Clinical Biochemistry 47 (2014) 1169–1187

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Clinical Biochemistry

j ourna l homepage: www.e lsev ie r .com/ locate /c l inb iochem

Review

Pharmacogenetics of chronic pain management

Bhushan M. Kapur a,b,c,⁎, Prateek K. Lala b, Julie L.V. Shaw c

a Department of Clinical Pathology, Sunnybrook Health Sciences Center, Toronto, Canadab Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children University of Toronto, Canadac Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Canada

⁎ Corresponding author at: Department of Clinical PathE-mail address: b.kapur@utoronto.ca (B.M. Kapur).

http://dx.doi.org/10.1016/j.clinbiochem.2014.05.0650009-9120/© 2014 The Authors. The Canadian Socie(http://creativecommons.org/licenses/by-nc-nd/3.0/).

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 8 March 2014Received in revised form 25 May 2014Accepted 27 May 2014Available online 7 June 2014

Keywords:Chronic painPain managementPharmacokineticsPharmacogeneticsOpioidsNSAIDsTriptans

Objective: The experience of chronic pain is one of the commonest reasons individuals seek medical atten-tion, making the management of chronic pain a major issue in clinical practice. Drug metabolism and responsesare affectedbymany factors,with genetic variations offering only a partial explanation of an individual’s response.There is a paucity of evidence for the benefits of pharmacogenetic testing in the context of pain management.

Design andmethods:We reviewed the literature between2000 and 2013, and references cited therein, usingvarious keywords related to pain management, pharmacology and pharmacogenetics.

Results:Opioids continue to be themainstay of chronic painmanagement. Several non-opioid based therapies,such as treatment with cannabinoids, gene therapy and epigenetic-based approaches are now available for thesepatients. Adjuvant therapies with antidepressants, benzodiazepines or anticonvulsants can also be useful in man-aging pain. Currently, laboratory monitoring of pain management patients, if performed, is largely through urinedrug measurements.

Conclusions:Drug half-life calculations can be used as functional markers of the cumulative effect of pharma-cogenetics and drug–drug interactions. Assessment of half-life and therapeutic effectsmay bemore useful than ge-

netic testing in preventing adverse drug reactions to pain medications, while ensuring effective analgesia.Definitive, mass spectrometry-based methods, capable of measuring parent drug and metabolite levels, are themost useful assays for this purpose. Urine drug measurements do not necessarily correlate with serum drugconcentrations or therapeutic effects. Therefore, they are limited in their use in monitoring efficacy and toxicity.© 2014 The Authors. The Canadian Society of Clinical Chemists. Published by Elsevier Inc. This is an open access

article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170Chronic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1171Pharmacogenetics and pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1171

Cytochrome P450 enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1171P-glycoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172Cyclooxygenases 1 and 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172Opioid receptor μ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172Catechol-O-methyltransferase (COMT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1173Clinical use of pharmacogenetics in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1173

Genetics and pain susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1173Chronic pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174

Drugs used in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174NSAIDs and acetaminophen in pain management (Table 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174Opioids and pain management (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174Issues with opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175Specific opioids used in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175

ology, Sunnybrook Health Science Centre, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada. Fax: +1 905 849 4389.

ty of Clinical Chemists. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license

1170 B.M. Kapur et al. / Clinical Biochemistry 47 (2014) 1169–1187

Weak opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175Codeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175Hydrocodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178Tramadol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178

Strong opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178Morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178Hydromorphone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178Fentanyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178Remifentanil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178Methadone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178Buprenorphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178Oxycodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179Oxymorphone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179Meperidine (pethidine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180Levorphanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180

Other medications in the treatment of chronic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180Triptans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182Ziconotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182

Novel therapies in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182Targeting epigenetic modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182Gene therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183

Therapeutic drug monitoring in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1184References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1184

Introduction

According to the International Association for the Study of Pain(IASP), pain is defined as an “unpleasant sensory and emotional experi-ence associated with actual or potential tissue damage, or described interms of such damage”. Several different subtypes of pain can be de-scribed, based on their neuropsychological basis and duration, includingneuropathic, nociceptive, psychogenic, referred, phantom, acute andchronic [1]. Chronic pain is very common, with one in three Americansand one in five Canadians reported to suffer from this problem [2,3]. Itis one of the most frequent reasons for individuals to seek medicalcare. If untreated, chronic pain can lead to physical and social dysfunctionand diminished quality of life.

Successful pain management provides adequate analgesia withoutexcessive adverse effects. Current pain management strategies largelyemploy the use of the World Health Organization (WHO) pain ladder,beginning with non-opioid medications, such as NSAIDs, progressingto weak opioids, and culminating with strong opioids, particularly incancer pain [4]. The WHO also recommends adjuvant therapy with an-tidepressant medications to aid in reducing anxiety often associatedwith chronic pain [4].

Management of pain can be complicated by lack of adherence, thepotential for abuse or dependence on themedications used and adversedrug side effects. Many factors can influence drug disposition, includinggenetic variation, which can further complicate management of thesepatients.

Genetic studies have identified several loci in which polymorphicchanges can influence the pharmacodynamics and kinetics of analgesicdrugs. Current patientmonitoring in painmanagement (if performed atall) is largely based on urine drugmeasurements. However, therapeuticdrug monitoring (TDM) via plasma drug levels and half-life may provemore useful in monitoring patients prescribed pain medications toensure efficacy while minimizing adverse drug reactions. TDM canalso be very useful for the identification of drug-related side effectsand patient-reported lack of effect (e.g., tolerance).

Finally, non-opioid analgesics are often tried as options for manage-ment of pain, particularly in individuals where opioids are not a suitable

choice. In addition, novel therapies, including targeting of epigeneticchanges and gene therapy-based approaches are further broadeningfuture options for the treatment of chronic pain.

Methods

We conducted an online systematic search for papers and relatedabstracts published between 2000 and 2013 using the National Libraryof Medicine database, PubMed. Using the following headings: “painmanagement medications”, “pain management drugs”, “chronic painmanagement”, “pharmacogenetics and pain management”, and “drugmonitoring and pain management”, we identified 6670 papers. The ab-stracts of all papers were reviewed and those that appeared to be rele-vant to the subject were selected for further study. References citedtherein, including original publications, were also selected for furtherreview.

Pain

Pain is the most common presenting physical symptom in primarycare, accounting for an enormous burden of patient suffering, qualityof life, work and social disability, and health care and societal costs [5].Pain is defined as an unpleasant sensory and emotional experienceassociated with actual or potential tissue damage [1]. However, the ex-perience of pain is highly subjective and idiosyncratic, and individualsdevelop pain thresholds through experiences of injury or pathology inearly life [1].

Neuropathic pain results from actual damage to nerve fibers them-selves in the central or peripheral nervous system [6]. This damage canlead to nerve dysfunction, causing numbness, weakness and/or loss ofreflexes. Common descriptions accompanying neuropathic pain include“burning”, “shooting” or “shock-like” sensations [7]. The most commoncauses of chronic neuropathic pain include diabetic neuropathy, post-herpetic neuralgia, fibromyalgia, lower back pain (radiculopathy dueto disc herniation) and osteoarthritis [8].

Nociceptive pain is caused by stimulation of specialized sensoryneurons, called nociceptors, by noxious stimuli including extremes of

1171B.M. Kapur et al. / Clinical Biochemistry 47 (2014) 1169–1187

temperature, or mechanical or chemical excitation. It is often catego-rized as somatic (derived from skin and deep tissue) or visceral(originating from internal organs). Due to high concentrations ofnociceptors in somatic tissues, chronic somatic pain is typically local-ized, and often results from degenerative or inflammatory processes.Nociceptive pain is frequently described as stabbing, pricking, burning,throbbing or cramping [9].

Psychogenic pain refers to painful sensations caused or amplified bymental or emotional factors with no evident physical tissue damage[10]. Referred pain is perceived at a site adjacent to or distant from thesite of painful stimulus; the mechanism for this process is not yet wellunderstood [11]. Phantom pain, a sub-type of referred pain, is the feelingof painful sensations from a part of the body which has been lost, andfrom which the brain no longer receives signals. Individuals who haveundergone limb amputation often experience phantom pain [12].

Acute and chronic are terms commonly used to describe the durationof painful sensations, but are difficult to categorically define. In general,acute pain resolves within weeks of the initial causative insult, whereaschronic pain is continuous, long-term pain which can last months oryears [13].

Chronic pain

The IASP defines chronic pain as that pain which persists past thenormal time of healing following an injury. However, since determiningthe end of the healing phase is problematic,most clinical definitions usea fixed time of persistent pain after initial onset. This demarcation be-tween acute and chronic pain is somewhat arbitrary, and typicallyranges from three months (e.g., for post-herpetic neuralgia) to sixmonths (e.g., for chronic lowbackpain) [14,15]. The treatment of chron-ic pain can be difficult because it is a complex condition influenced bygenetic makeup as well as physiological and psychological factors.

Chronic pain is a problem inmany societies,with prevalence rangingfrom 2% to 40% in the adult population, resulting in social and economicimpacts [16–18]. Chronic pain can interfere with an individual’s activi-ties of daily living, leading to work or school absenteeism, inability toparticipate in leisure activities, sleep disturbances and problems eating.In the United States, one in three Americans experiences chronic painand chronic pain is the most common reason for people to visit theirfamily doctor [3]; one in five Canadians is reported to suffer fromchronic pain [2]. It is therefore important that chronic pain be diagnosedaccurately and treated effectively. Recently, an increased focus on painmanagement has led to a six-fold increase in the sales of prescriptionopioids in the U.S. between1997 and 2006 [19]. Use of analgesics has in-creased from 7.2% of the U.S. population in 1988–1994 to 10.2% duringthe period 2007–2010 [20].

Pharmacogenetics and pain management

Pharmacogenetics refers to the way in which genetic differencesbetween individuals influence patient drug responses and drug disposi-tion [21]. Empirically, it is well understood that large inter-individualvariations exist with respect to the response to analgesics [22].Withconventional drug dosing, some patients will experience toxicitywhereas other patients will not receive adequate analgesia from thesame dose. Variations in drug efficacy can vary as much as 2- to 10-fold or even 100-fold among members of the same family [23–25].These differences can be due to pharmacodynamics factors, based onvariations in drug target receptors and downstream signal transduction,and pharmacokinetic factors, which affect drug metabolism and/orelimination, altering the relationship between drug dose and steadystate serum drug concentrations. Development of tolerance, whichmay occur through both dynamic and kinetic mechanisms, can alsoplay a significant role in this response variation.

Genetic variability is one factor playing a role in the way in whichdrugs affect physiology. Generally, genes affecting outcome of treatment

can be divided into two broad categories: those genes affecting pharma-cokinetics, and those affecting pharmacodynamics [22]. In the case ofpain management drugs, genes associated with altered pharmacokinet-ics include thosewhich encodemembers of the cytochrome P450 familyof enzymes, enzymes responsible for glucuronidation and drug trans-porter proteins [21,22]. Genes encoding cyclooxygenase enzymes, theopioid receptors and the enzyme catecholamine methyltransferase(COMT) can affect drug pharmacodynamics [21,22]. Světlík and col-leagues provide an up-to-date review of results from pharmacogeneticstudies of candidate genes in both the kinetic anddynamic domains [26].

Cytochrome P450 enzymes

The cytochrome P450 (CYP) enzymes comprise a category ofproteins whose biosynthesis is controlled by a large super-family ofgenes. Members of the CYP family play important roles in drug metab-olism and therefore influence the concentration of a drug present incirculation. The primary catalytic function of CYP enzymes is identifiedas the transfer of one oxygen atom frommolecular oxygen into varioussubstrates. Additionally, some CYP enzymes act as isomerases, reduc-tases, dehydrases, or nitric oxide (NO) synthases, and some can catalyseoxidative cleavage of esters [27].

CYPs are responsible for approximately 80% of all phase I metabo-lism reactions (Fig. 1) [27,28]. Genetic changes in CYP genes can resultin alterations in enzyme activities. One CYP isoformwhich has been ex-tensively studied with respect to genetic variation is CYP2D6. This en-zyme accounts for a very small percentage (b2%) (Fig. 1b) of all CYPsexpressed in the human body, but is responsible for the metabolism ofalmost 20% of all drugs (Fig. 1a), includingmany drugs used inmanage-ment of pain [29]. Most of these enzymes are polymorphic [30]; morethan 80 CYP2D6 variants have been identified which, functionally, areassociated with four general phenotypes: extensive metabolizer (EM),intermediate metabolizer (IM), poor metabolizer (PM) and ultra-rapidmetabolizer (UM) [31]. The prevalence of these phenotypes varies byethnicity [22] and there are several examples in which phenotypic dif-ferences in individuals have led to adverse drug reactions.

In 2004, a case reported by Gasche and colleagues described a 62-year-old male, with a history of chronic lymphocytic leukemia, whopresented with fatigue, dyspnea, fever and cough with a bronchoalveo-lar lavage culture revealing yeast [33]. Hewas treated with codeine as acough suppressant. However on day4 of treatment, hedeteriorated rap-idly and became unresponsive. Hewas given naloxone, an opioid recep-tor antagonist, which resulted in rapid improvement in his condition.Several factorswere at play in this case, leading to the patient’s rapid de-terioration. Genetic studies revealed that he had CYP2D6 duplications,causing him to be an ultra-rapid metabolizer of the pro-drug (codeine)to the active metabolite (morphine). Furthermore, CYP3A4 is also in-volved in codeine metabolism, specifically in the conversion of codeineto (relatively inactive) norcodeine. In this case, co-treatment withclarithromycin and voriconazole, both CYP3A4 inhibitors, resulted indecreased conversion of codeine to norcodeine, shunting more codeineinto the CYP2D6 morphine pathway. The patient also developed acuterenal failure which resulted in the accumulation of glucuronide metab-olites with opioid activity (morphine-6-glucuronide) [33].

Opioids, including codeine, are among the pain medications metab-olized by CYP2D6. In 2006, Koren and colleagues reported a case of abreast-fed infant who died at 13 days of age [34]. The infant’s motherhad been prescribed codeine for episiotomy pain. Stored breastmilk was found to contain higher than expected levels of morphine(87 ng/mL; expected 1.9–20.5 ng/mL). CYP2D6 genotyping revealedthat the infant’s mother was heterozygous for a CYP2D6 duplication,making her an UM of codeine to morphine. The infant died from CNSdepression and this, along with the genetic results, were consistentwith opioid toxicity resulting from increased conversion of codeine tomorphine. This case prompted the FDA in the USA as well as Health

b) a)

Fig. 1. Cytochrome p450: Abundance and proportions. a) Proportions of drugs metabolized by CYP 450 enzymes. Adapted from: Rendic S and Di Carlo FJ [27]. b) CYP Abundance inhuman liver. Adapted from Yeo et al. [32].

1172 B.M. Kapur et al. / Clinical Biochemistry 47 (2014) 1169–1187

Canada to advise physicians against the prescription of codeine tonursing mothers [35,36].

Studies have also shown that CYP polymorphisms have an influenceon the metabolism of non-steroidal anti-inflammatory drugs (NSAIDs)and have the potential to cause adverse drug reactions, most notablygastrointestinal (GI) bleeding, a frequent reaction resulting insignificant patient morbidity and mortality. The risk of GI bleeding isparticularly high with higher doses of NSAIDs [37]. Many NSAIDs aremetabolized by CYP2C9, which has been shown to have two allelic var-iants, referred to as CYP2C9*2 and CYP2C9*3 [37]. The CYP2C9 enzymesencoded by the *2 and *3 alleles are reported to have 50% and 15% of theactivity of the wild-type enzyme, respectively, resulting in poor metab-olism, and thus prolonged action, of NSAIDs in individuals with either ofthese two alleles [38,39].

Due to their platelet-inhibiting action, NSAIDs are also responsiblefor an increased risk of bleeding, particularly in patients taking the anti-coagulant warfarin [38], since CYP2C9 is also important for warfarinmetabolism. Patients with the CYP2C9 *2 or *3 genotypes taking bothan NSAID and warfarin have been shown to have a significantly higherrisk for an elevated prothrombin time, compared to patients with thewild-type 2C9 genotype [38].

Celecoxib is a selective COX-2 inhibitor which is metabolized byCYP2C9. In a study of patients prescribed celecoxib for rheumatoid orosteoarthritis, patients with the *2 or *3 genotypes showed an increasedelimination half-life compared to patients with the wild-type genotype[40]. In a similar study, the investigators looked at patients prescribedone of several different NSAIDs, including celecoxib, ibuprofen andnaproxen. They grouped the patients into those who experienced GIbleeding and thosewho did not, and performed CYP 2C9 genotype anal-ysis on all patients. Within the group of patients with GI bleeding, ahigher number of individuals had the *2 or *3 genotype compared tothe group not experiencing gastrointestinal bleeding [41]. The increasedrisk of bleedingwas believed to result from reduced CYP2C9 enzyme ac-tivity in patients with the *2 or *3 alleles, leading to increased NSAIDconcentrations [41].

P-glycoprotein

The ABCB1/MDR1 gene encodes P-glycoprotein, an efflux transporterthat influences drug transport in several tissues, particularly theintestine, kidney and brain [42,43]. P-glycoprotein is highly expressedin endothelial cells of the brain vasculature, and is believed to effectthe efflux of drugs across the blood brain barrier [43]. ABCB1/MDR1 isa highly polymorphic gene, with 38 single nucleotide polymorphisms(SNPs) identified in the coding region [44]. The activity of P-glycoprotein is thought to be affected by genetic variability, with certainSNPs leading to decreased P-glycoprotein expression and activity.

One study, which examined individuals prescribed oxycodone,found that people homozygous or heterozygous for variant ABCB1/MDR1 alleles reported larger decreases in pain, but also a higherfrequency of adverse drug reactions to oxycodone, presumably due todecreased efflux and therefore higher plasma concentrations of thedrug [42]. Genetic variability of ABCB1/MDR1 has also been found tobe associated with inter-individual differences in pain relief achievedby morphine [43]. In a study of Korean patients receiving intravenousfentanyl, certain ABCB1/MDR1 genotypes were associated withprolonged fentanyl-induced suppression of respiration rate [45].

Cyclooxygenases 1 and 2

Cyclooxygenase 1 and 2 are encoded by two separate genes, PTGS1(COX1) and PTGS2 (COX2). Genetic variation in either of these enzymeswould be expected to cause altered pharmacodynamic responses toNSAIDs. In a study which investigated post-surgical expression ofPTGS1 and PTGS2, in relation to SNPs in each gene, certain SNPs wereshown to be associated with altered expression of the PTGS2 transcript[46]. The authors also reported differences in patient response to twoNSAIDs, rofecoxib, a selective COX-2 inhibitor and ibuprofen, a non-selective COX inhibitor. In particular, the G → C polymorphism at−765, in the promoter region of PTGS2, was found to be associatedwith lower PTGS2 expression in individuals heterozygous (G/C) or ho-mozygous (C/C) for the minor allele, compared to those homozygousfor the major allele (G/G) [46]. Subjects with G/G genotype alsoreported lower pain intensity with rofecoxib treatment for 48 h follow-ing surgery, compared to G/C or C/C subjects. This difference was notdemonstrated for patients treated with ibuprofen. However, subjectswith G/C and C/C genotypes reported decreased pain intensity with ibu-profen treatment at 48 h following surgery, compared to G/G patients.This difference was not seen in subjects treated with rofecoxib [46].These data suggest that patients with increased PTGS2 expression(G/G genotype) benefittedmore from treatmentwith rofecoxib, where-as patients with decreased PTGS2 expression (G/C or C/C genotypes)benefited more from treatment with ibuprofen [46]. These findingsare likely explained by the selectivity of rofecoxib for COX-2, encodedby PTGS2.

Opioid receptor μ

Opioid receptor μ is the primary site of action for many endogenousopioids, as well as those used for analgesia. A number of SNPs have beendescribed in OPRM1, the gene encoding this receptor. The most wellcharacterized SNP in OPRM1 is A118G. A study by Janicki et al. [47]found the minor allele (G) present at lower frequency in subjects withchronic pain treatedwith opioids, compared to a control group of opioid

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naïve patients, suggesting that the G allele may confer protectionagainst pain.

Epidural opioids are commonly used to provide analgesia to womenduring labor. Women heterozygous or homozygous for the OPRM1A118G allele have been demonstrated to have higher pressure painthresholds than women homozygous for the more common A allele[48]. The A → G nucleotide substitution leads to an amino acid changefrom asparagine to aspartic acid, and is thought to result in higher bind-ing affinity of β-endorphin to the opioid-μ receptor. In another study ofwomen in labor, themedian effective dose (ED50) of intrathecal fentanylrequired to achieve effective analgesia was significantly higher inwomen homozygous for the A allele (26.8 μg) compared to womenheterozygous or homozygous for the G allele (17.7 μg) [49].

Catechol-O-methyltransferase (COMT)

The COMT enzyme is responsible for the inactivation of catechol-amines such as dopamine, norepinephrine and epinephrine. Severalpolymorphisms have been identified in the COMT gene; however, themost widely studied variant is a G to A nucleotide substitution resultingin an amino acid change from valine to methionine at codon 158(Val158Met). This amino acid change is reported to decrease thethermal stability of the COMT protein, resulting in reduced enzymaticactivity. In studies of cancer patients experiencing chronic pain, patientshomozygous for the more common Val 158 were found to requirehigher doses of morphine to achieve analgesia, compared to patientsheterozygous or homozygous for Met 158 [50,51]. These findingssuggest that variable COMT activity may influence the effects of opioids.Animal studies have demonstrated reduced neuronal enkephalin con-tent in the brain with chronic activation of dopaminergic transmission.The reduced enkephalin content has been shown to be followed by anupregulation of the opioid-μ receptor [52,53]. The lower doses of mor-phine required by individuals with the Met158 variant may be ex-plained by reduced COMT activity which is associated with increaseddopaminergic stimulation, resulting in upregulation of opioid-μreceptor expression in the brain, making morphine more effective.Another study demonstrated differences in morphine side effects,such as drowsiness, confusion and hallucinations, associated withcertain COMT variants, which influenced how well patients toleratedmorphine [54].

Fig. 2. Genetic and non-genetic factors effecting dru

Clinical use of pharmacogenetics in pain management

Ideally, pharmacogenetic studies aim to aid in the selection anddosing of an optimal drug therapy for a specific patient. Choosing theoptimal therapy should lead to maximized therapeutic benefit,improved patient adherence and a reduction in adverse drug reac-tions [55]. The cases of opioid overdose discussed above illustrate in-stances where knowledge of patient genotypes may have been usefulto improve patient outcomes. However, most pharmacogenetic studiesto date have examined variability in single candidate genes, such asCYP2D6, and associated outcomes [22]. There are limitations to this ap-proach, as very few drugs aremetabolized by a single enzyme. Genome-wide association studies (GWAS) may possibly improve upon this limi-tation. Furthermore, in addition to genetics, many other factors affectdrug responses, such as patient age, disease co-morbidities and, inparticular, co-medication [22,56] (Fig. 2). Genetics can only partiallyexplain the variability in patient responses to analgesic drugs. Patientsare very commonly prescribed several medications for multipleco-morbidities. Some medications induce CYP enzyme activity [57], asillustrated in the case above [33], while others inhibit activity [57],which can lead to altered metabolism unrelated to the patient’s CYPphenotype. In general, pharmacogenetic studies thus far in pain man-agement have failed to yield evidence of improved clinical outcomes as-sociated with knowledge of patient genotypes when prescribing painmedications. As GWAS studies continue, and panels of gene testing be-come more widely accessible, pharmacogenetics of pain managementmay yet become more clinically useful [58].

Genetics and pain susceptibility

An individual’s genetic susceptibility to chronic pain is thought to becomplex, involving multiple genes, similar to the genetics of otherchronic diseases, such as diabetes [21]. As discussed above, several can-didate genes have been identified, with specific mutations shown toalter pain perception profiles between individuals. Examples include:OPRM1, the gene encoding the μ-opioid receptor; COMT, encodingcatechol-O-methyltransferase, involved in the metabolism of catechol-amines; GCH1, encoding an enzyme involved in phenylalaninemetabo-lismand the production of dopamine; themelanocortin-1 receptorwithmutations showing sex-specific differences in pain perception; and

g metabolism. Adapted from Stamer et al. [22].

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members of the cytochrome P450 enzyme family, important for thebiotransformation of many drugs. Genome-wide association studiesand other types of genetic investigations will likely identify manymore genes involved in pain perception.

Chronic pain management

Successful pain management can be viewed as providing adequateanalgesia without excessive adverse effects [59]. In 1982, Rane and col-leagues [60] proposed a pharmacological approach to treat cancer painwith morphine. They proposed a step-wise approach that was lateradopted by the World Health Organization (WHO) in 1986 [61,62]. Al-though this WHO stepladder approach was originally aimed at thetreatment of chronic cancer pain (Fig. 3) [61,62], it is also widely usedin the treatment of chronic non-cancer pain [63]. The WHO analgesicladder recommends initial treatment of pain with non-opioids, such asNSAIDs and acetaminophen. If pain persists, treatmentwith aweak opi-oid, such as codeine or tramadol is recommended, followed by a strongopioid, such as morphine, until the patient is free of pain. At each stageof the treatment ladder, adjuvant medications, such as antidepressantsor anticonvulsants, may also be given to aid in alleviating patient anxi-ety; some of these adjuvant drugs may also act directly to counterpain [4,61]. Evident from this scheme is the fact that opioids remainthemainstay of chronic painmanagement andwill be discussed furtherbelow.

Drugs used in pain management

NSAIDs and acetaminophen in pain management (Table 1)NSAIDs such as aspirin and ibuprofen, as well as acetaminophen, act

by inhibiting the enzymes cyclooxygenase-1 and -2, which catalyze thesynthesis of prostaglandins. The inhibition of prostaglandin synthesisresults in the analgesic, anti-pyretic and anti-inflammatory propertiesof these drugs, with the exception of acetaminophen, which does notshow anti-inflammatory affects. Due to the widespread use of NSAIDs,they are the drugs most commonly associated with adverse effects,the most common of which are those involving the GI tract. Reducedprostaglandin levels in the gastrointestinal mucosa decrease mucusand bicarbonate secretions, thereby reducing their protective effectsagainst the acidic gastric environment. In addition, NSAIDs can be di-rectly toxic to the gastric mucosa, leading to ulceration, and potentiallyfatal bleeding in the most extreme cases. Furthermore, reduced prosta-glandin synthesis in the kidney has been shown to cause renal impair-ment. Chronic or acutely toxic acetaminophen exposure can lead toliver toxicity through hepatocellular necrosis [64,65]. Additionally, aspi-rin (acetylsalicylic acid) is associated with Reye’s syndrome, primarilyaffecting children [66,67], and high doses of salicylates can cause

Fig. 3. TheWHO three-stepanalgesic ladder.Adapted from [60,61]. Legend: The pain lad-der shows a progressive rationale for stronger opioids. Before a new medication isintroduced, it is important to wait until the previously administered drug has reached a“steady state” or full effect is achieved. *Adjuvants: antidepressants, anticonvulsants,steroids.

metabolic acidosis and respiratory depression. More recently, cardio-vascular risks associated with the use of NSAIDs have gained attention.NSAIDs, particularly COX-2 selective agents, such as celecoxib, havebeen reported to increase the risk for thrombotic events, myocardial in-farction and stroke in patients with coronary artery disease and athero-sclerosis [68,69]. These findings have prompted the American HeartAssociation to recommend use of acetaminophen or non-acetylated sa-licylates for the treatment of chronic pain in patients with coronary ar-tery disease [70]. Although classified with nonsteroidal anti-inflammatory agents, acetaminophen has minimal peripheral anti-inflammatory activity.

IV acetaminophen has become a part of the multimodal analgesiaapproach for pain. Intravenous acetaminophen was made availableover 10 years ago in Europe, but in the United States only very recently.Three randomized placebo controlled trials provided the bases of its ap-proval. Clinical studies show that for management of pain, intravenousacetaminophen injection was at least as effective as morphine injectionin renal colic and oral ibuprofen after cesarean delivery. In children asingle-dose acetaminophen injection was similar to meperidineintramuscular (IM) for pain after tonsillectomy [71]. Effects begin 5 to10 min after IV administration, and peak effects occur in about 1 hwith an effective duration of 4 to 6 h. Table 1 provides pharmacokineticdetails of specific NSAIDs and acetaminophen, as used in painmanagement.

Opioids and pain management (Table 2)Opioids remain the most potent analgesics available and are the

mainstay of chronic pain management in both cancer patients and pa-tients with non-malignant pain [2,72]. To manage chronic cancer pain,oral morphine is commonly administered at regular intervals. Chronicdosing can lead to pharmacological tolerance, but not to therapeuticfailure. In simple pharmacological terms, opioid-induced tolerance canbe described as a “shift to the right” in the dose–response curve; thatis, a higher dose is required over time to maintain the same level of an-algesia. Differentmechanisms have been proposed for the developmentof tolerance. Säwe and colleagues [73] investigated themetabolic corre-late to the development of tolerance to therapeutic effects bymeasuringmorphine, morphine-3- and morphine-6-glucuronide in plasma andurine samples. They showed that the conjugation ofmorphinewith glu-curonic acid is proportional to the dose during long-term treatmentwith escalating doses, suggesting that this metabolic pathway is subjectto neither auto-induction nor saturation. Both in vitro and in vivo studieshave shown that, on the cellular level, chronic opioid treatment leads toa rapid reduction of agonist response, accompanied by internalizationof opioid receptors [74]. These early adaptive processes as well aslong-term adaptations, such as receptor downregulation, or counter-regulatory processes such as adenylate cyclase superactivation, havebeen suggested to be crucial to the development of opioid tolerance[75–77].

In recent years, there has been an increased focus on pain manage-ment which has resulted in a societal escalation in opioid use, with opi-oids being currently among themost commonly prescribedmedicationsin developed nations [78]. Despite this, the suitability of opioids forchronic non-cancer pain treatment is under debate. The efficacy ofopioids in this clinical situation has only been reported in short-termtrials, and evidence for their overall benefit in long-term therapy islacking [79].

The analgesic properties of opioids beginwith their binding to opioidreceptors in the central nervous system (CNS). There are three opioidreceptor subtypes, mu (μ), kappa (κ) and delta (δ), which differ intheir function and specificity for the drugs they bind. Opioids them-selves can be classified, based on their interactionswith these receptors,as agonists, mixed agonists–antagonists and antagonists. The binding ofopioids to their G-protein coupled receptors produces signals causinghyperpolarization of neuronal cell membranes and the suppression ofneurotransmitter release, resulting in analgesia [78,80,81].

Table 1Properties of NSAIDs and acetaminophen used in the management of chronic pain⁎.

Drug# Common route ofadministration

Protein binding Bioavailability# Route of elimination Vd

L/kgt½(h)

Acetylsalicylic acid(aspirin ®) [164]

Oral 99% 80%–100% Renal 0.1–0.2 2–3(low doses)

Ibuprofen [165] Oral 99% 49%–73% Renal 0.14 0.9–2.5

Indomethacin [166] Oral 98% ~100 %(oral),80% to 90% (rectal)

RenalFecal

0.4–1.2 5–10

Acetaminophen [167] Oral 20% ~100% Renal 0.25 1–4

Celecoxib [168] Oral 97% unknown Renal 5.7–7.0 11–16

# All chemical formulas and bioavailability are from their respective pages in Wikipedia.⁎ [169].

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Issues with opioidsThe increased use of opioids for pain management has led to an ex-

pansion in opioidmisuse, resulting in an increased number of emergen-cy room visits related to drug-seeking behavior aswell as in the numberof opioid-related overdose deaths [82,83]. Although opioids are amongthe most commonly used analgesics, their clinical use is limited by thedevelopment of tolerance and physical dependence. Another growingconcern relates to the diversion of opioids from patients to otherindividuals not under medical supervision.

Opioids have several well-known side effects, including nausea, seda-tion and bowel dysfunction [84]. Themost serious potential adverse effectis respiratory depression and failure, which is the most common cause ofdeath related to opioid use [80]. Prolonged use leads to tolerance,resulting in higher dose requirements, which can lead to physical depen-dence, demonstrated by withdrawal symptoms in patients experiencingchills, muscle aches, vomiting, diarrhea, hyperthermia, anxiety and hostil-ity [80]. Additionally, opioid use can result in feelings of euphoria whichcan promote compulsive use leading to psychological dependence.

A detailedmedical assessment is recommended prior to prescriptionof opioids. This should include a detailed medical history, review ofmedical records, urine toxicology screen and psychological evaluation,including questionnaires aimed at determining an individual’s risk forabuse [84,85]. This is of particular importance in those populations athigher risk for opioid misuse. Chronic pain frequently occurs in individ-uals with psychological conditions, including anxiety and depression; itis estimated that 30%–60% of individuals with depression also experi-ence chronic pain [86]. Psychological conditions are often comorbid inindividuals with substance-abuse disorders, resulting in a high riskfor opioid abuse in many chronic pain patients including those withsubstance abuse issues and mental health disorders [85].

Newer opioid formulations have been designed in efforts to preventabuse. These include Embeda™, an extended-release morphine co-formulated with the opioid antagonist naltrexone, produced by Pfizer;and an extended-release form of oxycodone, called OxyNeo™, byPurdue Pharma [84]. OxyNeo™ contains polyethylene oxide, whichforms a viscous gel when in contact with water, rendering it unsuitablefor injection or snorting, and also more difficult to chew or crush [87].Buprenorphine, a semi-synthetic opioid was approved by the FDAin 2002. Sublingual preparations, used in addiction medicine, areco-formulated with the antagonist naloxone to prevent abuse.

Specific opioids used in pain managementOpioids can be classified as either weak or strong, depending on their

“analgesic ceiling”. This term is defined as the dose above which a drughas no further effect on pain [88].Weakopioids include tramadol, codeineand hydrocodone; strong opioids include morphine, methadone,buprenorphine, fentanyl, oxycodone, hydromorphone, oxymorphone,meperidine and levorphanol. Detailed pharmacokinetic information foreach of these drugs can be found in Table 2.

Weak opioids

Codeine

Codeine is considered a weak opioid, and is used for its analgesic,anti-tussive and anti-diarrheal properties. It is a pro-drug which re-quires biotransformation via hepatic CYP2D6 to the active metabolitemorphine [89]. Approximately 5%–10% of codeine is converted to mor-phine in the liver, while the remainder is either conjugated, forming

Table 2Properties of opioid medications commonly used in the management of chronic pain.

Drug# Common route ofadministration⁎

Protein binding Bioavailability# Route of elimination Vd⁎⁎

L/kgt½⁎⁎

(h)CYP

Buprenorphine [170,171] TD, B, IV 96% 31%(sublingual)

Renalbiliary

2–3 (IV)⁎

19 (B)26 (TD)

2–4 (parental)18–49 (sublingual)

3A4

Codeine [89] Oral b1% ~90%(oral)

Renal 2.5–3.5 1.2–3.9 3A4, 2D6

Fentanyl [89,172] TD, oral 79% 92% (transdermal)89% (intranasal)50% (buccal)33% (ingestion)

Renal 3–8 3–12 3A4

Hydro Hydrocodone codone [89,90] Oral 20%–50% ??????? Renal 3.3–4.7 3.4–8.8 2D6, 3A4

Hydromorphone [89,173] Oral, IV 19% 30%–35%, (Oral)52%–58%(intranasal)

Renal 2–4 3–9 glucuronidation

Levorphanol [89,120] IV, oral 40% 70% (oral); 100% (IV) Renal 10–13 11–16 glucuronidation

Methadone [108,109] Oral 87% 41%–99%(oral)

Renal 4–7 15–55 3A4 N 2B6 N 2D6

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Morphine [89,98] IV, IM, oral 35% 20%–40%(oral),36%–71% (rectally), 100%(IV/IM)

Renal (90%)Biliary (10%)

2–5 1.3–6.7 Glucuronidation (major)2D6 (minor)

Meperidine (Pethidine) [174,175] Oral, IV, IM 45%–64% 50%–60% (Oral),80%–90%(Oral, in cases of hepatic impairment)

hepatic 3.7–4.2 2–5 2B6, 3A4 & 2C19(minor)

Oxycodone [114] Oral 45% 60%–87% Renal 1.8–3.7 3–6 2D6

Oxymorphone [115] Oral 10–12% 10%(oral),40% (Intranasal), 100%(IV, IM)

Renalfecal

2.4 4–12 glucuronidation

Remifentanyl i.v 70% (bound to plasma proteins) Not applicableGiven iv

- - 1–20 min Nonspecific esterases

Tramadol [89,95] Oral 15–20% 70%–75%(oral),77%(rectal),100% (IM)

Renal 2.6–2.9 4.3–6.7 2D6 N 2B6, 3A4

# All chemical formulas and bioavailability are from their respective pages in Wikipedia.⁎ depends on formulation; 2–3 h for immediate release, 5 h for continuous release; TD transdermal; B buccal; IV intra venous.⁎⁎ [169].

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codeine-6-glucuronide (active), or methylated via CYP3A4, producingnorcodeine (inactive) [89].

Hydrocodone

This is a semi-synthetic drug, similar to codeine in structure and tomorphine in its effects [89]. Hydrocodone is metabolized by CYP2D6to active hydromorphone, which binds to the μ-opioid receptor, andby CYP3A4 to the inactive metabolite norhydrocodone [90].

Tramadol

Tramadol is a synthetic codeine analog that binds to the μ-opioidreceptor and inhibits the reuptake of serotonin and norepinephrine[89]. Tramadol has a lower risk of addiction than other opioids; howev-er, it is associated with two significant adverse drug reactions: seizureand serotonin syndrome [91]. Tramadol seizures usually occur in pa-tients already taking anticonvulsant medications. Serotonin syndromeis characterized by neuromuscular and autonomic hyperactivity aswell as altered mental status, due to excess serotonin activity in theCNS. Higher risk of this syndrome is associated with tramadol overdoseor co-administration of antidepressant medications, such as tricyclicantidepressants and selective serotonin reuptake inhibitors (SSRIs),which, in addition to tramadol, inhibit serotonin reuptake, leading tohigh serotonin levels in the synaptic space[92,93].

Tramadol is metabolized by CYP2D6 in the liver to its main metabo-lite, O-desmethyl-tramadol which shows a higher affinity for opioid re-ceptors than the parent drug [94]. Metabolism to the minor metabolite,N-desmethyl-tramadol occurs via CYP2B6 and CYP3A4 [95].

Strong opioids

Morphine

Morphine increases the threshold for pain perception by bindingstrongly to the μ-opioid receptor; it also has activity towards κ- andδ-opioid receptors. Morphine administered orally undergoes a largefirst-pass effect, resulting in oral bioavailability of 38% on average [96].The major morphine metabolites result from glucuronidation bythe hepatic isoenzyme UGT2B7 to inactive morphine-3-glucuronide(approximately 60%) and active morphine-6-glucuronide (up to 10%)[97]. CYP2D6 plays a minor role in morphine metabolism. Side effectsof morphine include sedation, nausea, a feeling of warmth, urinaryretention, euphoria, reduced ability to concentrate and constipation.The most serious side effect of morphine is potentially fatal respiratorydepression with morphine toxicity [89,98].

Hydromorphone

Hydromorphone, a hydrogenated ketone of morphine, is a syntheticopioid with effects similar to morphine [89]. When given orally,hydromorphone is rapidly absorbed by the GI tract and undergoesextensive first-pass metabolism in the liver. Like morphine, it isglucuronidated in the liver to hydromorphone-3-glucuronide andhydromorphone-6-glucuronide; hydromorphone-3-glucuronide hasno analgesic properties, but has been shown to exhibit neuroexcitatoryeffects [99]. Hydromorphone suppresses the cough reflex, similar toother opioids. Side effects of hydromorphone are dose-related and caninclude mood changes, euphoria, nausea, vomiting, and hypotension,as well as respiratory depression in large doses [89].

Fentanyl

Fentanyl is a highly lipophilic, synthetic opioid which is 100 timesmore potent than morphine. Its potency is due to its efficiency in cross-ing the blood brain barrier, rapidly gaining access to the central nervous

system [89,100,101]. Given intravenously, fentanyl has a very rapidonset but short duration of action, and is thus administered as a contin-uous infusion. In managing pain, fentanyl is most often providedthrough transdermal patches or buccal tablets [89]. This allows thedrug to distribute throughout fatty tissues, leading to slower releaseand prolonged effects. Fentanyl undergoes extensive pulmonaryfirst-pass metabolism as well as hepatic metabolism to the inactivemetabolite norfentanyl via CYP3A4 [89].

Remifentanil

Remifentanil is a μ-opioid receptor agonistwith an analgesic potencysimilar to that of fentanyl. It was studied for analgesic efficacy correlat-ing with expression of the serotonin transporter (5-HTT), as serotonincan influence the antinociceptive effects of opioids at the spinal cord.Remifentanil has a significantly better analgesic effect in individualswith a genotype coding for low 5-HTT expression (SA/SA and SA/LG)compared to those with high expression (LA/LA) [102]. It is predomi-nantly metabolized by non-specific esterases [103], and because of itsrapid systemic elimination and ultra-short half-file, it has a pharmacoki-netic advantage in clinical situations requiring predictable terminationof effect such as analgesia during labor [104]. In a systematic review,Leong and colleagues compared remifentanil with meperidine forlabor analgesia. They found remifentanil to be superior in reducingmean visual analog scale pain scores for labor pain after 1 h [105].Remifentanil crosses the placenta, but is rapidly metabolized andredistributed. Although maternal sedation and respiratory changes dooccur, they are without adverse neonatal or maternal effects [106].

Methadone

Methadone is a synthetic opioidwithmorphine-like effects. It is com-monly used in the treatment of opioid addiction, but also in the treat-ment of chronic pain [89,107,108]. Given orally, methadone has amuch higher bioavailability compared with oral morphine (70%–90%,compared to 38%, respectively). Due to its relatively slow metabolismand high lipid solubility, methadone also has a long half-life (between8 and 60 h), leading to longer term analgesia than with morphine [107,108]. Methadone is extensively metabolized by CYP3A4, and to a lesserextent by CYP1A2, -2D6, -2D8, -2C9/2C8, -2C19, and -2B6, to its inactivemetabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)[107–110]. Caution must be exercised when co-prescribing methadonewith QT-prolonging cardiac drugs due to methadone’s ability to interactwith voltage-gated potassium channels in the myocardium, also leadingto QT prolongation [111] and ventricular arrhythmias such as Torsadesde Pointes. Significant drug–drug interactions have been reported formethadone, when combined, for example, with fluoxetine, quetiapine,or promethazine [110].

Buprenorphine

As an alternative to methadone, buprenorphine can be used for thetreatment of opioid addiction [89]. It has also been approved forthe treatment of moderate to severe pain [112]. Similarly to morphine,buprenorphine must be used with caution in the setting of co-administration of other QT-prolonging medications or in individualswith hyperkalemia [112]. Buprenorphine has a ceiling effect withrespect to respiratory depression, thereby reducing the likelihood ofthis potentially fatal consequence, making it an attractive choice for an-algesia [113]. Given orally, buprenorphine undergoes extensive first-pass metabolism and is therefore usually administered by transdermalor buccal routes to improve bioavailability [112]. Prolonged analgesiacan be achieved with buprenorphine due to its lipophilic propertiesand its slow dissociation from opioid receptors. Buprenorphine ismetabolized by CYP3A4 in the liver primarily to nor-buprenorphine.

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Oxycodone

Oxycodone is a synthetic opioid, similar in structure to codeine andprescribed for moderate to severe pain [89]. This drug is commonlycompounded with other drugs, such as acetaminophen or ibuprofen[89]. Side effects of oxycodone treatment include euphoria, sedation,constipation, cough suppression and respiratory depression. The eupho-ria caused by oxycodone is quite pronounced and can therefore lead toabuse of and dependence on the drug. Oxycodone is metabolized, via

Table 3Antidepressants commonly used in pain management.

Drug# Common route ofadministration

Protein binding Bioavailability#

Amitriptyline [176] Oral N 90% 30%–60%due to first pas

Bupropion [177] Oral 85% ??????

Citalopram [178] Oral 50% 80%

Desipramine [179] Oral 70%–90% 73%–92%

Duloxetine [180] Oral N90% 32% to 80%

Fluoxetine [181] Oral 94% 72%

Venlafaxine [182] Oral 27% 42% ± 15%

# All chemical formulas and bioavailability data are from their respective pages in Wikipedi⁎ [169].

CYP2D6, to the potent metabolite oxymorphone (see below) as wellas noroxycodone, a weakly active metabolite [114].

Oxymorphone

Oxymorphone offers excellent analgesia, comparable to that ofmorphine, but with less sedative effects [115]. This results from thelipophilic nature of oxymorphone, allowing ease of access to the cen-tral nervous system. Oxymorphone undergoes extensive hepatic

Route of elimination Vd⁎

L/kgt½⁎

(h)CYP

s metabolismRenal 6–10 8–51 2D6

RenalFecal

40 4–24 2B6

Renal 12–16 25–40 2C19, 3A4, 2D6

Renal 22–59 12–54 2D6

RenalFecal

17–26 8–17 1A2,2D6

RenalFecal

20–42 1–3 days 2D6

renal 4–12 3–7 2D6, 3A4

a.

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first-pass metabolism, and its major route of metabolism is viaglucuronidation [89,115].

Meperidine (pethidine)

Meperidine (Demerol™), also known as pethidine, is a syntheticμ-opioid receptor agonist that is structurally similar to atropine.Pharmacologically, it represents both morphine and atropine. Thisunique property of an analgesic with spasmolytic and sedative actionaccounts for its wide range of clinical applications [116]. Althoughmeperidine efficacy has been questioned [117], a survey of intrapartumanalgesia practice in United Kingdom and Norway reported that thisopioid is still commonly used during labor [118,119].

Levorphanol

Levorphanol is a synthetic opioid, similar in structure to morphine,but more potent in its analgesic effects [89,120] and also has anticholin-ergic effects [120]. This drug is usually given orally or intravenously andis eliminated through glucuronidation in the liver [120].

Other medications in the treatment of chronic pain

Antidepressants

Tricyclic antidepressants (TCAs) and selective serotonin re-uptakeinhibitors (SSRIs) are commonly used as adjuvant therapy in thetreatment of chronic pain. Themechanisms bywhich thesemedicationsalleviate pain are not fully understood, but are believed to be mediatedthrough their inhibition of neurotransmitter reuptake in the synapticcleft. These mechanisms are related to pain signaling in descendingspinal pain pathways [121]. In addition to their analgesic role, antide-pressants are commonly used in pain management because depression

Table 4Anticonvulsant drugs used in pain management.

Drug# Common route ofadministration

Protein binding Bioavailability#

Carbamazepine [183,184] Oral 75% ??????

Gabapentin [185] Oral b 3% 27%–60% (inversely

Lamotrigine [186] Oral 55% 98%

Phenytoin [187,188] Oral, IV 87%–93% 70%–100%oral,24.4%(rectal, IV)

# All chemical formulas and bioavailability data are from their respective pages in Wikipedi⁎ [169].

is often a co-morbidity of chronic pain. Patients experiencing chronicpain have been shown to have 2–5 times the risk of developing depres-sion than the general population [122].

Common TCAs used in pain management include amitriptyline andimipramine (Table 3), administered at much lower doses for painmanagement than for psychiatric indications [22]. These two drugsare metabolized to the active metabolites nortriptyline and desipra-mine, respectively, by hepatic CYP2D6 [22]. Side effects of TCAs thatcan limit their use includeweight gain, anticholinergic effects, hypoten-sion and cardiovascular effects [22,121]. TCAs have been better charac-terized for their role in painmanagement than SSRIs [121].SSRIs used inpainmanagement include fluoxetine and citalopram(Table 3). SSRIs areoften better tolerated than TCAs, due to their milder side effects; how-ever, data regarding their efficacy in the treatment of chronic painhave been inconsistent [121].

More recently, antidepressants able to target several neurotransmit-ters, such as venlafaxine (serotonin, norepinephrine, and dopamine),duloxetine (serotonin and norepinephrine) and bupropion (serotoninand dopamine) have been more widely used in pain management(Table 3). Venlafaxine has been shown to be particularly efficaciouswhen prescribed in combination with gabapentin, a GABA analogueoften used to treat neuropathic pain [123].

Anticonvulsants

Anticonvulsants (Table 4) have been used in painmanagement sincethe 1960’s when these drugs were originally introduced for the treat-ment of epileptic seizures [124]. These medications work by a varietyof mechanisms to suppress the rapid firing of neurons. Phenytoin, oneof the first anticonvulsants introduced, reduces neuronal excitabilityby blocking sodium channels. It has been used in the treatment ofchronic neuropathic pain, but today its use for this indication is limiteddue to side effects, namely, sedation and motor disturbances [125].

Route of elimination Vd⁎

L/kgt½⁎

(h)CYP

Renal 0.8–1.8 18–65 3A4

proportional to dose) Renal 0.8–1.3 5–9 Not metabolized

Renal 0.9–1.3 12–62 glucuronidation

Biliary 0.5–0.8 8–60 2C19

a.

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Carbamazepine has largely replaced phenytoin in chronic painmanagement and has been shown to be effective in the treatment ofneuropathic pain, in particular trigeminal neuralgia [124,126] (a disor-der characterized by episodes of intense facial pain, originating fromthe trigeminal nerve) [126]. Side effects of carbamazepine includedrowsiness, blurred vision, nausea and vomiting. There is a dose–effectrelationship and it can be difficult to achieve a therapeutic effect in pa-tients who are sensitive to these side effects [125]. This is of particularrelevance in elderly patients, where conditions such as cardiac diseaseand hypernatremia can further complicate adverse effects [127]; thus,close monitoring of these patients is required [124,125].

Newer anticonvulsants, such as lamotrigine and gabapentin, areshowing promise in chronic pain management; gabapentin, in particu-lar, has been shown to be well tolerated with few side effects [128].Gabapentin binds to voltage-gated calciumchannels, leading to a reduc-tion in the release of the neurotransmitters glutamate and substance P.It has demonstrated effectiveness in the treatment of diabetic neuropa-thy, post-herpetic neuralgia, trigeminal neuralgia, multiple sclerosis,migraine as well as in chronic pain caused by malignancy [128].Lamotrigine has been shown to be useful in the treatment of trigeminal

Table 5Triptans used in migraine therapy [130,132].

Drug# Common route ofadministration

Protein binding Bioav

Almotriptan[131] Oral 35% 70%

Eletriptan[131] Oral 85% 50%

Frovatriptan[131] Oral 15% 20%–

Naratriptan[131] Oral 20%–30% 74%

Rizatriptan[131] Oral 14% 45%

Sumatriptan[131] Oral 14%–21% 15%(oral)96%(s.c)

Zolmitriptan[131] Oral, nasal 25% 40% (

# All chemical formulas and bioavailability data are from their respective pages in Wikipedi⁎ MAO: monoamine oxidase.⁎⁎ [169].

neuralgia and diabetic neuropathy [124]. However, careful titration oflamotrigine dose is required because of the risk of Stevens–Johnsonsyndrome, a life-threatening dermatological condition leading to cellnecrosis, causing the epidermis to separate from the dermis [129].

Triptans

Triptans are serotonin agonists with high affinity for the 5HT1B and5HT1D receptors [130,131]. The serotonergic system is known to play arole in the pathophysiology of migraines, leading to the developmentand prescription of triptans for this condition. Binding of these drugsto 5HT receptors in the brainstem and thalamus leads to the blockadeof vasoactive peptide release from perivascular trigeminal neurons,and thus reduced cerebral vasodilation [131]. Currently, there areseven triptanmolecules available, eachwith its unique pharmacokineticand pharmacodynamic profile. The fourmost commonly prescribed andwell characterized triptans are sumatriptan, naratriptan, zolmitriptanand rizatriptan (Table 5) [132]. Triptans are not recommended for mi-graine treatment in individuals with poorly controlled hypertension,

ailability# Route of elimination Vd⁎⁎

L/kgt½⁎⁎

(h)CYP

RenalFecal

2.5–4 3–4 3A4, MAO⁎, 2D6

Renal 2.1–3.3 3–7 3A4

30% Renal 3–4.2 20–30 1A2, 2D6

Renal 2–3 5–6 Unknown CYP

Renal 1.3–2.2 1.6–3.2 MAO, 1A2

Renal 1.3–4.6 1–4 MOA

oral) RenalFecal

7.0 1.6–3.8 1A2, MAO, 3A4

a.

1182 B.M. Kapur et al. / Clinical Biochemistry 47 (2014) 1169–1187

hepatic or renal impairment or coronary artery disease, as serotonergicblockade may exacerbate these conditions [131].

Benzodiazepines

Benzodiazepines play a role in the treatment of insomnia, muscletension, and, in particular, anxiety related to chronic pain [133]. Chronicpain patients experience increased anxiety compared to the generalpopulation, and this can often worsen the subjective experience ofpain. Evidence suggests that benzodiazepines are only effective intreating acute anxiety related to chronic pain, but are not effective inthe setting of chronic anxiety [133] (for which antidepressants havebeen found to be more effective). The caveats to benzodiazepine treat-ment for chronic pain are the potential for abuse as well as side effects,including paradoxical reactions (increased hostility, psychosis andbehavioral disturbances) [133].

Cannabinoids

Cannabis is an annual plant that grows wild in regions of mild ortropical weather, and has been used to treat pain for centuries. It is byfar the most widely cultivated, trafficked and abused illicit drug; halfof all drug seizures worldwide are of cannabis. The geographical spreadof those seizures is also global, covering practically every country of theworld. Delta-9-tetrahydrocannabinol (THC) is the active componentin cannabis, responsible for its analgesic and psychoactive effects.Ingestion of THC results in feelings of euphoria, relaxation and a generalsense of well-being. However, heavy cannabis use can result in halluci-nations, anxiety and depression [134,135].

Endogenous cannabinoids, referred to as endocannabinoids, havebeen identified, as well as two endocannabinoid receptors, the G-protein coupled receptors CB1 and CB2. High levels of CB1 are expressedin the brain and spinal cord, particularly in areas known to be involvedin nociception. CB2 is not as well characterized, but has been shown tohave lower expression levels in the brain than CB1. Endocannabinoidsare bioactive lipids which regulate neural activity by binding to CB1and CB2, causing inhibition of neurotransmitter release. Endogenousand exogenous cannabinoid activity results in anti-nociceptive effectsas well as short-term memory impairment, stimulation of appetiteand antiemetic effects [134–136].

THC acts synergistically with other analgesic agents, such asmorphine and some NSAIDs, though the mechanism for the synergisticaction between morphine and THC is unknown [134]. In the case ofNSAIDs, cannabinoids and prostaglandin share a similar structurewhich is believed to result in a convergence of signals. Activity of CB1 re-ceptors is increased by NSAIDs including ibuprofen and indomethacin.Furthermore, CB1 receptor antagonists block the analgesic effects ofibuprofen [134].

Evidence for the use of cannabinoids in pain management is lackingdue to the small number of clinical trials in this area. The best evidencefor cannabinoid use in chronic pain comes fromHIVandmultiple sclerosisstudies inwhich cannabinoidswere used to treat the chronic neuropathicpain associated with these conditions [136]. Smoking cannabis 3–5 timesper week was shown to be effective in alleviating neuropathic painassociated with HIV as well as AIDS-related anorexia [137,138]. Severalstudies demonstrated benefit of oral treatment with synthetic THC forcentral pain and spasticity associated with multiple sclerosis [139–142].

There are several issues associated with the use of cannabinoids inpainmanagement. Firstly, themethod of drug delivery poses a problem.Smoking of cannabis is the easiest delivery route and allows for ade-quate control of dose [135,136]. However, the adverse effects ofsmoking are well known, with THC contents varying depending onwhere and how the cannabis plants are grown. Canada, which allowsprescription of cannabis for chronic pain therapy, requires that patientsobtain their medicinal cannabis from a centralized source so that theTHC content may be monitored over time [136]. Similar strategies are

now under consideration in different parts of the world including theUnited States. Synthetic cannabinoids, such as dronabinol and nabilone,are available in the U.S. and Canada for use as antiemetics during cancerchemotherapy, and as adjunct therapies for neuropathic and chronicpain. They are not yet widely used, and are under further study to delin-eate their efficacy and pharmacological parameters in various clinicalcontexts [143]. Side effects include increased heart rate, blood pressurechanges, anxiety, psychomotor retardation, impaired memory and psy-chosis. Cannabinoids are contraindicated in pregnancy, uncontrolledhypertension, active ischemic heart disease, arrhythmias and schizo-phrenia. Clark and co-workers suggest guidelines for the use of thesecannabinoid compounds [144].

Cannabis and cannabinoids have a potential for dependence, whichcan lead to preoccupation and compulsion. Prescription of cannabinoidsfor chronic pain management requires clinician to appropriately selectpatient and adequately monitor to avoid the development of depen-dence [134,136]. Recently, Donoghue and colleagues report the interac-tion effect of cannabis use on gender and age of onset of schizophreniaand schizoaffective disorder. They show that use of cannabis is associat-ed with an earlier age of onset of schizophrenia. There is a significantinteraction between gender and cannabis use whereby the genderdifference in age of onset is diminished in cannabis users [145].

Ziconotide

Ziconotide is a synthetic conopeptide that selectively inhibits N-typevoltage-gated calcium channels, reducing the release of pain-modulating neurotransmitters. Conopeptides are derived from thevenom of predatory cone snails, and ziconotide is specifically derivedfrom the venom of a Pacific fish-hunting snail, Conus magus [146].

Ziconotide has been approved for intrathecal administration bycontinuous infusion for the treatment of severe chronic pain in situa-tions where patients are not responding to conventional therapies[147]. Evidence indicates that this drug is useful in the treatment ofboth neuropathic and non-neuropathic pain. Intrathecal administrationis required because, given intravenously, ziconotide demonstrates poorpenetration of the blood brain barrier and results in sympatholyticeffects leading to orthostatic hypotension [147]; oral preparations arenot available. Ziconotide is highly hydrophilic and is thought to moveslowly through the CSF to its target receptor, leading to a lag time toanalgesia upon administration. The efficacy of ziconotide shows awide inter-individual variation [147,148].

The most common side effects of ziconotide include dizziness,confusion, ataxia, memory impairment and hallucinations. However,there is also large inter-individual variation in the experience of side ef-fects [147]. Toxicity appears to be related to the rate of infusion and isreversible after discontinuation, but, because of low tissue diffusion,the effects can persist for several weeks [147,148]. Data regardingziconotidemetabolism are sparse. The drug is not believed to bemetab-olized in the CSF but rather cleared by transport into the systemiccirculation where it is degraded by serum proteases [147].

Novel therapies in pain management

Targeting epigenetic modifications

Epigenetics refers to functionally relevant genomic changes not in-volving alterations in nucleotide sequence, in response to developmen-tal or environmental cues. Epigenetic mechanisms are manifestedthrough dynamic, reversible chemical modifications in the genomeand are involved in differential gene expression throughout life[149]. The most well characterized epigenetic modifications are DNAmethylation and histone acetylation.

DNAmethylation is regulated by DNAmethyltransferases,while his-tone modifications are largely regulated by histone deacetylases(HDAC) [149]. Abnormal DNA methylation [150] and histone

1183B.M. Kapur et al. / Clinical Biochemistry 47 (2014) 1169–1187

acetylation [151,152] have been demonstrated to occur in pain states. Ithas also been proposed that primary injuriesmay result in lasting epige-netic marks leading to an increased risk of chronic pain [149], whichmay even persist trans-generationally. Drugs aimed at targeting the en-zymes responsible for epigenetic modifications are under developmentand in some cases have been approved by the FDA. While these drugshave been developed largely for the purpose of cancer treatment, theyare also believed to have potential in painmanagement. In animal injurymodels, rat hind-paw injection of Freund’s complete adjuvant (CFA)followed by intrathecal injection of zebularine, a DNA methyltransfer-ase inhibitor, was shown to reduce pain sensitivity [153]. In a similarrat model, pre-injection treatment with HDAC inhibitors was reportedto delay CFA-induced thermal hyperalgesia whereas post-injectiontreatment was shown to reduce the intensity of CFA-induced thermalhyperalgesia [154]. In human patients with type 2 diabetes, treatmentwith valproic acid, which is a known to act as a strong the HDAC inhib-itor, conferred improved pain sensitivity scores after treatmentcompared to before treatment [155].

Gene therapy

Gene therapy involves the use of viral vectors where the viral ge-nome is replaced with nucleic acid sequences encoding a promoter todrive gene expression as well as a transgene of interest [156]. For painmanagement therapies, the transgene encodes for an analgesic agent.Gene therapy based approaches have several advantages in painmanagement. In contrast to pharmacotherapies, gene therapy allowsfor persistent expression of a protein-based analgesic agent at the siteof action. These methods avoid the first-pass effect and can improvebioavailability [156]. Gene therapy can also reduce side effects associat-ed with systemic drug use. There are limitations to these approaches,including inadequate transgene expression and the evocation ofimmune responses against the viral vectors [156]. Nevertheless, newparadigms using non-viral insertion of therapeutic transgenes areunder way to bypass some of these limitations.

In a recent study, terminal cancer patients were given different genedoses of human PENK, encoding preproenkephalin, the protein precur-sor that is processed to 6-met-enkephalin and 1-leu-enkaphalin, endog-enous opioid peptide ligands for the delta opioid receptor [157].Patients in the two highest virus dose groups reported decreases in nu-meric rating scale (NRS) pain scores of up to 50% from before treatment.Patients in the higher dose groups reported substantial reductions inpain compared to patients in the lowest dose group. This study demon-strates proof-of-concept for gene therapy in pain management.

0500100015002000250030003500400045005000

EDD

P n

g/m

L

date of

Pt X

EDDP

UEW

Fig. 4. EDDP urine excretion window at steady state. Legend: *UEW urinary excretion win(EDDP) excretion window.

Therapeutic drug monitoring in pain management

In pain management, the rationale for drug monitoring has largelyfocused on monitoring patient adherence, detecting diversion, anddetecting the presence of illicit, non-prescription drugs. Traditionally,drug monitoring in pain management patients has been in the form ofurine drug testing.

Urine drug testing has been demonstrated to reduce illicit druguse and has been widely used in monitoring patients in treatmentfor drug addiction [158,159]. However, most urine methodologieshave been adapted from occupational deterrent-based testing forillicit drug use and have not been optimized for use in the painmanagement setting [160]. Given the chronicity of treatment drugadministration, and the wide range of drug half-lives (Tables 1–5)a “positive” urine result is to be expected if a patient is adherent intaking his/her medication. A “negative” urine results suggests non-compliance with the treatment protocol or urine sample tampering.To be used effectively in monitoring pain management patients,urine drug testing requires understanding of the principles of drugpharmacokinetics and pharmacodynamics, and an understandingof the type of information urine drug testing can provide alongwith an appreciation of the limitations of such testing [161].

Urine drug concentrations are often calculated relative to urinecreatinine concentrations in order to correct for in vivo dilution, whichcan vary through time, depending on an individual’s fluid intake.However, these calculations assume stable renal function and creatinineproduction, an assumption which can lead to errors if unjustified. Painmedications are usually prescribed to be taken in a chronic manner sothat steady state plasma concentrations and therapeutic pharmacody-namic effects can be achieved. Steady state drug concentrations inserum imply that the urine excretion window (UEW) of the drug/me-tabolite is also at “steady state” in patients with stable renal function.Fig. 4 shows the concentration of methadone metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in a patient receivingmethadone chronically. This figure clearly shows that urine creatininecorrection does not add value to the EDDP adherence monitoring.Here, patient non-adherence can be detected when the urine EDDPconcentration falls outside the UEW [162]. Extremely low creatinineconcentrations are indicative of potential adulteration and can be usefulin detecting specimens that have been tampered with [161]. Unfortu-nately, urine drug testing is not effective in estimating serum drugconcentrations or assessing drug efficacy.

In light of the limitations associated with urine drug testing, moni-toring of pain management patients through serum or plasma drugmeasurements has been advocated. Therapeutic drug monitoring

0.00

10.00

20.00

30.00

40.00

50.00

60.00

pHan

dU

Cr

analysis

Y

Creatinine PH

problem samples

dow. The green lines represent the 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine

1184 B.M. Kapur et al. / Clinical Biochemistry 47 (2014) 1169–1187

(TDM) involves the measurement of serum or plasma drug levels attimed intervals to determine whether steady state drug concentrationsare within the therapeutic or expected range given the drug dosage[163]. TDM can be used by clinicians to explain drug toxicity or lack ofefficacy, and can aid in adjusting drug doses or in choosing specificmedications [163]. A major advantage of plasma drug measurement isthat it integrates many factors affecting drug metabolism, as outlined inFig. 2. Half-lifemeasurement can be a functionalmarker of the cumulativeeffect of pathophysiological and drug–drug interactions and provide anoverall picture of the specific drug disposition and pharmacodynamicsin the individual patient. However, TDM requires the collection of serialblood samples from patients, which can be difficult and inconvenient[160,163]. Timing of sample collection also becomes an important consid-eration, depending on whether peak or trough measurements (or both)are to be monitored. The time window within which a particular drugor its metabolite can be detected in serum is an important considerationfor sample collection. To assist in appropriate clinical interpretation,knowledge of tolerance and pharmacokinetics of particular drug(s)under investigation is essential.

Summary and conclusions

The experience of chronic pain is one of the commonest reasons in-dividuals seek medical attention, making the management of chronicpain a major issue in clinical practice. Left untreated, chronic pain canlead to diminished quality of life and socioeconomic difficulties.

Opioids continue to be the mainstay of chronic pain management.However, opioid use can lead to abuse, diversion and physical depen-dence, meaning that opioidsmay not be suitable for all patients. An indi-vidual’s risk for abuse should be considered, by way of a detailed history,before opioids are prescribed. Several non-opioid based therapies arenowpotentially available for these patients, such as triptans, ziconotides,as well as novel therapies, such as treatment with cannabinoids and, inthe not-so-distant future, gene therapy or epigenetic-based approaches.Adjuvant therapies with antidepressants, benzodiazepines or anticon-vulsants can also be useful in managing pain, particularly in the treat-ment of anxiety and depression, which are commonly associated withchronic pain.

Genetic variability can have profound effects on drug metabolismand contribute to the inter-individual diversity in responses to painmedications. However, there is a paucity of evidence for the benefitsof pharmacogenetic testing in the context of pain management. Drugmetabolism and responses are affected by many factors, includingpharmacogenetics, with genetics offering only a partial explanation ofan individual’s response.

At this point in time, therapeutic drug monitoring, through plasmadrug measurements, may be more useful than pharmacogenetics inpreventing adverse drug reactions to pain medications, while ensuringeffective analgesia. Definitive, mass spectrometry based methods,capable of measuring parent drug and metabolite levels, are the mostuseful assays for this purpose. Drug half-life can be a functional markerof the cumulative effect of drug–drug interactions as well as pathophys-iological interactions that may affect the treatment drug’s disposition.Currently, monitoring of pain management patients, if performed atall, is largely through urine drug measurements, which do not correlatewith serum drug concentrations therefore limiting their use inmonitor-ing efficacy and toxicity. Direct determination of serum or plasma druglevels may provide a more clinically useful, if logistically more difficult,avenue for optimization of drug therapy, particularly in the context ofchronic pain management.

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