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Pharmacogenetics of Chronic Pain Management.

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Clinical Biochemistry xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Clinical Biochemistry
journal homepage: www.elsevier.com/locate/clinbiochem

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, Canada
b
Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children University of Toronto, Canada
c
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Objective: The experience of chronic pain is one of the commonest reasons individuals seek medical atten-
Received 8 March 2014 tion, making the management of chronic pain a major issue in clinical practice. Drug metabolism and responses
Received in revised form 25 May 2014 are affected by many factors, with genetic variations offering only a partial explanation of an individual’s response.
Accepted 27 May 2014 There is a paucity of evidence for the benefits of pharmacogenetic testing in the context of pain management.
Available online xxxx
Design and methods: We reviewed the literature between 2000 and 2013, and references cited therein, using
various keywords related to pain management, pharmacology and pharmacogenetics.
Keywords:
Chronic pain
Results: Opioids continue to be the mainstay of chronic pain management. Several non-opioid based therapies,
Pain management such as treatment with cannabinoids, gene therapy and epigenetic-based approaches are now available for these
Pharmacokinetics patients. Adjuvant therapies with antidepressants, benzodiazepines or anticonvulsants can also be useful in man-
Pharmacogenetics aging pain. Currently, laboratory monitoring of pain management patients, if performed, is largely through urine
Opioids drug measurements.
NSAIDs Conclusions: Drug half-life calculations can be used as functional markers of the cumulative effect of pharma-
Triptans cogenetics and drug–drug interactions. Assessment of half-life and therapeutic effects may be more 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 the
most useful assays for this purpose. Urine drug measurements do not necessarily correlate with serum drug
concentrations 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Chronic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Pharmacogenetics and pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Cytochrome P450 enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
P-glycoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Cyclooxygenases 1 and 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Opioid receptor μ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Catechol-O-methyltransferase (COMT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Clinical use of pharmacogenetics in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Genetics and pain susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Chronic pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Drugs used in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
NSAIDs and acetaminophen in pain management (Table 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Opioids and pain management (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Issues with opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Specific opioids used in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

⁎ Corresponding author at: Department of Clinical Pathology, Sunnybrook Health Science Centre, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada. Fax: +1 905 849 4389.
E-mail address: b.kapur@utoronto.ca (B.M. Kapur).

http://dx.doi.org/10.1016/j.clinbiochem.2014.05.065
0009-9120/© 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/).

Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
2 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx

Weak opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Codeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Hydrocodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Tramadol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Strong opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Hydromorphone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Fentanyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Remifentanil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Methadone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Buprenorphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Oxycodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Oxymorphone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Meperidine (pethidine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Levorphanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Other medications in the treatment of chronic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Triptans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Ziconotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Novel therapies in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Targeting epigenetic modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Gene therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Therapeutic drug monitoring in pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Introduction choice. In addition, novel therapies, including targeting of epigenetic

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 in
terms of such damage”. Several different subtypes of pain can be de-
scribed, based on their neuropsychological basis and duration, including
neuropathic, nociceptive, psychogenic, referred, phantom, acute and
chronic [1]. Chronic pain is very common, with one in three Americans
and one in five Canadians reported to suffer from this problem [2,3]. It
is one of the most frequent reasons for individuals to seek medical
care. If untreated, chronic pain can lead to physical and social dysfunction
and diminished quality of life.
Successful pain management provides adequate analgesia without
excessive adverse effects. Current pain management strategies largely
employ the use of the World Health Organization (WHO) pain ladder,
beginning with non-opioid medications, such as NSAIDs, progressing
to weak opioids, and culminating with strong opioids, particularly in
cancer pain [4]. The WHO also recommends adjuvant therapy with an-
tidepressant medications to aid in reducing anxiety often associated
with chronic pain [4].
Management of pain can be complicated by lack of adherence, the
potential for abuse or dependence on the medications used and adverse
drug side effects. Many factors can influence drug disposition, including
genetic variation, which can further complicate management of these
patients.
Genetic studies have identified several loci in which polymorphic
changes can influence the pharmacodynamics and kinetics of analgesic
drugs. Current patient monitoring in pain management (if performed at
all) is largely based on urine drug measurements. However, therapeutic
drug monitoring (TDM) via plasma drug levels and half-life may prove
more useful in monitoring patients prescribed pain medications to
ensure efficacy while minimizing adverse drug reactions. TDM can
also be very useful for the identification of drug-related side effects
and 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
changes and gene therapy-based approaches are further broadening
future options for the treatment of chronic pain.
Methods
We conducted an online systematic search for papers and related
abstracts published between 2000 and 2013 using the National Library
of Medicine database, PubMed. Using the following headings: “pain
management medications”, “pain management drugs”, “chronic pain
management”, “pharmacogenetics and pain management”, and “drug
monitoring 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 cited
therein, including original publications, were also selected for further
review.
Pain
Pain is the most common presenting physical symptom in primary
care, accounting for an enormous burden of patient suffering, quality
of life, work and social disability, and health care and societal costs [5].
Pain is defined as an unpleasant sensory and emotional experience
associated with actual or potential tissue damage [1]. However, the ex-
perience of pain is highly subjective and idiosyncratic, and individuals
develop pain thresholds through experiences of injury or pathology in
early life [1].
Neuropathic pain results from actual damage to nerve fibers them-
selves in the central or peripheral nervous system [6]. This damage can
lead to nerve dysfunction, causing numbness, weakness and/or loss of
reflexes. Common descriptions accompanying neuropathic pain include
“burning”, “shooting” or “shock-like” sensations [7]. The most common
causes of chronic neuropathic pain include diabetic neuropathy, post-
herpetic neuralgia, fibromyalgia, lower back pain (radiculopathy due
to disc herniation) and osteoarthritis [8].
Nociceptive pain is caused by stimulation of specialized sensory
neurons, called nociceptors, by noxious stimuli including extremes of

Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx
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 of
nociceptors 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 by
mental or emotional factors with no evident physical tissue damage
[10]. Referred pain is perceived at a site adjacent to or distant from the
site of painful stimulus; the mechanism for this process is not yet well
understood [11]. Phantom pain, a sub-type of referred pain, is the feeling
of painful sensations from a part of the body which has been lost, and
from which the brain no longer receives signals. Individuals who have
undergone limb amputation often experience phantom pain [12].
Acute and chronic are terms commonly used to describe the duration
of painful sensations, but are difficult to categorically define. In general,
acute pain resolves within weeks of the initial causative insult, whereas
chronic pain is continuous, long-term pain which can last months or
years [13].
Chronic pain
The IASP defines chronic pain as that pain which persists past the
normal time of healing following an injury. However, since determining
the end of the healing phase is problematic, most clinical definitions use
a fixed time of persistent pain after initial onset. This demarcation be-
tween acute and chronic pain is somewhat arbitrary, and typically
ranges from three months (e.g., for post-herpetic neuralgia) to six
months (e.g., for chronic low back pain) [14,15]. The treatment of chron-
ic pain can be difficult because it is a complex condition influenced by
genetic makeup as well as physiological and psychological factors.
Chronic pain is a problem in many societies, with prevalence ranging
from 2% to 40% in the adult population, resulting in social and economic
impacts [16–18]. Chronic pain can interfere with an individual’s activi-
ties of daily living, leading to work or school absenteeism, inability to
participate in leisure activities, sleep disturbances and problems eating.
In the United States, one in three Americans experiences chronic pain
and chronic pain is the most common reason for people to visit their
family doctor [3]; one in five Canadians is reported to suffer from
chronic pain [2]. It is therefore important that chronic pain be diagnosed
accurately and treated effectively. Recently, an increased focus on pain
management has led to a six-fold increase in the sales of prescription
opioids in the U.S. between 1997 and 2006 [19]. Use of analgesics has in-
creased from 7.2% of the U.S. population in 1988–1994 to 10.2% during
the period 2007–2010 [20].
Pharmacogenetics and pain management
Pharmacogenetics refers to the way in which genetic differences
between individuals influence patient drug responses and drug disposi-
tion [21]. Empirically, it is well understood that large inter-individual
variations exist with respect to the response to analgesics [22].With
conventional drug dosing, some patients will experience toxicity
whereas other patients will not receive adequate analgesia from the
same 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 on
variations in drug target receptors and downstream signal transduction,
and pharmacokinetic factors, which affect drug metabolism and/or
elimination, altering the relationship between drug dose and steady
state serum drug concentrations. Development of tolerance, which
may occur through both dynamic and kinetic mechanisms, can also
play a significant role in this response variation.
Genetic variability is one factor playing a role in the way in which
drugs affect physiology. Generally, genes affecting outcome of treatment
Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
3
can be divided into two broad categories: those genes affecting pharma-
cokinetics, and those affecting pharmacodynamics [22]. In the case of
pain management drugs, genes associated with altered pharmacokinet-
ics include those which encode members of the cytochrome P450 family
of enzymes, enzymes responsible for glucuronidation and drug trans-
porter proteins [21,22]. Genes encoding cyclooxygenase enzymes, the
opioid 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 pharmacogenetic
studies of candidate genes in both the kinetic and dynamic domains [26].
Cytochrome P450 enzymes
The cytochrome P450 (CYP) enzymes comprise a category of
proteins whose biosynthesis is controlled by a large super-family of
genes. Members of the CYP family play important roles in drug metab-
olism and therefore influence the concentration of a drug present in
circulation. The primary catalytic function of CYP enzymes is identified
as the transfer of one oxygen atom from molecular oxygen into various
substrates. Additionally, some CYP enzymes act as isomerases, reduc-
tases, dehydrases, or nitric oxide (NO) synthases, and some can catalyse
oxidative 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 result
in alterations in enzyme activities. One CYP isoform which has been ex-
tensively studied with respect to genetic variation is CYP2D6. This en-
zyme accounts for a very small percentage (b 2%) (Fig. 1b) of all CYPs
expressed in the human body, but is responsible for the metabolism of
almost 20% of all drugs (Fig. 1a), including many drugs used in manage-
ment of pain [29]. Most of these enzymes are polymorphic [30]; more
than 80 CYP2D6 variants have been identified which, functionally, are
associated with four general phenotypes: extensive metabolizer (EM),
intermediate metabolizer (IM), poor metabolizer (PM) and ultra-rapid
metabolizer (UM) [31]. The prevalence of these phenotypes varies by
ethnicity [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, who
presented with fatigue, dyspnea, fever and cough with a bronchoalveo-
lar lavage culture revealing yeast [33]. He was treated with codeine as a
cough suppressant. However on day 4 of treatment, he deteriorated rap-
idly and became unresponsive. He was given naloxone, an opioid recep-
tor antagonist, which resulted in rapid improvement in his condition.
Several factors were 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 codeine
to (relatively inactive) norcodeine. In this case, co-treatment with
clarithromycin and voriconazole, both CYP3A4 inhibitors, resulted in
decreased conversion of codeine to norcodeine, shunting more codeine
into the CYP2D6 morphine pathway. The patient also developed acute
renal 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 a
breast-fed infant who died at 13 days of age [34]. The infant’s mother
had been prescribed codeine for episiotomy pain. Stored breast
milk was found to contain higher than expected levels of morphine
(87 ng/mL; expected 1.9–20.5 ng/mL). CYP2D6 genotyping revealed
that the infant’s mother was heterozygous for a CYP2D6 duplication,
making her an UM of codeine to morphine. The infant died from CNS
depression and this, along with the genetic results, were consistent
with opioid toxicity resulting from increased conversion of codeine to
morphine. This case prompted the FDA in the USA as well as Health
4 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx
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 in
human liver. Adapted from Yeo et al. [32].
Canada to advise physicians against the prescription of codeine to
nursing mothers [35,36].
Studies have also shown that CYP polymorphisms have an influence
on the metabolism of non-steroidal anti-inflammatory drugs (NSAIDs)
and have the potential to cause adverse drug reactions, most notably
gastrointestinal (GI) bleeding, a frequent reaction resulting in
significant patient morbidity and mortality. The risk of GI bleeding is
particularly high with higher doses of NSAIDs [37]. Many NSAIDs are
metabolized by CYP2C9, which has been shown to have two allelic var-
iants, referred to as CYP2C9*2 and CYP2C9*3 [37]. The CYP2C9 enzymes
encoded by the *2 and *3 alleles are reported to have 50% and 15% of the
activity of the wild-type enzyme, respectively, resulting in poor metab-
olism, and thus prolonged action, of NSAIDs in individuals with either of
these two alleles [38,39].
Due to their platelet-inhibiting action, NSAIDs are also responsible
for an increased risk of bleeding, particularly in patients taking the anti-
coagulant warfarin [38], since CYP2C9 is also important for warfarin
metabolism. Patients with the CYP2C9 *2 or *3 genotypes taking both
an NSAID and warfarin have been shown to have a significantly higher
risk for an elevated prothrombin time, compared to patients with the
wild-type 2C9 genotype [38].
Celecoxib is a selective COX-2 inhibitor which is metabolized by
CYP2C9. In a study of patients prescribed celecoxib for rheumatoid or
osteoarthritis, patients with the *2 or *3 genotypes showed an increased
elimination half-life compared to patients with the wild-type genotype
[40]. In a similar study, the investigators looked at patients prescribed
one of several different NSAIDs, including celecoxib, ibuprofen and
naproxen. They grouped the patients into those who experienced GI
bleeding and those who did not, and performed CYP 2C9 genotype anal-
ysis on all patients. Within the group of patients with GI bleeding, a
higher number of individuals had the *2 or *3 genotype compared to
the group not experiencing gastrointestinal bleeding [41]. The increased
risk of bleeding was believed to result from reduced CYP2C9 enzyme ac-
tivity in patients with the *2 or *3 alleles, leading to increased NSAID
concentrations [41].
P-glycoprotein
The ABCB1/MDR1 gene encodes P-glycoprotein, an efflux transporter
that influences drug transport in several tissues, particularly the
intestine, kidney and brain [42,43]. P-glycoprotein is highly expressed
in endothelial cells of the brain vasculature, and is believed to effect
the efflux of drugs across the blood brain barrier [43]. ABCB1/MDR1 is
a 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 certain
SNPs leading to decreased P-glycoprotein expression and activity.
Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
b)
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 higher
frequency of adverse drug reactions to oxycodone, presumably due to
decreased efflux and therefore higher plasma concentrations of the
drug [42]. Genetic variability of ABCB1/MDR1 has also been found to
be associated with inter-individual differences in pain relief achieved
by morphine [43]. In a study of Korean patients receiving intravenous
fentanyl, certain ABCB1/MDR1 genotypes were associated with
prolonged 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 enzymes
would be expected to cause altered pharmacodynamic responses to
NSAIDs. In a study which investigated post-surgical expression of
PTGS1 and PTGS2, in relation to SNPs in each gene, certain SNPs were
shown to be associated with altered expression of the PTGS2 transcript
[46]. The authors also reported differences in patient response to two
NSAIDs, 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 associated
with lower PTGS2 expression in individuals heterozygous (G/C) or ho-
mozygous (C/C) for the minor allele, compared to those homozygous
for the major allele (G/G) [46]. Subjects with G/G genotype also
reported lower pain intensity with rofecoxib treatment for 48 h follow-
ing surgery, compared to G/C or C/C subjects. This difference was not
demonstrated for patients treated with ibuprofen. However, subjects
with 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) benefitted more from treatment with rofecoxib, where-
as patients with decreased PTGS2 expression (G/C or C/C genotypes)
benefited more from treatment with ibuprofen [46]. These findings
are likely explained by the selectivity of rofecoxib for COX-2, encoded
by PTGS2.
Opioid receptor μ
Opioid receptor μ is the primary site of action for many endogenous
opioids, as well as those used for analgesia. A number of SNPs have been
described in OPRM1, the gene encoding this receptor. The most well
characterized SNP in OPRM1 is A118G. A study by Janicki et al. [47]
found the minor allele (G) present at lower frequency in subjects with
chronic pain treated with opioids, compared to a control group of opioid
 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx
naïve patients, suggesting that the G allele may confer protection
against pain.
Epidural opioids are commonly used to provide analgesia to women
during labor. Women heterozygous or homozygous for the OPRM1
A118G allele have been demonstrated to have higher pressure pain
thresholds than women homozygous for the more common A allele
[48]. The A → G nucleotide substitution leads to an amino acid change
from 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 of
women in labor, the median effective dose (ED50) of intrathecal fentanyl
required to achieve effective analgesia was significantly higher in
women homozygous for the A allele (26.8 μg) compared to women
heterozygous 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. Several
polymorphisms have been identified in the COMT gene; however, the
most widely studied variant is a G to A nucleotide substitution resulting
in an amino acid change from valine to methionine at codon 158
(Val158Met). This amino acid change is reported to decrease the
thermal stability of the COMT protein, resulting in reduced enzymatic
activity. In studies of cancer patients experiencing chronic pain, patients
homozygous for the more common Val 158 were found to require
higher doses of morphine to achieve analgesia, compared to patients
heterozygous or homozygous for Met 158 [50,51]. These findings
suggest 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 an
upregulation 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 increased
dopaminergic stimulation, resulting in upregulation of opioid-μ
receptor expression in the brain, making morphine more effective.
Another study demonstrated differences in morphine side effects,
such as drowsiness, confusion and hallucinations, associated with
certain COMT variants, which influenced how well patients tolerated
morphine [54].
Fig. 2. Genetic and non-genetic factors effecting drug metabolism. Adapted from Stamer et al. [22].
Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
5
Clinical use of pharmacogenetics in pain management
Ideally, pharmacogenetic studies aim to aid in the selection and
dosing of an optimal drug therapy for a specific patient. Choosing the
optimal 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 useful
to improve patient outcomes. However, most pharmacogenetic studies
to date have examined variability in single candidate genes, such as
CYP2D6, and associated outcomes [22]. There are limitations to this ap-
proach, as very few drugs are metabolized by a single enzyme. Genome-
wide association studies (GWAS) may possibly improve upon this limi-
tation. Furthermore, in addition to genetics, many other factors affect
drug responses, such as patient age, disease co-morbidities and, in
particular, co-medication [22,56] (Fig. 2). Genetics can only partially
explain the variability in patient responses to analgesic drugs. Patients
are very commonly prescribed several medications for multiple
co-morbidities. Some medications induce CYP enzyme activity [57], as
illustrated in the case above [33], while others inhibit activity [57],
which can lead to altered metabolism unrelated to the patient’s CYP
phenotype. 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 pain
medications. As GWAS studies continue, and panels of gene testing be-
come more widely accessible, pharmacogenetics of pain management
may yet become more clinically useful [58].
Genetics and pain susceptibility
An individual’s genetic susceptibility to chronic pain is thought to be
complex, involving multiple genes, similar to the genetics of other
chronic diseases, such as diabetes [21]. As discussed above, several can-
didate genes have been identified, with specific mutations shown to
alter pain perception profiles between individuals. Examples include:
OPRM1, the gene encoding the μ-opioid receptor; COMT, encoding
catechol-O-methyltransferase, involved in the metabolism of catechol-
amines; GCH1, encoding an enzyme involved in phenylalanine metabo-
lism and the production of dopamine; the melanocortin-1 receptor with
mutations showing sex-specific differences in pain perception; and
6 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx
members of the cytochrome P450 enzyme family, important for the
biotransformation of many drugs. Genome-wide association studies
and other types of genetic investigations will likely identify many
more genes involved in pain perception.
Chronic pain management
Successful pain management can be viewed as providing adequate
analgesia without excessive adverse effects [59]. In 1982, Rane and col-
leagues [60] proposed a pharmacological approach to treat cancer pain
with morphine. They proposed a step-wise approach that was later
adopted by the World Health Organization (WHO) in 1986 [61,62]. Al-
though this WHO stepladder approach was originally aimed at the
treatment of chronic cancer pain (Fig. 3) [61,62], it is also widely used
in the treatment of chronic non-cancer pain [63]. The WHO analgesic
ladder recommends initial treatment of pain with non-opioids, such as
NSAIDs and acetaminophen. If pain persists, treatment with a weak opi-
oid, such as codeine or tramadol is recommended, followed by a strong
opioid, such as morphine, until the patient is free of pain. At each stage
of the treatment ladder, adjuvant medications, such as antidepressants
or anticonvulsants, may also be given to aid in alleviating patient anxi-
ety; some of these adjuvant drugs may also act directly to counter
pain [4,61]. Evident from this scheme is the fact that opioids remain
the mainstay of chronic pain management and will be discussed further
below.
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 the
synthesis of prostaglandins. The inhibition of prostaglandin synthesis
results in the analgesic, anti-pyretic and anti-inflammatory properties
of these drugs, with the exception of acetaminophen, which does not
show 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. Reduced
prostaglandin levels in the gastrointestinal mucosa decrease mucus
and bicarbonate secretions, thereby reducing their protective effects
against the acidic gastric environment. In addition, NSAIDs can be di-
rectly toxic to the gastric mucosa, leading to ulceration, and potentially
fatal 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 to
liver toxicity through hepatocellular necrosis [64,65]. Additionally, aspi-
rin (acetylsalicylic acid) is associated with Reye’s syndrome, primarily
affecting children [66,67], and high doses of salicylates can cause
Fig. 3. The WHO three-step analgesic ladder. Adapted from [60,61]. Legend: The pain lad-
der shows a progressive rationale for stronger opioids. Before a new medication is
introduced, it is important to wait until the previously administered drug has reached a
“steady state” or full effect is achieved. *Adjuvants: antidepressants, anticonvulsants,
steroids.
Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
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, have
been 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 Heart
Association 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 analgesia
approach for pain. Intravenous acetaminophen was made available
over 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, intravenous
acetaminophen injection was at least as effective as morphine injection
in renal colic and oral ibuprofen after cesarean delivery. In children a
single-dose acetaminophen injection was similar to meperidine
intramuscular (IM) for pain after tonsillectomy [71]. Effects begin 5 to
10 min after IV administration, and peak effects occur in about 1 h
with an effective duration of 4 to 6 h. Table 1 provides pharmacokinetic
details of specific NSAIDs and acetaminophen, as used in pain
management.
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. Chronic
dosing can lead to pharmacological tolerance, but not to therapeutic
failure. In simple pharmacological terms, opioid-induced tolerance can
be described as a “shift to the right” in the dose–response curve; that
is, a higher dose is required over time to maintain the same level of an-
algesia. Different mechanisms have been proposed for the development
of tolerance. Säwe and colleagues [73] investigated the metabolic corre-
late to the development of tolerance to therapeutic effects by measuring
morphine, morphine-3- and morphine-6-glucuronide in plasma and
urine samples. They showed that the conjugation of morphine with glu-
curonic acid is proportional to the dose during long-term treatment
with escalating doses, suggesting that this metabolic pathway is subject
to neither auto-induction nor saturation. Both in vitro and in vivo studies
have shown that, on the cellular level, chronic opioid treatment leads to
a rapid reduction of agonist response, accompanied by internalization
of opioid receptors [74]. These early adaptive processes as well as
long-term adaptations, such as receptor downregulation, or counter-
regulatory processes such as adenylate cyclase superactivation, have
been 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 the most commonly prescribed medications
in developed nations [78]. Despite this, the suitability of opioids for
chronic non-cancer pain treatment is under debate. The efficacy of
opioids in this clinical situation has only been reported in short-term
trials, and evidence for their overall benefit in long-term therapy is
lacking [79].
The analgesic properties of opioids begin with their binding to opioid
receptors in the central nervous system (CNS). There are three opioid
receptor subtypes, mu (μ), kappa (κ) and delta (δ), which differ in
their function and specificity for the drugs they bind. Opioids them-
selves can be classified, based on their interactions with these receptors,
as agonists, mixed agonists–antagonists and antagonists. The binding of
opioids to their G-protein coupled receptors produces signals causing
hyperpolarization of neuronal cell membranes and the suppression of
neurotransmitter release, resulting in analgesia [78,80,81].
 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx 7

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

Drug# Common route of Protein binding Bioavailability# Route of elimination Vd t½

administration L/kg (h)

Acetylsalicylic acid Oral 99% 80%–100% Renal 0.1–0.2 2–3

(aspirin ®) [164] (low doses)

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

Indomethacin [166] Oral 98% ~100 %(oral), Renal 0.4–1.2 5–10

80% to 90% (rectal) Fecal

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].

Issues with opioids
The increased use of opioids for pain management has led to an ex-
pansion in opioid misuse, resulting in an increased number of emergen-
cy room visits related to drug-seeking behavior as well as in the number
of opioid-related overdose deaths [82,83]. Although opioids are among
the most commonly used analgesics, their clinical use is limited by the
development of tolerance and physical dependence. Another growing
concern relates to the diversion of opioids from patients to other
individuals not under medical supervision.
Opioids have several well-known side effects, including nausea, seda-
tion and bowel dysfunction [84]. The most serious potential adverse effect
is respiratory depression and failure, which is the most common cause of
death 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 experiencing
chills, muscle aches, vomiting, diarrhea, hyperthermia, anxiety and hostil-
ity [80]. Additionally, opioid use can result in feelings of euphoria which
can promote compulsive use leading to psychological dependence.
A detailed medical assessment is recommended prior to prescription
of opioids. This should include a detailed medical history, review of
medical records, urine toxicology screen and psychological evaluation,
including questionnaires aimed at determining an individual’s risk for
abuse [84,85]. This is of particular importance in those populations at
higher risk for opioid misuse. Chronic pain frequently occurs in individ-
uals with psychological conditions, including anxiety and depression; it
is estimated that 30%–60% of individuals with depression also experi-
ence chronic pain [86]. Psychological conditions are often comorbid in
individuals with substance-abuse disorders, resulting in a high risk
for opioid abuse in many chronic pain patients including those with
substance abuse issues and mental health disorders [85].
Newer opioid formulations have been designed in efforts to prevent
abuse. 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™, by
Purdue Pharma [84]. OxyNeo™ contains polyethylene oxide, which
forms a viscous gel when in contact with water, rendering it unsuitable
for injection or snorting, and also more difficult to chew or crush [87].
Buprenorphine, a semi-synthetic opioid was approved by the FDA
in 2002. Sublingual preparations, used in addiction medicine, are
co-formulated with the antagonist naloxone to prevent abuse.
Specific opioids used in pain management
Opioids can be classified as either weak or strong, depending on their
“analgesic ceiling”. This term is defined as the dose above which a drug
has no further effect on pain [88]. Weak opioids include tramadol, codeine
and hydrocodone; strong opioids include morphine, methadone,
buprenorphine, fentanyl, oxycodone, hydromorphone, oxymorphone,
meperidine and levorphanol. Detailed pharmacokinetic information for
each 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 metabolite
morphine [89]. Approximately 5%–10% of codeine is converted to mor-
phine in the liver, while the remainder is either conjugated, forming

Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
 Table 2

8
Properties of opioid medications commonly used in the management of chronic pain.
j.clinbiochem.2014.05.065
Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/

Drug# Common route of Protein binding Bioavailability# Route of elimination Vd⁎⁎ t½⁎⁎ CYP
administration⁎ L/kg (h)

Buprenorphine [170,171] TD, B, IV 96% 31% Renal 2–3 (IV)⁎ 2–4 (parental) 3A4
(sublingual) biliary 19 (B) 18–49 (sublingual)
26 (TD)

Codeine [89] Oral b1% ~90% Renal 2.5–3.5 1.2–3.9 3A4, 2D6
(oral)

B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx

Fentanyl [89,172] TD, oral 79% 92% (transdermal) Renal 3–8 3–12 3A4
89% (intranasal)
50% (buccal)
33% (ingestion)

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) Renal 2–4 3–9 glucuronidation
52%–58%
(intranasal)

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

Methadone [108,109] Oral 87% 41%–99% Renal 4–7 15–55 3A4 N 2B6 N 2D6
(oral)
 Morphine [89,98] IV, IM, oral 35% 20%–40% Renal (90%) 2–5 1.3–6.7 Glucuronidation (major)
j.clinbiochem.2014.05.065
Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/

(oral), Biliary (10%) 2D6 (minor)

36%–71% (rectally), 100%
(IV/IM)

Meperidine (Pethidine) [174,175] Oral, IV, IM 45%–64% 50%–60% (Oral), hepatic 3.7–4.2 2–5 2B6, 3A4 & 2C19(minor)
80%–90%
(Oral, in cases of hepatic impairment)

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

B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx

Oxymorphone [115] Oral 10–12% 10% Renal 2.4 4–12 glucuronidation
(oral), fecal
40% (Intranasal), 100%
(IV, IM)

Remifentanyl i.v 70% (bound to plasma proteins) Not applicable - - 1–20 min Nonspecific esterases
Given iv

Tramadol [89,95] Oral 15–20% 70%–75% Renal 2.6–2.9 4.3–6.7 2D6 N 2B6, 3A4
(oral),
77%
(rectal),
100% (IM)

#
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].

9
10 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx
codeine-6-glucuronide (active), or methylated via CYP3A4, producing
norcodeine (inactive) [89].
Hydrocodone
This is a semi-synthetic drug, similar to codeine in structure and to
morphine in its effects [89]. Hydrocodone is metabolized by CYP2D6
to active hydromorphone, which binds to the μ-opioid receptor, and
by CYP3A4 to the inactive metabolite norhydrocodone [90].
Tramadol
Tramadol is a synthetic codeine analog that binds to the μ-opioid
receptor 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: seizure
and serotonin syndrome [91]. Tramadol seizures usually occur in pa-
tients already taking anticonvulsant medications. Serotonin syndrome
is characterized by neuromuscular and autonomic hyperactivity as
well as altered mental status, due to excess serotonin activity in the
CNS. Higher risk of this syndrome is associated with tramadol overdose
or co-administration of antidepressant medications, such as tricyclic
antidepressants and selective serotonin reuptake inhibitors (SSRIs),
which, in addition to tramadol, inhibit serotonin reuptake, leading to
high 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 binding
strongly to the μ-opioid receptor; it also has activity towards κ- and
δ-opioid receptors. Morphine administered orally undergoes a large
first-pass effect, resulting in oral bioavailability of 38% on average [96].
The major morphine metabolites result from glucuronidation by
the 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 effects
of morphine include sedation, nausea, a feeling of warmth, urinary
retention, euphoria, reduced ability to concentrate and constipation.
The most serious side effect of morphine is potentially fatal respiratory
depression with morphine toxicity [89,98].
Hydromorphone
Hydromorphone, a hydrogenated ketone of morphine, is a synthetic
opioid with effects similar to morphine [89]. When given orally,
hydromorphone is rapidly absorbed by the GI tract and undergoes
extensive first-pass metabolism in the liver. Like morphine, it is
glucuronidated in the liver to hydromorphone-3-glucuronide and
hydromorphone-6-glucuronide; hydromorphone-3-glucuronide has
no analgesic properties, but has been shown to exhibit neuroexcitatory
effects [99]. Hydromorphone suppresses the cough reflex, similar to
other opioids. Side effects of hydromorphone are dose-related and can
include 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 times
more potent than morphine. Its potency is due to its efficiency in cross-
ing the blood brain barrier, rapidly gaining access to the central nervous
Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
system [89,100,101]. Given intravenously, fentanyl has a very rapid
onset but short duration of action, and is thus administered as a contin-
uous infusion. In managing pain, fentanyl is most often provided
through transdermal patches or buccal tablets [89]. This allows the
drug to distribute throughout fatty tissues, leading to slower release
and prolonged effects. Fentanyl undergoes extensive pulmonary
first-pass metabolism as well as hepatic metabolism to the inactive
metabolite norfentanyl via CYP3A4 [89].
Remifentanil
Remifentanil is a μ-opioid receptor agonist with an analgesic potency
similar to that of fentanyl. It was studied for analgesic efficacy correlat-
ing with expression of the serotonin transporter (5-HTT), as serotonin
can influence the antinociceptive effects of opioids at the spinal cord.
Remifentanil has a significantly better analgesic effect in individuals
with 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 its
rapid systemic elimination and ultra-short half-file, it has a pharmacoki-
netic advantage in clinical situations requiring predictable termination
of effect such as analgesia during labor [104]. In a systematic review,
Leong and colleagues compared remifentanil with meperidine for
labor analgesia. They found remifentanil to be superior in reducing
mean visual analog scale pain scores for labor pain after 1 h [105].
Remifentanil crosses the placenta, but is rapidly metabolized and
redistributed. Although maternal sedation and respiratory changes do
occur, they are without adverse neonatal or maternal effects [106].
Methadone
Methadone is a synthetic opioid with morphine-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 a
much higher bioavailability compared with oral morphine (70%–90%,
compared to 38%, respectively). Due to its relatively slow metabolism
and high lipid solubility, methadone also has a long half-life (between
8 and 60 h), leading to longer term analgesia than with morphine [107,
108]. Methadone is extensively metabolized by CYP3A4, and to a lesser
extent by CYP1A2, -2D6, -2D8, -2C9/2C8, -2C19, and -2B6, to its inactive
metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)
[107–110]. Caution must be exercised when co-prescribing methadone
with QT-prolonging cardiac drugs due to methadone’s ability to interact
with voltage-gated potassium channels in the myocardium, also leading
to QT prolongation [111] and ventricular arrhythmias such as Torsades
de Pointes. Significant drug–drug interactions have been reported for
methadone, when combined, for example, with fluoxetine, quetiapine,
or promethazine [110].
Buprenorphine
As an alternative to methadone, buprenorphine can be used for the
treatment of opioid addiction [89]. It has also been approved for
the 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 individuals
with hyperkalemia [112]. Buprenorphine has a ceiling effect with
respect to respiratory depression, thereby reducing the likelihood of
this 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 transdermal
or buccal routes to improve bioavailability [112]. Prolonged analgesia
can be achieved with buprenorphine due to its lipophilic properties
and its slow dissociation from opioid receptors. Buprenorphine is
metabolized by CYP3A4 in the liver primarily to nor-buprenorphine.
 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx 11

Oxycodone CYP2D6, to the potent metabolite oxymorphone (see below) as well

Oxycodone is a synthetic opioid, similar in structure to codeine and
prescribed for moderate to severe pain [89]. This drug is commonly
compounded 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 to
abuse of and dependence on the drug. Oxycodone is metabolized, via
as noroxycodone, a weakly active metabolite [114].
Oxymorphone
Oxymorphone offers excellent analgesia, comparable to that of
morphine, but with less sedative effects [115]. This results from the
lipophilic nature of oxymorphone, allowing ease of access to the cen-
tral nervous system. Oxymorphone undergoes extensive hepatic

Table 3
Antidepressants commonly used in pain management.

Drug# Common route of Protein binding Bioavailability# Route of elimination Vd⁎ t½⁎ CYP
administration L/kg (h)

Amitriptyline [176] Oral N 90% 30%–60% Renal 6–10 8–51 2D6

due to first pass metabolism

Bupropion [177] Oral 85% ?????? Renal 40 4–24 2B6

Fecal

Citalopram [178] Oral 50% 80% Renal 12–16 25–40 2C19, 3A4, 2D6

Desipramine [179] Oral 70%–90% 73%–92% Renal 22–59 12–54 2D6

Duloxetine [180] Oral N90% 32% to 80% Renal 17–26 8–17 1A2,2D6
Fecal

Fluoxetine [181] Oral 94% 72% Renal 20–42 1–3 days 2D6
Fecal

Venlafaxine [182] Oral 27% 42% ± 15% renal 4–12 3–7 2D6, 3A4

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

Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
12 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx

first-pass metabolism, and its major route of metabolism is via
glucuronidation [89,115].
Meperidine (pethidine)
Meperidine (Demerol™), also known as pethidine, is a synthetic
μ-opioid receptor agonist that is structurally similar to atropine.
Pharmacologically, it represents both morphine and atropine. This
unique property of an analgesic with spasmolytic and sedative action
accounts for its wide range of clinical applications [116]. Although
meperidine efficacy has been questioned [117], a survey of intrapartum
analgesia practice in United Kingdom and Norway reported that this
opioid 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 and
is eliminated through glucuronidation in the liver [120].
Other medications in the treatment of chronic pain
is often a co-morbidity of chronic pain. Patients experiencing chronic
pain 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 and
imipramine (Table 3), administered at much lower doses for pain
management than for psychiatric indications [22]. These two drugs
are metabolized to the active metabolites nortriptyline and desipra-
mine, respectively, by hepatic CYP2D6 [22]. Side effects of TCAs that
can limit their use include weight gain, anticholinergic effects, hypoten-
sion and cardiovascular effects [22,121]. TCAs have been better charac-
terized for their role in pain management than SSRIs [121].SSRIs used in
pain management include fluoxetine and citalopram (Table 3). SSRIs are
often better tolerated than TCAs, due to their milder side effects; how-
ever, data regarding their efficacy in the treatment of chronic pain
have 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 (serotonin
and dopamine) have been more widely used in pain management
(Table 3). Venlafaxine has been shown to be particularly efficacious
when prescribed in combination with gabapentin, a GABA analogue
often used to treat neuropathic pain [123].

Antidepressants Anticonvulsants

Tricyclic antidepressants (TCAs) and selective serotonin re-uptake
inhibitors (SSRIs) are commonly used as adjuvant therapy in the
treatment of chronic pain. The mechanisms by which these medications
alleviate pain are not fully understood, but are believed to be mediated
through their inhibition of neurotransmitter reuptake in the synaptic
cleft. These mechanisms are related to pain signaling in descending
spinal pain pathways [121]. In addition to their analgesic role, antide-
pressants are commonly used in pain management because depression
Anticonvulsants (Table 4) have been used in pain management since
the 1960’s when these drugs were originally introduced for the treat-
ment of epileptic seizures [124]. These medications work by a variety
of mechanisms to suppress the rapid firing of neurons. Phenytoin, one
of the first anticonvulsants introduced, reduces neuronal excitability
by blocking sodium channels. It has been used in the treatment of
chronic neuropathic pain, but today its use for this indication is limited
due to side effects, namely, sedation and motor disturbances [125].

Table 4
Anticonvulsant drugs used in pain management.

Drug# Common route of Protein binding Bioavailability# Route of elimination Vd⁎ t½⁎ CYP
administration L/kg (h)

Carbamazepine [183,184] Oral 75% ?????? Renal 0.8–1.8 18–65 3A4

Gabapentin [185] Oral b 3% 27%–60% (inversely proportional to dose) Renal 0.8–1.3 5–9 Not metabolized

Lamotrigine [186] Oral 55% 98% Renal 0.9–1.3 12–62 glucuronidation

Phenytoin [187,188] Oral, IV 87%–93% 70%–100% Biliary 0.5–0.8 8–60 2C19

oral,
24.4%
(rectal, IV)

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

Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx 13

Carbamazepine has largely replaced phenytoin in chronic pain
management and has been shown to be effective in the treatment of
neuropathic pain, in particular trigeminal neuralgia [124,126] (a disor-
der characterized by episodes of intense facial pain, originating from
the trigeminal nerve) [126]. Side effects of carbamazepine include
drowsiness, blurred vision, nausea and vomiting. There is a dose–effect
relationship and it can be difficult to achieve a therapeutic effect in pa-
tients who are sensitive to these side effects [125]. This is of particular
relevance in elderly patients, where conditions such as cardiac disease
and hypernatremia can further complicate adverse effects [127]; thus,
close monitoring of these patients is required [124,125].
Newer anticonvulsants, such as lamotrigine and gabapentin, are
showing 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 calcium channels, 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
neuralgia and diabetic neuropathy [124]. However, careful titration of
lamotrigine dose is required because of the risk of Stevens–Johnson
syndrome, a life-threatening dermatological condition leading to cell
necrosis, causing the epidermis to separate from the dermis [129].
Triptans
Triptans are serotonin agonists with high affinity for the 5HT1B and
5HT1D receptors [130,131]. The serotonergic system is known to play a
role in the pathophysiology of migraines, leading to the development
and prescription of triptans for this condition. Binding of these drugs
to 5HT receptors in the brainstem and thalamus leads to the blockade
of vasoactive peptide release from perivascular trigeminal neurons,
and thus reduced cerebral vasodilation [131]. Currently, there are
seven triptan molecules available, each with its unique pharmacokinetic
and pharmacodynamic profile. The four most commonly prescribed and
well characterized triptans are sumatriptan, naratriptan, zolmitriptan
and rizatriptan (Table 5) [132]. Triptans are not recommended for mi-
graine treatment in individuals with poorly controlled hypertension,

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

Drug# Common route of Protein binding Bioavailability# Route of elimination Vd⁎⁎ t½⁎⁎ CYP
administration L/kg (h)

Almotriptan[131] Oral 35% 70% Renal 2.5–4 3–4 3A4, MAO⁎, 2D6
Fecal

Eletriptan[131] Oral 85% 50% Renal 2.1–3.3 3–7 3A4

Frovatriptan[131] Oral 15% 20%–30% Renal 3–4.2 20–30 1A2, 2D6

Naratriptan[131] Oral 20%–30% 74% Renal 2–3 5–6 Unknown CYP

Rizatriptan[131] Oral 14% 45% Renal 1.3–2.2 1.6–3.2 MAO, 1A2

Sumatriptan[131] Oral 14%–21% 15% Renal 1.3–4.6 1–4 MOA

(oral)
96%
(s.c)

Zolmitriptan[131] Oral, nasal 25% 40% (oral) Renal 7.0 1.6–3.8 1A2, MAO, 3A4
Fecal

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

Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
14 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx
hepatic or renal impairment or coronary artery disease, as serotonergic
blockade may exacerbate these conditions [131].
Benzodiazepines
Benzodiazepines play a role in the treatment of insomnia, muscle
tension, and, in particular, anxiety related to chronic pain [133]. Chronic
pain patients experience increased anxiety compared to the general
population, and this can often worsen the subjective experience of
pain. Evidence suggests that benzodiazepines are only effective in
treating acute anxiety related to chronic pain, but are not effective in
the setting of chronic anxiety [133] (for which antidepressants have
been 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 and
behavioral disturbances) [133].
Cannabinoids
Cannabis is an annual plant that grows wild in regions of mild or
tropical weather, and has been used to treat pain for centuries. It is by
far the most widely cultivated, trafficked and abused illicit drug; half
of all drug seizures worldwide are of cannabis. The geographical spread
of those seizures is also global, covering practically every country of the
world. Delta-9-tetrahydrocannabinol (THC) is the active component
in cannabis, responsible for its analgesic and psychoactive effects.
Ingestion of THC results in feelings of euphoria, relaxation and a general
sense of well-being. However, heavy cannabis use can result in halluci-
nations, anxiety and depression [134,135].
Endogenous cannabinoids, referred to as endocannabinoids, have
been identified, as well as two endocannabinoid receptors, the G-
protein coupled receptors CB1 and CB2. High levels of CB1 are expressed
in the brain and spinal cord, particularly in areas known to be involved
in nociception. CB2 is not as well characterized, but has been shown to
have lower expression levels in the brain than CB1. Endocannabinoids
are bioactive lipids which regulate neural activity by binding to CB1
and CB2, causing inhibition of neurotransmitter release. Endogenous
and exogenous cannabinoid activity results in anti-nociceptive effects
as well as short-term memory impairment, stimulation of appetite
and antiemetic effects [134–136].
THC acts synergistically with other analgesic agents, such as
morphine and some NSAIDs, though the mechanism for the synergistic
action between morphine and THC is unknown [134]. In the case of
NSAIDs, cannabinoids and prostaglandin share a similar structure
which 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 of
ibuprofen [134].
Evidence for the use of cannabinoids in pain management is lacking
due to the small number of clinical trials in this area. The best evidence
for cannabinoid use in chronic pain comes from HIV and multiple sclerosis
studies in which cannabinoids were used to treat the chronic neuropathic
pain associated with these conditions [136]. Smoking cannabis 3–5 times
per week was shown to be effective in alleviating neuropathic pain
associated with HIV as well as AIDS-related anorexia [137,138]. Several
studies demonstrated benefit of oral treatment with synthetic THC for
central pain and spasticity associated with multiple sclerosis [139–142].
There are several issues associated with the use of cannabinoids in
pain management. Firstly, the method 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 of
smoking are well known, with THC contents varying depending on
where and how the cannabis plants are grown. Canada, which allows
prescription of cannabis for chronic pain therapy, requires that patients
obtain their medicinal cannabis from a centralized source so that the
THC content may be monitored over time [136]. Similar strategies are
Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
now under consideration in different parts of the world including the
United States. Synthetic cannabinoids, such as dronabinol and nabilone,
are available in the U.S. and Canada for use as antiemetics during cancer
chemotherapy, and as adjunct therapies for neuropathic and chronic
pain. They are not yet widely used, and are under further study to delin-
eate their efficacy and pharmacological parameters in various clinical
contexts [143]. Side effects include increased heart rate, blood pressure
changes, anxiety, psychomotor retardation, impaired memory and psy-
chosis. Cannabinoids are contraindicated in pregnancy, uncontrolled
hypertension, active ischemic heart disease, arrhythmias and schizo-
phrenia. Clark and co-workers suggest guidelines for the use of these
cannabinoid compounds [144].
Cannabis and cannabinoids have a potential for dependence, which
can lead to preoccupation and compulsion. Prescription of cannabinoids
for chronic pain management requires clinician to appropriately select
patient 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 schizophrenia
and schizoaffective disorder. They show that use of cannabis is associat-
ed with an earlier age of onset of schizophrenia. There is a significant
interaction between gender and cannabis use whereby the gender
difference in age of onset is diminished in cannabis users [145].
Ziconotide
Ziconotide is a synthetic conopeptide that selectively inhibits N-type
voltage-gated calcium channels, reducing the release of pain-
modulating neurotransmitters. Conopeptides are derived from the
venom of predatory cone snails, and ziconotide is specifically derived
from the venom of a Pacific fish-hunting snail, Conus magus [146].
Ziconotide has been approved for intrathecal administration by
continuous 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 of
both neuropathic and non-neuropathic pain. Intrathecal administration
is required because, given intravenously, ziconotide demonstrates poor
penetration of the blood brain barrier and results in sympatholytic
effects leading to orthostatic hypotension [147]; oral preparations are
not available. Ziconotide is highly hydrophilic and is thought to move
slowly through the CSF to its target receptor, leading to a lag time to
analgesia upon administration. The efficacy of ziconotide shows a
wide 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 is
reversible after discontinuation, but, because of low tissue diffusion,
the effects can persist for several weeks [147,148]. Data regarding
ziconotide metabolism are sparse. The drug is not believed to be metab-
olized in the CSF but rather cleared by transport into the systemic
circulation 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 manifested
through dynamic, reversible chemical modifications in the genome
and are involved in differential gene expression throughout life
[149]. The most well characterized epigenetic modifications are DNA
methylation and histone acetylation.
DNA methylation is regulated by DNA methyltransferases, while his-
tone modifications are largely regulated by histone deacetylases
(HDAC) [149]. Abnormal DNA methylation [150] and histone
 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx
acetylation [151,152] have been demonstrated to occur in pain states. It
has also been proposed that primary injuries may result in lasting epige-
netic marks leading to an increased risk of chronic pain [149], which
may even persist trans-generationally. Drugs aimed at targeting the en-
zymes responsible for epigenetic modifications are under development
and in some cases have been approved by the FDA. While these drugs
have been developed largely for the purpose of cancer treatment, they
are also believed to have potential in pain management. In animal injury
models, 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 similar
rat model, pre-injection treatment with HDAC inhibitors was reported
to delay CFA-induced thermal hyperalgesia whereas post-injection
treatment was shown to reduce the intensity of CFA-induced thermal
hyperalgesia [154]. In human patients with type 2 diabetes, treatment
with valproic acid, which is a known to act as a strong the HDAC inhib-
itor, conferred improved pain sensitivity scores after treatment
compared 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 to
drive gene expression as well as a transgene of interest [156]. For pain
management therapies, the transgene encodes for an analgesic agent.
Gene therapy based approaches have several advantages in pain
management. In contrast to pharmacotherapies, gene therapy allows
for persistent expression of a protein-based analgesic agent at the site
of action. These methods avoid the first-pass effect and can improve
bioavailability [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 of
immune responses against the viral vectors [156]. Nevertheless, new
paradigms using non-viral insertion of therapeutic transgenes are
under way to bypass some of these limitations.
In a recent study, terminal cancer patients were given different gene
doses 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 in
pain compared to patients in the lowest dose group. This study demon-
strates proof-of-concept for gene therapy in pain management.
Pt XY
5000
4500
4000
3500
UEW
EDDP ng/mL
3000
2500
2000
1500
1000
500
0 0.00
date of analysis
EDDP
Fig. 4. EDDP urine excretion window at steady state. Legend: *UEW urinary excretion window. The green lines represent the 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
(EDDP) excretion window.
Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
15
Therapeutic drug monitoring in pain management
In pain management, the rationale for drug monitoring has largely
focused on monitoring patient adherence, detecting diversion, and
detecting the presence of illicit, non-prescription drugs. Traditionally,
drug monitoring in pain management patients has been in the form of
urine drug testing.
Urine drug testing has been demonstrated to reduce illicit drug
use and has been widely used in monitoring patients in treatment
for drug addiction [158,159]. However, most urine methodologies
have been adapted from occupational deterrent-based testing for
illicit drug use and have not been optimized for use in the pain
management setting [160]. Given the chronicity of treatment drug
administration, and the wide range of drug half-lives (Tables 1–5)
a “positive” urine result is to be expected if a patient is adherent in
taking 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 drug
pharmacokinetics and pharmacodynamics, and an understanding
of the type of information urine drug testing can provide along
with an appreciation of the limitations of such testing [161].
Urine drug concentrations are often calculated relative to urine
creatinine concentrations in order to correct for in vivo dilution, which
can vary through time, depending on an individual’s fluid intake.
However, these calculations assume stable renal function and creatinine
production, an assumption which can lead to errors if unjustified. Pain
medications are usually prescribed to be taken in a chronic manner so
that steady state plasma concentrations and therapeutic pharmacody-
namic effects can be achieved. Steady state drug concentrations in
serum 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 receiving
methadone chronically. This figure clearly shows that urine creatinine
correction does not add value to the EDDP adherence monitoring.
Here, patient non-adherence can be detected when the urine EDDP
concentration falls outside the UEW [162]. Extremely low creatinine
concentrations are indicative of potential adulteration and can be useful
in detecting specimens that have been tampered with [161]. Unfortu-
nately, urine drug testing is not effective in estimating serum drug
concentrations or assessing drug efficacy.
In light of the limitations associated with urine drug testing, moni-
toring of pain management patients through serum or plasma drug
measurements has been advocated. Therapeutic drug monitoring
60.00
50.00
40.00
pH and UCr
30.00
20.00
problem samples
10.00
Creatinine PH
16 B.M. Kapur et al. / Clinical Biochemistry xxx (2014) xxx–xxx
(TDM) involves the measurement of serum or plasma drug levels at
timed intervals to determine whether steady state drug concentrations
are within the therapeutic or expected range given the drug dosage
[163]. TDM can be used by clinicians to explain drug toxicity or lack of
efficacy, and can aid in adjusting drug doses or in choosing specific
medications [163]. A major advantage of plasma drug measurement is
that it integrates many factors affecting drug metabolism, as outlined in
Fig. 2. Half-life measurement can be a functional marker of the cumulative
effect of pathophysiological and drug–drug interactions and provide an
overall picture of the specific drug disposition and pharmacodynamics
in the individual patient. However, TDM requires the collection of serial
blood 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 drug
or its metabolite can be detected in serum is an important consideration
for 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 chronic
pain a major issue in clinical practice. Left untreated, chronic pain can
lead 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 opioids may 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 are
now potentially available for these patients, such as triptans, ziconotides,
as well as novel therapies, such as treatment with cannabinoids and, in
the 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 with
chronic pain.
Genetic variability can have profound effects on drug metabolism
and contribute to the inter-individual diversity in responses to pain
medications. However, there is a paucity of evidence for the benefits
of pharmacogenetic testing in the context of pain management. Drug
metabolism and responses are affected by many factors, including
pharmacogenetics, with genetics offering only a partial explanation of
an individual’s response.
At this point in time, therapeutic drug monitoring, through plasma
drug measurements, may be more useful than pharmacogenetics 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 the most
useful assays for this purpose. Drug half-life can be a functional marker
of 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 at
all, is largely through urine drug measurements, which do not correlate
with serum drug concentrations therefore limiting their use in monitor-
ing efficacy and toxicity. Direct determination of serum or plasma drug
levels may provide a more clinically useful, if logistically more difficult,
avenue for optimization of drug therapy, particularly in the context of
chronic pain management.
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Please cite this article as: Kapur BM, et al, Pharmacogenetics of chronic pain management, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.05.065
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