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Continuing war on pain: a personalizedapproach to the therapy with nonsteroidalanti-inflammatory drugs and opioidsLidija Bach-Rojecky1, Dalia Vad-unec1, Katarina Zunic1, Jelena Kurija1, Sara Sipicki1, RyanGregg2, Ivan Mikula3 & Dragan Primorac*,3,4,5,6,7,8

1Department of Pharmacology, University of Zagreb Faculty of Pharmacy & Biochemistry, A Kovacica 1, 10000 Zagreb, Croatia2OneOme LLC, 807 Broadway St NE #100, Minneapolis, MN 55413, USA3St Catherine Specialty Hospital, 10000 Zagreb & 49210 Zabok, Croatia4Department of Forensic Sciences, Eberly College of Science, 517 Thomas St, State College, Penn State University, PA 16803, USA5Department of Pediatrics, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia6Department of Pediatrics, School of Medicine, University of Osijek, Ulica Cara Hadrijana 10, 31000 Osijek, Croatia7Department of Pediatrics, Faculty of Dental Medicine and Health, University ofOsijek, Crkvena 21, 31000 Osijek, Croatia8Department of Biotechnology, School of Medicine, University of Rijeka, Brace Branchetta 20/1, 51000 Rijeka, Croatia9Children’s Hospital Srebrnjak, Srebrnjak 100, 10000 Zagreb, Croatia*Author for correspondence: [email protected]

Successful pain management requires the delivery of analgesia with minimal risk of adverse drug reactions.Nonsteroidal anti-inflammatory drugs and opioids remain the mainstay of treatment for the majority ofpatients. Unfortunately, almost 50% of all patients experience inadequate pain relief and serious sideeffects. Allelic variants in genes coding for target proteins, transporters and enzymes, which govern anal-gesic drugs action and their fate in the organism, might explain inter-individual variability in pain severityand in drug-induced pain relief and toxicities. Additionally, it seems that epigenetic changes contribute tothe highly variable response to pain treatment. Therefore, pharmacogenomic testing might be a valuabletool for personalization of pain treatment, with a multidisciplinary team approach involved.

First draft submitted: 2 October 2018; Accepted for publication: 6 November 2018; Published online:28 November 2018

Keywords: analgesic effect • epigenetics • genes • nonsteroidal anti-inflammatory drugs • opioids • pain treatment• pharmacogenetics • side effects • toxicity

Chronic pain affects around 27% of the adult European population and represents a huge burden not only foraffected individuals, but for health care system, society and economy as well. It has an enormous negative impacton a patient’s quality of life, daily functioning, work productivity and interpersonal communication [1,2]. Morethan 116 million Americans have pain that persists for weeks to years. The total financial costs of this epidemic are$560–635 billion per year, according to Relieving Pain in America [3].

Among the most frequently observed persistent pain conditions in general population are those affecting themusculoskeletal system, like low back pain, temporomandibular joint disorder and chronic widespread pain [4].Despite different nonpharmacological approaches available nowadays, pharmacotherapy is unavoidable for themajority of patients. According to the data collected by the Agency for Medicinal Products and Medical Devicesof Croatia, around 25 million euros were spent on analgesic drugs in 2016; furthermore, those are only the directcosts of pain management [5]. The calculations of indirect costs such as sick leaves or diminished work capabilityare currently lacking in Croatia.

Two pharmacologically distinct groups of analgesics represent a mainstay for the pain treatment: nonsteroidalanti-inflammatory drugs (NSAIDs) and opioids. Each group includes various molecules with a common basicmechanism of action; however, with some differences which might favor selection of one drug over another incertain conditions and patient population [1]. Despite a long history of use in different clinical settings and well-established pharmacological profile, these drugs still generate two significant challenges. One is their ineffectivenessin some patients and types of pain and the other equally important is their safety profile. Additionally, long-term

Per. Med. (Epub ahead of print) ISSN 1741-054110.2217/pme-2018-0116 C© 2018 Future Medicine Ltd

Review Bach-Rojecky, Vad-unec, Zunic et al.

use of opioids is compromised with a high incidence of misuse that leads to the development of addiction anddeaths because of overdoses [6].

Complex pathophysiological mechanisms of pain and unpredictable effects of the common analgesics are par-ticularly interesting from the pharmacogenomic point of view [7]. For example, musculoskeletal pain conditionshave a genetic basis that is under dynamic influence of different environmental factors (e.g., smoking, physicalinjury) thus producing specific pain phenotypes [4]. Gene polymorphisms that can affect either pharmacodynamicor pharmacokinetic of the drugs might influence their analgesic effect [8]. Moreover, patient characteristics suchas age, sex (chronic pain is more prevalent in female), lifestyle (diet, physical activity, sleep status, smoking, al-cohol consuming, obesity and bodyweight), as well as previous illnesses and comorbidities, such as cancer anddiabetes, etc., can have a significant impact on pain perception and treatment outcomes. Different environmental,as well as psychological factors (poor mental status associated with chronic pain), ethnocultural differences andsocioeconomic background, may additionally increase the chronic pain burden for each individual [9,10].

It can be challenging to identify the extent to which a drug response is influenced solely due to geneticdifference [11]. Keeping in mind the pathophysiological complexity of chronic pain and interindividual differencesin pain sensitivity and response to analgesics, treatment should be personalized [12].

In this paper, we will critically review the pharmacological properties of commonly used analgesics, in otherwords, NSAIDs and opioids, with short insight into the possible influence of genes on their effectiveness and safety.

NSAIDs as a first-line therapy to combat the painNSAIDs, also known as COX inhibitors after their main mechanism of action, represent a heterogeneous group ofdrugs commonly used for their analgesic, antipyretic and anti-inflammatory effects. They are considered a first-linetherapy for managing a pain of low to medium intensity of different localization and etiology [1,8].

They inhibit the catalytic activity of two isoforms of enzyme cyclooxygenase, referred to as COX-1 and COX-2(Figure 1A). The result of competitive inhibition of either isoform is the inhibition of prostanoid synthesis [1,13]. Bothisoenzymes convert arachidonic acid, a phospholipid ester from the cell membranes, into unstable prostaglandinPGG2 followed by the conversion into PGH2, which is a substrate for the synthesis of five prostanoids: PGD2,PGE2, PGF2α, prostacyclin (PGI2) and thromboxane A2 (TxA2). These products regulate numerous biologicalprocesses, including inflammation, hemostasis, gastroprotection, renal hemodynamics – among others [1,14].

Pharmacological properties of COX inhibitors largely depend on their chemical structure because it governsmultiple variables: the affinity of the drug for the respective isoenzyme (selective or nonselective), speed (rapid orslowly-acting) and type (reversible or irreversible) of interaction with the active site of the enzyme. Relative COXselectivity has been described as the ratio of concentration necessary to inhibit the activity of COX-1 or COX-2 by50% (IC50) in vitro (Figure 1B). Drugs with preferential affinity for COX-2 have selectivity ratios >1 [1].

According to mechanistic features, NSAIDs can be divided as follows: irreversible COX-1 and COX-2 inhibitor(aspirin), more selective reversible COX-2 inhibitors (celecoxib, etoricoxib, parecoxib; diclofenac and etodolac;meloxicam), nonselective reversible COX inhibitors (paracetamol [acetaminophen]; indomethacin; ibuprofen,ketoprofen, naproxen, dexketoprofen and piroxicam) [12]. However, due to weak anti-inflammatory effect intherapeutic dose range, paracetamol and aspirin are not considered as NSAIDs [17].

COX-1 is constitutively expressed in majority of tissues where it performs important, mostly protective physi-ological functions. The product of COX-1 in platelets is TxA2, an important mediator of platelet activation andaggregation. The best characterized role of COX-1 is in gastroprotection [1,18]. Strong and repeated inhibitionof COX-1 results in hypoproduction of PGE2 and PGI2, and consequently decreased secretion of mucus andbicarbonates. Thus, inhibition of COX-1 results in increased secretion of gastrointestinal acid that can have toxiceffects in these circumstances, by promoting ulcerations and bleeding of the gastric mucosa. In addition, lowerTxA2 production in platelets also contributes to the slower mucosal regeneration due to prolonged bleeding time.The described mechanisms are largely responsible for gastrointestinal side effects of NSAIDs [19].

COX-2 is the enzyme isoform expressed constitutively in some tissues, for example, vascular endothelium andkidneys where it catalyzes the production of PGE2 and PGI2 with significant role in the regulation of plateletaggregation, vasodilatation and renal hemodynamics [8,20]. During inflammation or tissue damage, expression ofCOX-2 is induced by inflammatory mediators such as the TNF-α or interleukins produced by monocytes andmacrophages [1,20]. Drugs with high-degree selectivity for COX-2 enzyme, like celecoxib and etoricoxib, exertstrong anti-inflammatory effect with better gastrointestinal tolerability in comparison to nonselective counterparts.However, they carry a risk for cardiovascular (CV) adverse events because of the impaired vasodilation, increased

10.2217/pme-2018-0116 Per. Med. (Epub ahead of print) future science group

A personalized approach to pain therapy Review

His513

Ile434

Phe518

Tyr385

Ser530

Ile523

Ser516

His90

Tyr355

Arg120

Tyr355

Arg120

Val523

Ser530

Tyr385

Phe518Val434

Arg

513

Ala51

6

His90

-2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5

Log (IC50 of COX-1/IC50 of COX-2)

Indomethacin

Ketoprofen

Acetylsalicylic acid

Naproxen

Ibuprofen

Piroxicam

Diclofenac

Paracetamol

Meloxicam

Celecoxib

Etoricoxib

COX-2 selectivity

COX-1 selectivity

Figure 1. COX enzymes and selectivity of NSAIDs. (A) Schematic representation of structural differences between COX-1 (green; left)and COX-2 (red; right) enzyme. The amino acids Tyr385 and Ser530 (purple) are important for the activity of both enzymes. COX-2 has awider binding site pocket in comparison to COX-1 because of substitution of Ile434, His 513 and Ile523 (lighter green) in COX-1 with lessbulky amino acid residues in COX-2, Val434, Arg513 and Val523 (orange). Larger molecules like coxibs cannot enter the narrowerhydrophobic entrance channel of COX-1 and do not fit into the COX-1 smaller active site [15]. (B) Selectivity of nonsteroidalanti-inflammatory drugs (NSAIDs) for COX-1/2 was determined using a whole blood assay. This chart represents the log (IC50 of COX-1relative to the IC50 of COX-2) for NSAIDs and clearly demonstrates their affinity towards either COX-1 or COX-2 [16].


Table 1. Pharmacokinetic properties of different COX-inhibitors.Drug Bioavailability

(%)Cmax (μg/ml) Tmax (h) Half-life (h) Binding to

plasma proteins(%)

Metabolism Excretion Ref.

Paracetamol 70–90 9.85 1 1.9–2.5 10–20 Glucuronidation (main pathway),CYP2E1 (minor contribution)

Mostly urine [24,25]

Acetylsalicylic acid 80–100 3–7 1 0.4–0.6 88–93 Hydrolysis to salicylates,conjugation with glycine andglucuronic acid


Diclofenac 100 0.4–1.3 1.25 1.1 99.7 CYP2C9 (hydroxylation),glucuronidation

65% urine, 35%feces

[24,27,28]

Indomethacin 100 0.5–3 1–1.5 1 90 CYP2C9 (O-demethylation,deacetylation)

60% urine, 40%feces

[29]

Ibuprofen 80–100 61.6 1.5–3 1.8–2 99 CYP2C9 (hydroxylation),glucuronidation


Ketoprofen ≈85 2.5–4 1.3 1.1–2.5 99.2 Glucuronidation Mostly urine [31]

Dexketoprofentrometamol

≈85 2.5 0.25–0.75 ≈2 99.2 Glucuronidation Mostly urine [32]

Naproxen 74–99 37.2 0.5–3 12–15 99.7 CYP2C9; CYP1A2 (dealkylation),acyl glucuronidation


Meloxicam 89 ≈1.5 9–11 22–24 99 CYP2C9; CYP3A4 (oxidation) ≈50% urine,≈50% feces

[33]

Piroxicam 100 2.63 2.4 50 99 CYP2C9 (hydroxylation),conjugation

Mostly urine [34–37]

Celecoxib – 0.71 2.8 11.2 97 CYP2C9 (hydoxilation),glucuronidation

Urine and feces [38]

Etoricoxib 100 0.095–2.2 1 22 91.9 CYP3A4; CYP2D6; CYP2C9;CYP1A2; CYP2C19 (methylhydroxylation, N-oxidation)

70% urine, 20%feces

[39,40]

platelet reactivity and disturbed renal blood flow [14]. Since all NSAIDs inhibit both COX isoenzymes, cardiotoxicityis a class effect. Among COX inhibitors, naproxen has shown a better CV safety profile, which is probably dueto its prolonged and significant inhibition of COX-1 in platelets [21]. According to several meta-analyses, risks forgastrointestinal and CV side effects as well as risk for renal failure are dependent on the applied doses and theduration of treatment. It is generally recommended that NSAIDs should be taken in the lowest effective dose andfor the shortest period possible [17].

The goal of pain treatment is to achieve and maintain effective drug concentration in the site of injury as quicklyas possible, and at the same time to minimize its systemic concentration. Thus, pharmacokinetic properties ofNSAIDs (rate of absorption, the time to maximal plasma concentration, half-life, tissue versus plasma distribution,elimination) and the type of pharmaceutical formulations (immediate- or extended-release tablets, oral solutions,suppositories and parenteral solutions) can significantly influence their efficacy and tolerability [1]. After repeatedadministration, acidic NSAIDs such as diclofenac and ibuprofen, achieve higher and more sustainable concentra-tions in inflamed tissues. Despite their short plasma half-lives, this testifies their long-term effect. Moreover, thisfeature allows rapid recuperation of prostanoid production in the endothelium, kidneys and platelets, thus makingthese drugs safer and more tolerable in comparison to drugs with longer plasma half-lives, like meloxicam andpiroxicam [1,22]. Unfortunately, this benefit is sustained only with lower doses and immediate-release formulations,as extended-release formulations carry an increased risk of adverse effects [20].

Hepatic biotransformation via cytochrome P450 (CYP450) enzyme system, mostly subfamily 2D6 and 2C9,and renal excretion are the principal routes of metabolism and elimination of the majority of NSAIDs. Accordingly,NSAIDs are not recommended for patients with severe renal and/or hepatic impairment [23]. Furthermore, due toa quite strong plasma protein binding, NSAIDs cannot be efficiently removed by hemodialysis (Table 1) [13].

In order to improve the pharmacokinetic profile of available drugs, different pharmaceutical approaches can beemployed. One such example is dexketoprofen – an active S(+) enantiomer of ketoprofen, which achieves fasteronset of analgesic effect with lower doses and better tolerability profile compared with racemic (S,R) ketoprofen [41].



In conclusion, pharmacological differences between drugs and patient history must be taken into considerationwhen selecting an optimal drug for pain management. As for all medicines, positive and negative aspects of treatmentshould be evaluated with caution for each individual.

Opioid agonists as the most powerful weapon to conquer the painEven nowadays, opioids are the most effective drugs for pain management. They relieve moderate to severe acuteand chronic pain in cancer patients and patients experiencing nonmalignant pain [8,42]. Drugs can be appliedvia different routes, like oral (most drugs, except fentanyl and congeners, buprenorphine), buccal, transdermal,intravenous, intramuscular and intraspinal.

Morphine, once described as a golden standard in pain therapy, is still considered as the representative drugof the opioid group. Its popularity is grounded on natural origin, longevity in pain management, well-knownpharmacological properties, established therapeutic and adverse effects profile. Opioid drugs can be classifiedaccording to their origin, as natural, semi synthetic and pure synthetic; an intensity of action, from moderate toextremely potent; duration of action, from short-acting to long-acting – among others [43].

Opioids, either endogenous or exogenous, activate opioid receptors. Three major classes of opioid receptorshave been identified: mu (μ) opioid receptor (MOR), kappa (κ) opioid receptor (KOR) and delta (δ) opioidreceptor (DOR). They are widely distributed in the peripheral tissues and through the central nervous system,thus mediating different physiological effects, like gastrointestinal motility and smooth muscle tone, nociception,motivation and hormonal processes. Accordingly, opioid drugs produce analgesia and mood altering effect; regulatethe gastrointestinal, neurohormonal, respiratory and CV function [44].

Although endogenous opioid peptides exert affinity toward all three types of opioid receptors, drugs havepreferential affinity toward MOR, while buprenorphine and pentazocine have additional activity on KOR, actingeither as antagonist or agonist, respectively [43]. Drugs can be classified according to their mode of action onopioid receptors either as full agonists (morphine, codeine, methadone, tramadol, tapentadol, oxycodone, fentanyl,sufentanyl, hidromorphone), partial agonists with high affinity but low intrinsic activity (buprenorphine) or mixedagonists–antagonists (pentazocine) [42,43].

Opioid receptors belong to a family of G-protein coupled receptors. Upon activation by an agonist, receptorprotein undergoes conformational change, resulting in a various downstream intracellular events, that might in-clude the following: inhibition of the adenylyl cyclase (AC) and consequently reduced cellular cyclic adenosine3′,5′-monophosphate (cAMP) concentration and protein kinase A (PKA) activity; reduced postsynaptic neuronalexcitability due to the membrane hyperpolarization and opening of potassium channels; and inhibition of calciuminflux into the presynaptic nerve terminals with resulting reduced neurotransmitter release [43]. Opioid drugs differ-entially activate postreceptor signaling pathways and influence MOR desensitizatioin, resensitization, endocytosisor recycling [45]. Complex pharmacology of opioid system might explain observed clinically significant differencesbetween various opioid drugs in their effectiveness, risk of adverse effects, including development of tolerance andaddiction.

Except for dissimilarities in pharmacodynamics (affinity toward opioid receptor subtypes, intrinsic activity, dis-sociation rate from the receptor, the fate of drug-receptor complex on the neuronal membrane), there are someconsiderable differences in pharmacokinetic parameters between opioid drugs which might influence their thera-peutic effect as well as safety profile (Table 2). Thus, lipophilic drugs (fentanyl, hydromorphone, buprenorphine)exert rapid onset of the analgesic effect due to the faster transport through the blood–brain barrier, unlike morehydrophilic drugs, such as morphine. Duration of action is largely dependent on drug half-life, degree of bio-transformation and activity of metabolites. Lipophilic drugs are gradually accumulated in tissues (muscles and fat)and clearance mechanisms become saturated after repeated administration. Thus short-acting fentanyl becomeslonger-acting after prolonged use [43]. Codeine is a prodrug of morphine, therefore its analgesic activity as well assafety depends on the degree of biotransformation and activity of metabolic enzyme CYP2D6. Some opioids, likeoxycodone and methadone, undergo extensive metabolic reactions by the CYP450 enzyme systems in the liver tometabolites that are inactive, partially active or even more active in comparison to the parent drug. Morphine, onthe other hand primarily undergoes glucuronidation by 5′-diphospho-glucuronosyltransferase-2B7 (UGT2B7) toinactive morphine-3-glucoronide and active morphine-6-glucuronide metabolites [46]. Opioids and its metabolitesare eliminated primarily in urine; consequently, dose adjustments are required in patients with renal impairmentand in elderly patients because of decline in renal function and smaller volume of distribution [43].

future science group 10.2217/pme-2018-0116


Table 2. Pharmacokinetic characteristics of different opioid agonists.Drug (route ofadministration)

Bioavailability (%) Cmax (ng/ml) Tmax (h) Half-life (h) Binding toplasma proteins(%)

Metabolism Excretion Ref.

Morphine-sulfate(PO-IR)

30 10 0.5–1.5 2–3.5 20–35 Glucuronidation,N-demethylation

Mostly urine [46–48]

Hydromorphone(PO)

50 1–1.3 0.5–1 2–3 7.1 Glucuronidation Mostly urine [46,49]

Codeine (PO) 50 149 1 2.9 7 CYP2D6 (N-demetylation tomorphine); CYP3A4(O-demetylation),glucuronidation


Oxycodone (PO) 60–87 15.5 1,6 3–5 45 CYP3A4 (N-demethylation),CYP2D6 (O-demetylation)


Tramadol (PO) 68–84 592 1–2 6 20 CYP2D6; CYP3A4(O-demethylation)


Tapentadol (PO) 32 64.2 1–1.5 4 20 Glucuronidation Mostly urine [46,52,53]

Buprenorfine (SL) 51 2.7 1.2 16.2 96 CYP3A4 (N-dealkylation),glucuronidation

Mostly feaces [46,54]

Fentanyl(transmucosal, SL)

50 0.8 0.4 3.7 84 CYP3A4 (N-dealkylation) Mostly urine [46,55]

Pentazocine (PO) 18.4 50 1.74 3.4 56–66 Glucuronidation Mostly urine [56,57]

IR: Immediate release; PO: Per os; SL: Sublingual.

Tramadol and tapentadol are synthetic opioids with a typical mechanism of action. Tramadol is used as racemicmixture where S(+) enantiomer binds and inhibits serotonin reuptake but also activates MOR, while R(-) enan-tiomer selectively inhibits noradrenaline (NA) reuptake and activates α2-adrenergic receptors. According to thepublished studies, tramadol exerts better effect on neuropathic pain than morphine due to the modulation ofmonoaminergic pathways in the dorsal horn of the spinal cord. In contrast to tramadol, tapentadol is a strongerMOR agonist and has superior NA reuptake inhibition. Hence, tapentadol demonstrates a lower risk of sero-tonin syndrome and better gastrointestinal safety profile, and is a safer option in patients with hypertension thantramadol [52].

The most commonly reported opioid-induced side effects include nausea and vomiting, sedation, dizziness,paradoxical hyperalgesia, myosis, suppression of cough reflex, pruritus and modulation of the immune system.Respiratory depression caused by reduced ventilation of CO2 and modulation of the respiratory rhythm is apotential cause of death after an overdose. Continuous use may cause the development of tolerance and physicaldependence, as well as aberrant behaviors which could lead to drug abuse and addiction [58].

Because adverse effects may profoundly influence patients quality of life and adherence to the therapy, severalstrategies for preventing and managing adverse effects are suggested; such as: dose reduction (some adverse effectsare dose-dependent); opioid rotation (substituting one drug with alternate at an equieffective dose); alternatingthe route of administration (e.g., changing from oral administration to subcutaneous, intravenous, sublingual ortransdermal); symptomatic management of side effects (for example, laxatives for constipation, anti-emetics fornausea, antihistamines for pruritus) [59].

Intentional opioids abuse, increased opioids prescribing, diversion and misuse are major public health concernsworldwide. In the USA, the fatalities from prescription opioid overdose have increased four-times between 1999and 2015. Moreover, around 1000 nonfatal opioid overdose accidents per day alarm healthcare providers aboutthe seriousness of the opioid crisis situation [6]. To prevent these events, the pharmaceutical industry is focusedon developing abuse-deterrent formulations, for example oral formulations with polymer matrix (oxycodone) orpolyethylene oxide matrix (oxymorphone, tapentadol), which are protected from crushing, extracting or dissolvingthe active substance in water. Furthermore, combining opioid agonist (oxycodone and buprenorphine) with anantagonist (naloxone or naltrexone) will prevent agonist effect only after intravenous misuse, and not if it is takenper os or sublingually. Incorporation of aversive ingredients, for example, lauryl sulfate or niacin in formulationswith oxycodone, will provoke adverse responses if applied in higher doses or by divergent route [60,61].

In conclusion, the use of opioid analgesics for severe pain treatment is growing constantly, despite rising concernsabout their effectiveness in the treatment of chronic noncancer pain. In parallel, the world is witnessing the growing



problem of their misuse. Therefore, healthcare providers should carefully consider the benefits and risks of opioiddrugs based on their pharmacological characteristics and behavioral effects that underlie therapeutic as well asadverse effects [62].

Can genes interfere with the pain treatment?It is estimated that genetic contribution to the development of chronic pain of musculoskeletal origin is around50%. The studies apostrophized the significance of at least six genes or gene clusters, mostly associated with opioid,adrenergic and catecholamine (i.e., dopaminergic and serotonergic) pathways, which are reproducibly connectedwith pain development [4]. However, the genetic background of various painful conditions is beyond the scope ofthis review, instead focusing on genetic polymorphisms related to the effectiveness and safety of analgesics.

Polymorphisms of the gene encoding for catechol-O-methyltransferase (COMT), an enzyme that degradescatecholamines, is most frequently linked to divergent pain processing in both, animals and humans [4]. COMThas also been identified as influencing analgesic drug efficacy, as well. The most studied functional SNP of COMTis rs4680, where A to G transition results in a Val to Met amino-acid substitution, and lower enzymatic activity.Although several clinical studies demonstrated that Val158Met (AA) carriers have an increased sensitivity to theanalgesic effects of opioids compared with AG and GG genotypes [63–65], further investigations into the correlationbetween opioid therapeutic dose range and COMT polymorphisms are warranted before drawing specific dosingconclusion [66].

Opioids’ effects may be influenced by polymorphisms in OPRM1 gene encoding for the MOR, with more than100 allelic variants identified so far. One of the most studied is the SNP rs1799971 (118 A>G), which results inAsn to Asp substitution [11]. The frequency of the OPRM1 188A>G variant differs between ethnic population, withthe highest frequency among individuals of Asian ancestry (35–50%), and lesser frequency among individuals ofEuropean (15.4%), Hispanic (14%) and African ancestry (4.7%) [67]. Persuasive evidence in favor of this functionalpolymorphism comes from some clinical studies with morphine, where GG genotype was related to a reducedanalgesic effect and requirements for higher doses [11].

In contrast to the limited evidence surrounding genes involved in pharmacodynamics of analgesics having an im-pact on their pharmacological profile, the highly polymorphic genes encoding for enzymes responsible for analgesicmetabolism can significantly change drugs effects and their fate in the organism. For example, the hepatic enzymeCYP2C9 is involved in the biotransformation of several analgesics, including celecoxib, flurbiprofen, meloxicam,piroxicam, diclofenac and neurologic agents like phenytoin and fosphenytoin. Up to now, 67 allelic variants of theCYP2C9 gene have been identified altogether [68]. It is estimated that CYP2C9*2 and CYP2C9*3 are present inEuropean population with the prevalence of 14 to 8%, respectively. These variants can decrease NSAID metabolism,resulting in elevated NSAID concentrations, as well as increased risk for adverse events and overdose. It has beenshown that the risk for upper gastrointestinal bleeding associated with NSAIDs is higher in people carrying theCYP2C9*3 variant [69]. Presence of the *2 and *3 alleles is also associated with elevated concentrations of pheny-toin and fosphenytoin, resulting in an increased risk of toxicity. The Clinical Pharmacogenomics ImplementationConsortium has authored guidelines on phenytoin/fosphenytoin dosing and CYP2C9 phenotype, recommend-ing physicians consider reducing phenytoin/fosphenytoin dose by 25% in CYP2C9 intermediate metabolizers(i.e., *1/*2 or *1/*3), and reducing the dose by 50% in CYP2C9 poor metabolizers (i.e., *2/*2, *2/*3, *3/*3),and recommend therapeutic drug monitoring to avoid toxicities [70].

Furthermore, CYP2D6 is responsible for the metabolism of many opioid analgesics, including codeine, oxy-codone and tramadol. Its function is directly related to the number of wild-type or abnormal alleles inherited,so patients can be categorized as poor, intermediate, extensive or ultrarapid metabolizers [7]. The analgesic effectsof codeine and tramadol are attributed to their O-demethylation via CYP2D6 to a more potent MOR agonistsmorphine and O-desmethyltramadol, respectively. Thus, poor metabolizers cannot experience a full analgesic effectafter standard dosing of these drugs opioid prodrugs. On the contrary, ultrarapid metabolizers have a higher riskof adverse effects and overdose, due to an increased concentration of those active metabolites. It is estimated thatcodeine therapy poses a risk of either lack of effect or adverse drug reactions for around one out of seven Caucasiansdue to extremely low or high morphine formation [71]. Because of the risks associated with CYP2D6 ultrarapidmetabolism, breastfeeding is not recommended during treatment with codeine or tramadol. Additionally, the USFDA has issued a black box warning for children who are CYP2D6 ultrarapid metabolizers and prescribed codeinefollowing a tonsillectomy or adenoidectomy, due to previous reports of respiratory depression and death in childrentaking codeine who were identified as CYP2D6 ultrarapid metabolizers [72].



Table 3. Polymorphisms of genes related to analgesic drug action.Drugs Protein Gene Genotype PK/PD effects Effect on clinical outcomes Ref

Morphine COMT COMT rs4680; 158 A�G Lower enzymatic activity Reduced drug dosage [11,65,66]

Opioid analgesics MOR OPRM1 rs1799971; 118A�G

Loss of a N-glycosylation sitein the extracellular region ofthe receptor

Reduced analgesic effect andrequirements for higher doses

[11,67]

Celecoxib, flurbiprofen,meloxicam, piroxicam,diclophenac, phenytoin andfosphenytoin

CYP2C9 CYP2C9 rs1799853;CYP2C9*2

Reduced enzymatic activity Elevated NSAID concentrations,increased risk for adverse events(higher risk for uppergastrointestinal bleeding) andoverdose

[11,69,70]

Codeine, oxycodone,tramadol

CYP2D6 CYP2D6 CYP2D6*1/*1xN*1/*2xN

Ultrarapid metabolizers Higher risk of adverse effects andoverdose

[11,71,72]

rs3892097;CYP2D6*4

Poor metabolizers Poor metabolizers cannotexperience a full analgesic effectafter standard dosing of opioidprodrugs

Propofol CYP2B6 CYP2B6 rs3745274:c.516G�T

Reduced enzymatic activity Dosage adjustment [73–75]

COMT: Catechol-O-methyltransferase; MOR: Mu (μ) opioid receptor; NSAID: Nonsteroidal anti-inflammatory drug; PD: Pharmacodynamics; PK: Pharmacokinetics; xN: Thenumber of gene copy.

Other analgesic agents, like propofol, are also metabolized via the CYP450 pathway. Propofol is metabolizedby CYP2B6, with only a few clinical studies identifying the CYP2B6 c.516G>T polymorphism impacting themetabolic profile of propofol. Further studies with larger patient populations are necessary to further characterizethe impact of CYP2B6 polymorphisms on the pharmacokinetics of both ketamine and propofol [73–75] (Table 3).

Variations in genes coding for UGT superfamily may potentially play a significant role in the clearance of mostanalgesic drugs since glucuronidation is an important final step in drugs biotransformation. Because the majorpathway for the metabolism of morphine is glucuronidation, genetic polymorphism in UGT2B7 was investigatedin several studies. Although the results are mostly inconclusive, in one study it was shown that in patients with sicklecell anemia, the presence of UGT2B7–840G allele significantly decreased morphine biotransformation into thefinal metabolites, morphine-3- and morphine-6 glucuronide [76]. Among nonopioid analgesics, there is evidencethat polymorphism in the UGT1A gene (rs8330) is connected to the increased paracetamol glucuronidation in theliver. This can be an important determinant of an individual’s risk for paracetamol-induced liver injury [77].

The efficacy and safety of opioids may additionally be compromised by polymorphisms of genes encodingfor different transporters that regulate drugs absorption, distribution and elimination. Among those, the mostinvestigated is P-gp, which belongs to the ATP-binding cassette (ABC) superfamily of efflux transporters. ABCB1gene encodes for P-gp, and is highly polymorphic, with 38 SNPs identified in the coding region. The bestcharacterized is the functional SNP rs1045642 (3435C>T), which does not change the amino acid sequence,results in reduced P-gp function. The frequency of this type of polymorphism is 50–60% among Caucasians,40–50% among Asians and 10–30% among Africans [42]. Due to the distribution of P-gp in the blood–brainbarrier, this polymorphism might affect the penetration of the drugs, like morphine, methadone and fentanyl,into the brain and consequently their efficacy. For these drugs, dose adjustments might be needed in patients withABCB1 polymorphism; however, there are no clear guidelines regarding this issue [7].

In summary, allelic variants in genes coding for target proteins, transporters and enzymes, which govern analgesicdrugs action and their fate in the organism might explain interindividual variability in pain perception, severity andin drug-induced pain relief and toxicities. Therefore, the relevance of pharmacogenetics in optimizing pain therapyis more than obvious but clear guidelines for its implementation in the clinical settings are required. For now, theClinical Pharmacogenetics Implementation Consortium has established guidelines on individualizing treatmentwith tramadol and codeine based on the rate of CYP2D6 metabolism [11].

Pharmacogenomics in pain managementSuccessful pain management requires the delivery of analgesia with minimal risk of adverse drug reactions. Clinicianstreating pain have noted that responses to pain medications can vary to a great degree (∼40-fold). Almost 50% ofall patients experience inadequate pain relief and serious adverse drug reactions with many of the most commonlyused perioperative analgesics [78].



At this point the following drugs for the pain treatment contain pharmacogenomics information in FDAlabel, Clinical Pharmacogenetics Implementation Consortium or Dutch Pharmacogenetics Working Group clin-ical guidelines: opioids (codeine, oxycodone, tramadol) and nonopioid, anti-inflammatory and neuropathic paindrugs (celecoxib, amitriptyline, desipramine, clomipramine, doxepin, imipramine, nortriptyline, protriptyline,trimipramine, venlafaxine). In collaboration with OneOme, St Catherine’s Hospital just launched innovative phar-macogenomics tests (RightMed R©) ‘covering’ following genes: CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6,CYP3A4, CYP3A5, OPRM1 and COMT in order to have as successful pain management as possible with minimalrisk of adverse drug reactions.

Possible influence of epigenetics on the pain treatmentDevelopment of sensitization of the nociceptive system (after tissue and/or peripheral nerve injury or prolongedinflammation) and pain chronification (the transition of acute to chronic pain) are under strong influence ofenvironmental factors, such as diet, exercise, stress, toxins, medications, drug abuse and many others which alter thegenes involved in pain perception and predispose individual vulnerability toward painful signals [79–81]. For example,among female smokers’ chronic pain condition has been reported more frequently than in female nonsmokers,although the evidence for a direct causal relationship between smoking and pain is relatively weak [11,80].

Epigenetic changes such as histone acetylation regulated by histone acetyltransferases and histone deacetylases,DNA methylation regulated by DNA methyltransferases and miRNAs dysregulation are contributing factors foronset and progression of different pain types, as was repeatedly demonstrated in different animal pain models [79,82].

In the experimental model of postsurgical pain in mice it was demonstrated that epigenetic changes in genescoding for brain-derived neurotrophic factor and dynorphine contribute to postoperative hypersensitization andreduce opioid response after prolonged treatment [83]. This result, when combined with other studies suggestthat epigenetic modifications probably contribute to the opioid analgesics effects on pain and on their adverseeffects, such as paradoxical hyperalgesia and addiction [82,84]. Recently, Li et al. showed that DNA demethylationof chemokine receptor CXCR4 gene promoter region significantly contributes to inflammatory hyperalgesia inrats [84].

Although mostly preclinical, findings from different pain models provide a theoretical basis for the treatmentof chronic pain from an epigenetic point of view. Hypothetically, pain therapy might benefit from drugs thatare able to modulate epigenetic contribution to pain pathophysiology (such as histone deacetylases and DNAmethyltransferase inhibitors). Despite several drugs in the preclinical and clinical phases of the investigation, it willtake some time before we can improve the pain treatment with epigenetic modulators [82].

Even though it was demonstrated in human gastric mucosa and colon carcinoma cells that a long-term ad-ministration of different NSAIDs affects epigenetic modulation of several growth genes, similar effects were notdemonstrated for pain-related genes so far [85]. On the contrary, opioids are associated with different types ofepigenetic regulation, such as miRNA upregulation and downregulation [86], increased methylation of OPRM1gene [87].

In conclusion, research on epigenetic mechanisms related to the pain and analgesic drug actions is becomingan interesting field for researchers and clinicians, but for now, we can only speculate about the contribution ofepigenetics to the pain treatment.

Conclusion & future perspectivesDespite an enormous effort put to the pain investigation during past several decades, chronic pain still represents ahuge challenge for both researchers and clinicians. Findings from the laboratories contribute to the clarification ofcomplex pain pathophysiology; however, the pain treatment in clinical practice is still grounded on two classes ofanalgesic drugs. Basic knowledge about their pharmacology and side effects profile is warranted for effective andsafe pain treatment. Considering challenges in individual pain treatment, pharmacogenomic studies might be ofcrucial importance in clarifying interindividual differences in analgesic effect and tolerability of the drugs. However,with the exception of codeine and tramadol, guidelines supporting pharmacogenetic testing that assist in selectingthe optimal dose for the individual patient are currently lacking. A multidisciplinary team approach may be thebest way toward enabling timely, evidence-based, cost-effective and most importantly, successful pain managementinterventions [88,89].



Executive summary

Nonsteroidal anti-inflammatory drugs as a first-line therapy to combat the pain• Nonsteroidal anti-inflammatory drugs are considered first-line therapy for managing a pain of low to medium

intensity of different localization and etiology.

• Factors to keep in mind include: COX1/COX2 selectivity, type of pharmaceutical formulation, patient history ofsevere renal or liver impairment, potential gastro- and cardiotoxicity.

Opioid agonists as the most powerful weapon to conquer the pain• Opioids relieve moderate to severe acute and chronic pain in cancer patients and patients experiencing

nonmalignant pain.

• Affinity to opioid receptors, CYP2D6 metabolizer type and abuse-deterrent formulations are some of the mainpoints to consider when choosing an opioid drug.

Can genes interfere with the pain treatment?• Allelic variants in genes coding for target proteins (OPRM1), transporters (P-gp) and enzymes (CYP2D6, UGT,

COMT) might explain interindividual variability in pain perception, severity and in drug-induced pain relief andtoxicities.

Pharmacogenomics in pain management• Almost 50% of all patients experience inadequate pain relief and serious adverse drug reactions with many of

the most commonly used perioperative analgesics.

• In collaboration with OneOme, St. Catherine’s Hospital just launched innovative pharmacogenomics tests(RightMed R©) “covering” following genes: CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5,OPRM1, and COMT.

Possible influence of epigenetics on the pain treatment• Epigenetic modifications probably contribute to the opioid analgesics effects on pain and on their adverse

effects, such as paradoxical hyperalgesia and addiction.

• Opioids are associated with different types of epigenetic regulation, such as miRNA upregulation anddownregulation, increased methylation of OPRM1 gene, but no such evidence has emerged for nonsteroidalanti-inflammatory drugs and pain-related genes.

Conclusion• Considering challenges in individual pain treatment, pharmacogenomic studies might clarify interindividual

differences in analgesic efficacy and tolerability.

• A multidisciplinary team approach may enable timely, evidence-based, cost-effective and most importantly,successful pain management interventions.

Acknowledgements

We would like to thank our dear friend and colleague B Racki for sharing with us his passion and love toward design, and for

giving us a lot of useful advices while drawing image of COX enzymes. We also thank V Drinovac Vlah for critically reading the

manuscript.

Financial & competing interests disclosure

St Catherine Specialty Hospital (represented by D Primorac and I Mikula) and OneOme LLC (represented by R Gregg), partnering to

bring innovative, actionable pharmacogenomics comprehensive testing (RightMed) to patients. The authors have no other relevant

affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject

matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Author’s contributions

L Bach-Rojecky was responsible for conception of the work, literature search, drafting the text and final approval. D Vad-unec

was responsible for literature search, drafting the text, figures designing and final approval. K Zunic was responsible for literature

search, drafting the text, manuscript editing and final approval. J Kurija was responsible for literature search, drafting the text, table

designing and final approval. S Sipicki was responsible for literature search, drafting the text, table designing and final approval.

R Gregg was responsible for drafting the text, critical revising of the manuscript and final approval. I Mikula was responsible for

drafting the text, critical revising of the manuscript and final approval. D Primorac was responsible for conception of the work,

drafting the text, critical revising of the manuscript and final approval.



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continuingwaronpain:apersonalized ......as age, sex (chronic pain is more prevalent in female),...

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