Recent advancements in molecular biology genome sequencing have revolutionized medicine and kindled the prospect of precise, personalized medical care. The complex interplay of pain response variability and pharmacogenomic diversity is a dynamic challenge to treating pain. Now with the completion of the Human Genome Mapping project in 2003 and the ongoing expansion of the Human Pain Genetics Database (HPGDB), the field’s understanding of interindividual pain response variability has expanded rapidly.

The HPGDB is a global inventory of genetic influences on pain perception and tolerance.¹ As of 2018, the HPGDB has incorporated 294 peer-reviewed studies reporting a total of 434 genetic variants associated with the pain experience.¹ This chapter will focus on genetic variants that have been widely recognized for their strong association to pain modulation (such as opioid receptor mu 1, catechol-O-methyltransferase [COMT], adenosine triphosphate binding cassette transporter B1 [ABCB1], and CYP2D6) and how an understanding of these genetic variants could be used to guide patient care.²

Pain is a complex and multivariable experience. A patient’s pain phenotype is affected by both inherent genetic predisposition and intertwined environmental factors, including socioeconomic status, mental health, and medical comorbidities.³ Pain phenotype heritability is estimated to be between 25% and 50%.⁴ Rarely, pain conditions like hereditary sensory and autonomic neuropathy types I-V may adhere to classic mendelian inheritance (see Table 5.1).⁵ However, for most genetic variants associated with pain, inheritance is considered non-mendelian.⁵

The International Association for the Study of Pain defines pain as “an aversive sensory and emotional experience typically caused by or resembling that caused by an actual or potential tissue injury.”⁶ Acute nociceptive pain is typically triggered from direct tissue injury and serves a physiological protective function to warn of potential harm.⁷ As the damaged tissues heal, acute pain is expected to resolve; however, for a segment of the population, the pain persists and develops into a chronic pathological condition.⁸

In contrast to the physiologic protective function of acute pain, chronic pain is more of a pathological detrimental process. According to the Institute of Internal Medicine in 2011, chronic pain is a true public health epidemic, impacting 116 million Americans at an annual health care cost of $600 billion.⁹ The pathophysiology of chronic pain involves a complex neuroplastic mechanism that takes place before and after injury.¹⁰ Recent studies have focused on the intricate interplay of several factors implicated in the development of chronic pain: genetic predisposition, nerve growth factor modulation, microglial activation, and 5′ adenosine monophosphate-activated protein kinase regulation.¹⁰ Therapy targeting these chronic pain mechanisms may prevent or alter this neuroplastic process.¹⁰

A current field of interest is genetic polymorphisms and how these variants can affect receptors, transporters, and enzymes that can cause alterations in pain sensitivity in chronic pain conditions. Nociception can be modulated at different anatomical sites at the cellular level, and differences in genomic variation that have an impact at these sites have been linked to differences in pain perception for several known conditions.¹¹,¹²,¹³ Four conditions observed for differences in pain sensitivity are catecholamine-induced musculoskeletal pain, low back pain (LBP), fibromyalgia, and chronic fatigue syndrome (CFS).¹⁴

Elevation of catecholamine hormones (eg, dopamine, epinephrine, norepinephrine) are associated with chronic musculoskeletal pain conditions. Notable differences in pain perception are linked with the COMT gene, which codes for COMT, the enzyme which is responsible for both peripheral and central catecholamine breakdown.¹⁴,¹⁵,¹⁶ Patients with inhibited or downregulated COMT have been noted to have increased activation of both beta-2 and beta-3 adrenergic receptors, leading to increased expression of IL-6, which is proinflammatory.¹⁶ These specific receptors cause reduced activity of catecholamines in other processes and lead to hyperalgesia and allodynia.¹⁴

Lower back pain is the number one cause of disability in the industrialized world.¹⁴ Related to LBP’s complex nature, it is implicated in psychological, mechanical, and pathological conditions.¹⁴ One gene implicated in the pain response due to LBP is the IL-1 gene. Gene polymorphisms of IL-1 show differences in pain intensity and duration when controlled for age.¹⁴,¹⁷,¹⁸,¹⁹ One specific cause of LBP that is of interest for studying genetic influences is intervertebral herniation (LDH). Several single-nucleotide polymorphisms in genes involved with pain transmission have been linked with disc herniation.¹⁸,²⁰,²¹ Studies show that specific polymorphisms might also play a role in the prognosis and resolution of symptoms.¹²,¹⁸ Other biomarkers and gene variants that have been implicated with LBP and LDH are IL-6 and IL-1Ra (an inhibitor of IL-1).¹⁴,¹⁹