductal gray (PAG). The PAG in turn sends massive projections to the rostral ventromedial medulla (RVM) [1], which modulates signal transmission at the dorsal horn of the spinal cord [37].

A noxious stimulus induces a motivational state, e.g., a drive to escape, terminate, and avoid the causative tissue-damaging process [14]. However, the maintenance of body homeostasis often entails additional and competing evolutionary goals such as a sufficient nutritional state [30]. In case of competing interests the organism has to “decide” whether to rest and take care of a wound or alternatively despite pain and possible additional damage continue to forage. The latter entails physical activity and increases the likelihood of survival by avoiding starvation. In this case the DPMS down-regulates pain to not interfere with survival related activity such as foraging, whereas in the former case i.e. if the organism “decides” to engage in recuperative inactivity, activation of the DPMS is not required. This absence or reduction of DPMS activation might have negative consequences, because, as I will discuss next, DPMS activation is an effective mechanism for preventing pain persistence [9].

Cross-sectional studies show a link between DPMS activation and chronic pain [12,19,25]. The engagement of descending inhibition has been discussed as a mechanism involved in the prevention of pain persistence [9,42,45]. Rodents showing activation of the DPMS at the time of injury show less neuropathic pain [8]. Furthermore, studies show that exercise produces analgesia in models of non-inflammatory muscle pain when performed as a preventative tool before and as a therapeutic tool when started after the muscle insult (summarized in [20]). In longitudinal human studies it has been shown that temporal summation, an indicator of DPMS activation, can predict pain after thoracotomy (n=84) [41] and hysterectomy (n=159) [33]. Another indicator of the activation of the DPMS is conditioned pain modulation (CPM), which has been shown to predict the risk of persistent pain after thoracotomy (n=62) [46], abdominal surgery (n=20) [43] and funnel chest surgery (n=31), where the latter study only observed a weak effect that was not statistically significant [16].

Sports and exercise can be seen as the modern day surrogate of physical activity related to “survival relevant” activity. In general, exercise provides an activation level of the body that is more aligned with our evolutionary shaped physiology and thus it is not surprising that exercise and sports are amongst the most effective measures preventing and improving diseases with a probable evolutionary mismatch component such as obesity, type II diabetes [22] and chronic pain [35].

Large studies have shown that the likelihood of developing chronic musculoskeletal pain is significantly decreased in individuals exhibiting moderate leisure-time activity [13,18]. Likewise, it has been suggested that physical inactivity is a risk factor for the development of chronic pain. This is based on immunological and neural processes [31]. Evidence for this notion comes from studies showing that blocking opioid receptors in the PAG or RVM can abolish the protective effects of regular physical activity in acute pain [21]. As mentioned above, activation of the DPMS during the acute and chronic state of an injury could be relevant for the prevention of pain persistence. In addition it has been shown that activity of the DPMS is related to daily activity levels: more active rodents show a larger conditioned pain modulation [15]. The DPMS and its cortical origins are also related to psychological aspects of pain modulation [5]. Again, this domain is positively affected by exercise, as recent studies could show that the strongest effects for reducing pain catastrophizing in chronic pain patients was achieved by a combination of cognitive behavioral therapy and exercise [29,32].

Importantly, this framework generates testable hypotheses and leads to practical recommendations. The main hypothesis is that physical activity during the acute injury phase can help to prevent pain persistence. The exact nature of exercise is probably less important [7,28], but intensity of the exercise should be high. Many studies have shown that a certain level of intensity is required to activate the DPMS [24]. However, exercise should not reach exhaustion, because this can block the analgesic effects of exercise [6].

Some caution is also warranted. Importantly, exercise in the acute phase needs professional guidance and support to avoid additional or worsening of existing injuries. Furthermore, additional studies are necessary to investigate, which forms of injury benefit from acute phase exercise. Unfortunately, the DPMS can also facilitate pain and thus support [26] and maintain pain persistence [40]. In these disorders (e.g. fibromyalgia) exercise might not be beneficial [24].

Finally, studies investigating the transition from acute to chronic pain and experimentally manipulating the level of physical activity in the acute phase and assessing DPMS activation using CPM or TS will be important to test the core prediction of this hypothesis [11,45]. In addition, experimental studies in which healthy volunteers are exposed to daily painful stimulation [4,34] can provide additional insights. Although, these studies do not lead to chronic pain, the observed neuroplastic changes leading to sensitization can be studied in great detail using advanced neuroimaging techniques and might be related to those observed in chronic pain. Consequently, these studies can be helpful with respect to identifying neuronal mechanisms underlying the beneficial effect of exercise in the acute phase for the prevention of pain persistence.