In their landmark 1965 article, Melzack and Wall^[9] wrote “it is possible for central nervous system activities subserving attention, emotion, and memories of previous experience to exert control over the sensory input.” But they acknowledged “the manner in which the appropriate central activities are triggered into action presents a problem.” Fifty-three years later, Borsook et al.^[1] have gone a long way to solving this problem.

The question of why some people and not others develop chronic pain that seems refractory to treatment has challenged pain researchers and clinicians since chronic pain was first delineated. Although it is possible to believe that these people just have not had the “right” treatment, this is unlikely as no treatment has proven universally effective in relieving chronic pain. For example, in the case of chronic low back pain, the most common and globally disabling form of chronic pain,^[17] treatments typically achieve only small pain reductions that are not much greater than those for placebos and well short of what patients usually seek.^[8] The effects of analgesic agents and antiepileptics for different types of chronic pain are also quite limited, helping a small proportion of patients only.^[12,13]

As is common in apparently inexplicable conditions, especially when no obvious physical cause has been identified, various psychological “explanations” have been proffered. In the case of chronic pain, these have included concepts such as “pain-prone personality”,^[4] “masked depression,”^[7] and “compensation neurosis.”^[10] As Merskey^[11] pointed out, these sorts of explanations for what have been described as “medically unexplained symptoms” have not been helpful in advancing our understanding or treatment of patients with chronic pain, and none of these labels have stood up to rigorous investigation.^[2,16]

More recent psychological and social explanations for chronic pain have focussed less on causation and psychopathology and more on the influence of normal psychological processes that may influence the experience and impact of pain through mechanisms such as modulation and mediation.^[3,15,18] Although these lines of study have more robust theoretical and empirical bases than the earlier attempts to use abnormal psychology constructs to explain the development and persistence of chronic pain, they have been relatively silent on the possible roles of biological contributors to chronic pain and how they may relate to the influence of psychological constructs such as learning, attention, perception, memory, and emotions. But there are notable exceptions, as can be seen in the work of researchers such as Flor^[6,14] and Davis^[5] and their colleagues. Nevertheless, if we are to solve the challenge posed by Melzack and Wall,^[9] we also need to make sense of the burgeoning literature on the biological contributors to chronic pain as well. In this edition of PAIN, Borsook et al.^[1] have tried to do just that.

In their comprehensive review, Borsook et al.^[1] set out to consider the broad landscape of contributions and interactions of biological, social, and psychological factors towards the evolution of treatment-resistant chronic pain. Not surprisingly, given the size of the task, in the end, they have focused more heavily on the biological factors rather than social and psychological ones, and they acknowledge there is still work to be performed to clarify all the potential mechanisms that produce or exacerbate persistent pain. But, from what is known, they consider how differences in the relative contribution of factors such as stress, age, genetics (and epigenetics), environmental characteristics, and immune responsivity may produce different risk profiles for disease development, pain severity, and chronicity. Admittedly, the complexity of the topic necessitates careful reading, but the authors provide some assistance to the general reader using terms such as “stickiness” as a soubriquet for capturing the effect of the multiple influences on the persistence of pain, which may lead to pain and maladaptive coping becoming rigidly fixed or “stuck,” and intractable.

The review incorporates methods from other fields, such as Network Biology, which may be used to model or simulate a complex multifactorial entity like pain, and also covers the familiar constructs and processes that have been widely reported in the pain research literature, such as homeostasis, resilience, allostasis, drug-induced hyperalgesia, synaptic plasticity, endogenous regulation, centralization, and sensitization. To the authors’ credit, this article cogently describes where each of these constructs and processes may fit into the picture of pain chronification and treatment resistance. In this regard, the authors have made a major contribution to our field. Importantly, the authors conclude by articulating a research agenda aimed at extending the knowledge summarised here, as well as potential therapeutic opportunities. These include the development of more neurobiologically informed pain therapies—both pharmacological and psychological—that might offer, singly or in combination, the prospect of reversing pain stickiness and unlocking fixed pain behaviours to facilitate resilience and a return to homeostasis. It may have taken us 50 years to get here, but it also reminds us, if we had not realized already, the foresight of Melzack and Wall.