Prescription opioids are used for some chronic pain conditions. However, generally, long-term therapy has unwanted side effects which may trigger addiction, overdose, and eventually cause deaths. Opioid addiction and chronic pain conditions have both been associated with evidence of genetic and epigenetic alterations. Despite intense research interest, many questions about the contribution of epigenetic changes to this typology of addiction vulnerability and development remain unanswered.
1. Introduction
Chronic pain represents significant public health concerns and prescription opioids are a common treatment option for cancer pain management, for end-of-life treatment, in relation to surgery, and for short-term use in severe acute/chronic pain conditions not related to cancer
[1]. The non-medical use of opioids and their negative health consequences among people who use drugs have been studied since 2007 after the spread of the opioid crisis. However, in the last few years, we have witnessed a new opioid crisis, even among young people and categories of workers, particularly in North America, the Middle East, Asia, and Africa. This crisis is related to the non-medical use of prescription opioids that can result in opioid misuse, defined as “use contrary to the directed or prescribed pattern of use, regardless of the presence or absence of harm or adverse effects”
[2]. Signs of an increase in methadone, buprenorphine, fentanyl, codeine, morphine, tramadol, and oxycodone misuse and the increased prescription rates for opioids for pain management have also been observed in Europe resulting in an increase of vulnerable cohorts of long-term opioid users
[3]. The central issue is that long-term opioid therapy is associated with many side effects such as addiction, development of tolerance, and opioid-induced hyperalgesia. In addition, in 2018 more than one-third of overdose deaths involved pharmaceutical opioids with the number of overdose deaths rising from 3442 in 1999 to 17,029 in 2017
[4][5].
Opioid drugs act not only in nociceptive processes but also in modulating gastrointestinal, endocrine, and autonomic functions, as well as in affecting cognition and reward systems
[6]. The relationship between pain states and substance abuse/misuse has been recently examined. Opioids carried an increased susceptibility to abuse even during initial exposure for pain treatment; in particular, when too many opioid drugs are prescribed for conditions not supposed to be treated by opioids or if healthcare systems are not set up to control the number of opioid prescriptions to an individual patient (doctor shopping)
[7][8][9].
Nevertheless, it is important to note that the lack of consistent findings regarding the identification of personal risk factors that may predict opioid misuse in chronic pain patients was recently evidenced in the literature
[10]. Among the possible risk factors, the individual genetic variability in conjunction with chronic pain, both affecting stress and reward systems, lead to differential responses to opioids and may determine the transition risk from therapeutic use to opioid addiction. Addiction is a multifactorial condition as both genetics and psychosocial factors can trigger opioid addictive behaviors. Polymorphisms in the
μ-opioid receptor 1 (
OPRM1), the cytochrome P450 2D6 (
CYP2D6), the catechol-O-methyl transferase (
COMT) genes and in the ATP-binding cassette family genes have been found to be associated with differences in morphine consumption and metabolization process
[11]. The main environmental factors important for developing opioid/substance abuse are described as psychiatric medication prescriptions, mood disorders, specific mental health diagnoses, and adverse childhood experiences
[12][13].
2. Prescription Opioids Pain Relievers
Opioid receptors are widely distributed both centrally and in the periphery, particularly in the periaqueductal grey,
locus ceruleus, rostral ventral medulla, and in the
substantia gelatinosa of the dorsal horn. The major mechanism through which opioids relieve pain is the stimulation of descending inhibitory neurons through activation of the μ opioid MOP receptors. Common prescription opioids responsible for this opioid-induced analgesia effect are morphine, codeine, tramadol, fentanyl, hydromorphone, buprenorphine, hydrocodone, oxycodone, oxymorphone, methadone, and tapentadol
[14].
Opioid medications are often prescribed for acute episodes of pain for short-term use or for cancer-related pain. Opioids are also used for chronic non-cancer pain in selected cases when non-opioid and adjuvant therapies have failed and other pain medications have proven ineffective. These drugs are defined as highly effective and safe analgesics when used appropriately and included in a multifaceted strategy by competent clinicians
[15].
However, since opioid-induced pain relief and addiction do not act through distinct mechanisms in distinct brain areas, opioid drugs could not only have a simple analgesic effect but also affect or compromise the ability to feel pleasure and socialize as well as the reward system
[16]. Neural changes were likened between chronic pain and long-term substance abuse; in fact, dysfunctional learning may trigger both these pathological states, producing an extensive reorganization in chronic pain and converting functional rewards into the craving characteristic of addiction
[17].
In light of the fact that the opioid analgesic efficacy often decreases with continuous use and that patients with refractory complex chronic pain are at high risk of abuse, a two-level strategy might be set up to contrast the opioid crisis. The first level would include prescription monitoring programs and dose limitations to prevent abuse/misuse; the second could increase research at the molecular level to identify the central and peripheral mechanisms underlying the drug action and to explore precision medicine options.
3. Epigenetics and Prescription Opioids
The term epigenetics refers to the study of heritable changes in the gene function that do not involve changes in the DNA sequence
[18]. Epigenetics includes three main mechanisms: DNA methylation and chromatin-related modifications, both affecting the ability of transcriptional machinery to access the DNA tightly packed into chromatin, and non-coding RNAs (ncRNAs).
DNA methylation, the addition of a methyl group on the 5th carbon of the DNA cytosine, is shown particularly relevant in CpG islands, regions of the genome containing a large number of CpG dinucleotide repeats
[19]. It regulates gene expression facilitating the recruiting of proteins involved in the gene repression or inhibiting the binding of transcription factors to DNA
[20]. Thus, DNA methylation plays a critical role in the regulation of gene expression. Whole-genome methylation profiling has made it possible to better explore demethylation and de novo methylation in the maternal and paternal genomes during development. This enables highlighting of more complex dynamics within the heterogeneous methylation level at CpG-rich promoters in different cell types. Many unannotated sequences and inactive transposons affected by this epigenetic mark were revealed
[21]. Opioids have been demonstrated to stimulate DNA methylation. One study identified the global DNA methylation at LINE-1 as significantly correlated with increased chronic pain. Thus, it was hypothesized that opioid analgesics might be causally associated with increased genome-wide DNA methylation
[22].
The chromatin modifications include those related to histone tails, such as histone methylation, chromatin remodeling, and post-translational modifications affecting electrostatic nucleosome interactions. These changes have been clinically and pre-clinically evidenced to be associated with opioid exposures
[23]. Concerning prescription opioids, oxycodone exposure was shown to induce long-term epigenetic consequences in the ventral tegmental area (VTA) of the developing brain with an enrichment of the repressive histone mark, H3K27me3, in prolonged oxycodone withdrawal and with consistent inhibition of the gene regulation
[24]. The other chromatin modifications are related to the chromatin structure that is hierarchically folded at different levels in the nucleus with a 3D organization
[25]. Previous works evidenced a correlation between the effects of opioids and chromatin remodelers such as CREB, Sox10, and BRG1
[26][27][28]. However, no studies have thoroughly explored prescription opioids’ effect on chromatin structure remodeling.
The third important regulator of transcriptional activity is represented by ncRNAs
[29], i.e., RNA not translated into proteins. ncRNAs act through a variety of mechanisms such as post-transcriptional silencers or activators. Moreover, they are involved in regulating protein-coding and non-coding genes’ expression, in the guide of chromatin-modifying complexes to specific genomic loci, in the modulation of transcriptional programs, and providing molecular scaffolds
[30]. ncRNAs have already been correlated with opioid exposure. In particular, morphine, fentanyl, and heroin were found to modulate the expression of specific micro-RNAs
[31][32]. Additional studies are required to understand the functional consequences of these epigenetic changes.
The nociceptive response was demonstrated to activate these epigenetic mechanisms by modulating pain genes and possibly mediating the transition from acute to chronic pain. Studies highlight that also opioids are involved in diverse types of epigenetic regulation and thus they might influence the analgesic effects or the increased risk of continued opioid intake and development of a substance use disorder following long-term opioid therapy
[33][34].
However, the identification of specific factors associated with the individual opioid response or with side effect vulnerability has just been launched. The molecular mechanisms through which some individuals develop negative consequences associated with prolonged prescription opioid use, including hyperalgesia, addiction, sleep problems, hypogonadism, fractures, and surgical failures
[35][36] are poorly understood. The following paragraphs provide an overview of the animal and human studies investigating epigenetic changes associated with opioid therapy initiated for pain relief. The studies are illustrated in
Table 1;
Table 2, respectively.
Table 1. Epigenetic changes after prescribed opioid exposure in experimental models.
Table 2. Epigenetic changes after prescribed opioid exposure in humans.