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Keywords: Opioids, Differential pharmacokinetics, Background
morphine, Opioid induced constipation.
Introduction
“The greatest happiness mankind can gain is not from pleasure,but
relief of pain.” John Milton, Paradise Lost. Mankind seeks out
analgesics for imminent pain relief despite the wide array of
analgesics available, opioids are a formidable choice. The greatest
limitation of opioid usage is its addiction liability. The dened
daily dose for statistical purposes of opioid analgesics was about
110 per million inhabitants/ day in Mexico as compared to 43879
per million inhabitants per day in the USA [1]. Use of opioid
painkillers increases fourfold in Australia in 10 years while most
of the world lacks access to basic pain relief [2].
Analgesic choices are difcult due to addiction liability, adverse
effects and singular mechanism of action. Combinations of
analgesics are an enticing option, for achieving maximal
analgesia with minimal adverse reactions. The individual options
of analgesics can be enhanced by opting for the route that gives
maximal analgesia with minimal adverse reaction. Moreover,
subsets of population such as geriatric, pediatric, pregnant, hepatic
failure, renal failure, and compromised respiration need special
emphasis on the choice of analgesia. The choice of analgesic also
varies on the etiology of pain i.e. post operative pain, palliative
care oncology patients, neuropathic pain etc. There is a lot of
published data on analgesics but, the focus varies among different
studies. The available published data do come up with seemingly
small insights into analgesic choices based on pharmacokinetics
and adverse reactions.
This study forays into the realm of analgesics, based on variations
in pharmacokinetics of different opioids, with their doses and their
routes.
Methodology
This study delved into the basis of pharmacokinetics for optimizing
the choice of the opioid analgesic. A pubmed search using the
National Library of Medicine’s PubMed website (http://www.
ncbi.nlm.nih.gov/PubMed) for Articles published in English over
the 30-year period of 1983-2016 was done on the topic. Which
showed 603 on 12th October 2016 at 5:30 pm GMT articles using
Journal of Anesthesia & Pain Medicine
Volume 1 | Issue 2 | 1 of 2
J Anesth Pain Med, 2016
Opioid Analgesic Choices Based On Pharmacokinetics
Research Article
Tanya Manisha Machado* and Princy Louis Palatty
Father Muller Medical College, Mangalore, Karnataka, India
*Corresponding author
Tanya Manisha Machado, Father Muller Medical College,
Mangalore, Karnataka, India, Tel: +91-7411338151; E-mail: Tanya.
nicole94@gmail.com.
Submitted: 10 Oct 2016; Accepted: 03 Nov 2016; Published: 07 Nov 2016
Abstract
Introduction: This study looks the multiple factors- specically the pharmacokinetics that are involved while
selecting an opioid to ensure its optimum efcacy. Combinations of analgesics are an enticing option, for achieving
maximal analgesia with minimal adverse reactions. The choice of analgesic depends on the sub-population it
caters to, and the etiology of pain involved.
Methodology: 112 articles involving an inclusion criteria of “pharmacokinetic aspects in combination of opioid”
from a Pubmed search were assessed. Associations among the opioids and suggested guidelines were drawn after
thoughtful analysis.
Discussion: Single-injection neuraxial; fentanyl and sufentanil are preferred over parenteral opioids. Remifentanil
and Dexmedetomidine are preferred for ICU patients. Tramadol can be used for mild to moderate pain, and
morphine is the choice for severe and intractable pain. The parenteral routes is commonly used but it is beset with
pain and other adverse drug reactions.
Conclusion: Combination of analgesics having varied mechanisms of action is advocated for optimizing analgesic
therapy. Opioid analgesics are widely used but ferreting out the appropriate dose, route and agent is the crux in
effect analgesic. A holistic approach that considers all aspects of an opioid need to be considered before selection,
and the pharmacokinetics aspect plays a pivotal role.
Volume 1 | Issue 2 | 2 of 2J Anesth Pain Med, 2016
an inclusion criteria of “pharmacokinetic aspects in combination of
opioid” this ltered down to 112 articles. The investigators combed
through the 112 and focused on articles, drawing conclusions from
these published papers Table 1.
Result
Table 2 [3-27].
All Articles That Involved Humans In Their Study
Sr.
No
Opioid used In
the study Workers and paper reference Year
1Combination of
various opioids
Ladd LA, et al.. [3] 2005
Joseph V. Pergolizzi Jr, et al. [4] 2015
Lawrence Librach, et al. [5] 1995
Jeffrey A. Gudin, et al. [6] 2013
2 Buprenorphine Duchar S, et al. [7] 2012
3 Fentanyl Lewis Nelson, et al. [8] 2009
Noah D. Syroid, et al. [9] 2010
4 All opioids
Kanwal jeet J. S, et al. [10] 2010
Vijay Sharma, et al. [11] 2009
Robert H. Dworkin, et al. [12] 2010
Nalini Vadivelu, et al. [13] 2010
Marie Fallon, et al. [14] 2006
Karel allegaerta, et al. [15] 2013
Anand KJS, et al. [16] 2006
Pascal H Vuilleumier, et al. [17] 2012
5 Oxycodone
James P. Zacnya, et al. [18] 2009
Samer CF, et al. [19] 2012
Gary Vorsanger, et al. [20] 2011
Ryan M Frank, et al. [21] 2016
Krishna Devarakonda, et al. [22] 2014
6 Remifentanil Wolfram Wilhelm, et al. [23] 2008
7 Sufentanil Timothy I, et al. [24] 2014
8
Methadone Amin Rostami-Hodjegan, et al. [25] 1999
Tramadol William W Stoops, et al. [26] 2013
Justin C Stricklanda, et al. [27] 2015
Discussion
In our quest for optimizing analgesic choices our literature review
lead us to analyze 112 papers. The pharmacokinetic aspects
in determining the choice in analgesics were gleaned from the
literature. This study has focused only on the opioid analgesic,
singly or in combination with other opioids/ other agents. (i.e.
local anesthetics, NSAIDs, GABA analogues). The present day
opioid analgesics have been classied to be used as a template in
for analgesic choices (Table 3).
Classication of opioid agonists
Endogenous
opioids
Natural opium
alkaloids
Semisynthetic
opium
derivatives
Synthetic opium
substitutes
Endorphins
Phenantherine
derivatives:
Morphine, Codeine,
Thebaine
Morphine
derivatives:
Hydromorphine,
Oxymorphine,
Heroine
Morphinans:
Levorphenol,
Dextromethorphan
Enkephalins
Benzylisorquinoline
derivatives:
Papaverine,
Narcotine
Codeine
derivetives:
Hydrocodone,
Oxycodone,
Dihydrocodiene,
Pholcodine
Diphenylprolylamine
series: Methadone,
Propoxyphene
Dynorphins
Thebaine
derivatives:
Buprenorphine
(partial agonist
at µ opioid
receptor)
Benzomorphans:
Pentazocine,
Phenazocine (opioid
agonist-antagonists)
Endomorphins
Phenylpiperidines:
Mepridine,
Fentanyl, Sufentanil,
Alfentanil,
Remifentanil,
Loperamide,
Diphenoxylate
Nociceptin
Miscellneous:
Dextromoramide
tartarate,
Dipipanone HCl
The opioid analgesic pharmacokinetic parameters have been
tabulated (Table 4) [28]. The pharmacokinetics of a drug are
sectioned into absorption, distribution, metabolism and excretion.
Absorption
Opioids have moderate gastro intestinal absorption from oral
morphine and hydromorphone dose. Hence it is also used as a
suppository. More lipophilic agents have guaranteed absorption
from the buccal and nasal epithelium [29]. Morphine undergoes,
rst pass metabolism and hence parenteral route is preferred
[30]. The liposolubility is inversely proportional to their spinal
selectivity, which is higher for morphine, than for other more
lipophilic drugs, such as fentanyl and sufentanil [31]. The limited
and slow transfer from the CFS, morphine presents a slow onset of
action, extensive and prolonged rostral spread resulting in delayed
respiratory depression (6-12 hours) and a broad band of analgesia
surrounding the site of injection, and a relative long duration
Volume 1 | Issue 2 | 3 of 2J Anesth Pain Med, 2016
Drug name Metabolizing
enzyme Metabolites Site of action Vol. of
Distribution
Equi analgesic
oral dose
Equi analgesic
parentral dose Remarks
Fentanyl CYP3A4 Norfentanyl [I] ++
Sufentanyl ++
Afentanyl Preferred in
neonates
Remifentanil Esterases ++
Preferred in those
with liver and
kidney failure
Morphine Glucuronide
Morphine3
glucoronide
Morphine6
glucoronide
Histamine
liberator +
30 mg q3-4h
(round the clock
dosing) 60 mg
q3-4 (single dose/
intermittent)
10 mg q3-4
Hydromorphone Glucuronide + 7.5 mg q3-4h 1.5 mg q3-4h
Meperidine CYP2B6
CYP3A4 300 mg q2-3h 100 mg q3h
oxymorphone - 1 mg q3-4h
Levorphanol 4 mg q6-8 2 mg q6-8
Buprenorphine -0.3-0.4 mg
q6-8h
Butorphanol - 2 mg q3-4h
Pentazocin
Brenazocin
Codine CYP2D6 130 mg q3-4h 75mg q3-4h
Oxycodone CYP2D6
CYP3A4 30 mg q3-4h -
Hydrocodone CYP2D6
CYP3A4 30 mg 3-4h -
Methadone CYP2D6
CYP3A4 20 mg q6-8h 10 mg q6-8h
Tramadol
CYP3A4
CYP2D6
Glucuronide
O-demethy-
tramadol [A]
Anti-cholinergic,
Opioid receptor,
Norepinephrine,
Serotonin
reuptake inhibitor
100 mg 100 mg
propoxyphene 130 mg -
Used in
combination with
tapentadol for
elderly patients
Table 4: Pharmacokinetics. KEY: [I]= Inactive metabolite; [A]= active metabolite; [T]=Toxic metabolite; - = not avalible.
of action (18-24hours) [32]. The qualication stems from data
suggesting that lipophilic opioids, particularly sufentanil, produce
analgesic plasma concentrations after intrathecal administration
[31].
The relatively rapid movement of sufentanil into plasma to produce
analgesic concentrations is responsible for the early respiratory
arrests reported when this drug was administered intrathecally,
occurring within the rst 20-30 min after intrathecal injection [31].
Perhaps the best clinical evidence of the limited ability of sufentanil
to reach the spinal cord dorsal horn after intrathecal administration
is the dose required producing analgesia. A common sufentanil
dose is 10μg, which is equivalent to 10mg of morphine based on
their relative potency following IV administration. However, a
typical intrathecal morphine dose is only 100 μg, thus intrathecal
administration results in a 100-fold decrease in the relative potency
of morphine and sufentanil [31].
The use of a lipophilic opioid such as fentanyl has been shown to
be effective when given by other routes such as the transmucosal
route and in formulations such as a buccal tablet, due to the
lipophilic nature of the drug and its rapid onset of action [29]. The
rapid onset of action of fentanyl can match the rapid onset of action
for most forms of breakthrough pain. The rapid onset of action by
the intranasal route has been evaluated as another alternative route
for the management of breakthrough pain [29].
Volume 1 | Issue 2 | 4 of 2J Anesth Pain Med, 2016
Remifentanil is an ultra-short acting opioid that gets rapidly
metabolized by nonspecic blood and tissue esterases. It is similar
to fentanyl, and possesses a high afnity for μ-receptors while
a lower afnity for δ- and κ-receptors [33]. Fentanyl rapidly
distributes with sequestration in fat and it extensively binds to
human plasma proteins [29]. It is metabolized mainly by the liver
and is excreted via the kidney. Elimination half-life varies from
6 to 32 hrs. Action starts almost immediately with intravenous
administration and after 7-8 min with intramuscular dosing.
The peak effect that the drug achieves is observed in 5-15 min
following intravenous injection. Duration of the analgesic effect
is 1-2 h on intramuscular administration [29]. So it has a faster
onset of action but a shorter duration of action than morphine. The
opioids are hydrophilic or hydrophobic (Table 5) [29].
Hydrophillic and Hydrophobic Opioids
Hydrophillic Hydrophobic
Morphine Fentanyl
Hydromorphine Sufentanyl
Remifentanyl
Opioids have been delivered by varied routes of administration
(Table 6).For the neonates, continuous opioid infusion is preferred
in the following routes Spinal /intrathecal, Epidural, Caudal routes
[6].
Routes of Administration of Opioids
Oral route Parentral
Tablets Transdermal patch
Buccal tablet Intravenous
Oral sustained release Sub cutaneous injection
Lollipop Intrathecal infusion
Sub lingual
Epidural-
- Extended release
- Bolus
- Continious infusion
Intradermal
Via catheter
Suppository
Intranasal
Distribution of Opioid Drug
One third of morphine in the blood gets protein bound, and
tissue concentration of morphine diminishes after 24 hours. Both
metabolites morphine-6-glucuronide and morphine-3-glucuronide
can cross the blood brain barrier. Fentanyl and its congeners
require a short time to peak their analgesic effect, though they
demonstrate a much shorter duration of action when administered
intravenously. Propoxyphene on oral administration reach their
highest values in the plasma within 1-2 hours [28].
Metabolism
Fentanyl undergoes fast rst-pass metabolism that precludes its
use orally. Fentanyl has a wide range of dose formulations i.e.
Buccal tablet, transdermal patch, oral, transmucosal fentanyl,
an intranasal fentanyl spray. The main metabolites of fentanyl
are phenyl acetic acid and nor fentanyl [34]. It is still possible
that variations in metabolic phenotypes combined with the
low training dose used in this study contributed to differential
drug effects and variability in discrimination performance The
metabolite of oxycodone are: noroxycodone, oxymorphone [30].
Renal dysfunction with oxycodone can occur due to deposition of
multiple active metabolites [30,35] (Table 7).
Transdermal Buprenorphine is the choice for renally impaired in
those who require opioid therapy [36]. Liver impairment is not a
clinically signicant outcome, because of the low-activity of its
metabolites. Precautions should be taken in patients with asthma
or chronic obstructive pulmonary disease (COPD) specially
when shifting from full agonist to partial agonist as withdrawal
symptoms can ensue. Example: buprenorphine - a partial agonist
[14].
Caution should be taken when administering opioids in
combination with acetaminophen, in alcoholics/malnourished as
CYP2e1 is induced, that could lead to acetaminophen producing
its toxic metabolite N-Acetyl-P-Benzoquinone Imine [14,37,38].
Patients with cirrhosis have a high tendency for renal dysfunction
with opioids like Meperidine. Most opioids need dose titration
according to glomerular ltration rate to preempt adverse drug
reactions [14]. In cirrhotic patients with intractable pain Tramadol
is a preferred choice as it has additional effect on peripheral pain
pathway in low doses with good tolerability. Tramadol can lead
to seizures and serotonin syndrome [29]. Interaction of diazepam
with methadone causes increased methadone levels in the blood by
reducing renal clearance. Methadone kinetics show marked inter
individual variability [14,34].
BOLD is a blood oxygen level-dependent- (fMRI) functional
magnetic resonance imaging, used to observe different areas of
the brain or other organs, which are found to be active at any
given time [39]. Morphine and remifentanil have been reported
to induce positive changes in (BOLD) signal, reported regional
positive increases in blood oxygen level-dependent signal [39].
Remifentanil is the preferred option in renal or liver impairment as
they are metabolized by esterases [10,22].
Alcohol increases the maximum plasma concentration (Cmax)
of certain opioids-oxymorphone, hydromorphone and morphine.
Volume 1 | Issue 2 | 5 of 2J Anesth Pain Med, 2016
Caution should be exercised when using long acting opioids in
combination with prescription/social use of alcohol [14]. The
active metabolites of opioids have varying pharmacodynamics
or pharmacokinetic action. Single- and multiple-dose
pharmacokinetics of biphasic immediate-release/ extended-release
hydrocodone bitartrate/acetaminophen (MNK-155) compared
with immediate-release hydrocodone bitartrate/ibuprofen and
immediate-release tramadol HCl/acetaminophen showed similar
peak concentration, steady state concentration and adverse effects
[40]. In neonates it has been noted that there is decreased clearance
of opioids [22]. Sufcient data on usage of opioids in pregnant
women are unavailable from pub med as only 1.29% clinical trials
are indexed in PubMed [41].
Adverse drug Reactions
Opioid bowel dysfunction is not only due to their direct action
but also could have spinal/supraspinal constipating effect. Opioids
that bind to GIT opioid receptors lead to opioid induced bowel
dysfunction i.e. opioid induced bowel dysfunction that affects
motility, sphincter usage and secretion [42]. The GIT Symptoms
with opioids have been characterized in Vide Table 8 [42].The
Vide Table 9 [43] gives the entire list of opioid drug reactions.
Tramadol interacts with anti-depressant drugs [16].
Opioid Adverse Drug Reaction List
Bowel disease
Chest wall rigidity
Epileptic seizures r myoclonic seizures
Headache
Hypotension
Induced bowel dysfunction
Nausea
Opioid induced constipation
Pruritis
Pyrexia
Respiratory depression
Sedation
Urine retention
Vomiting
Choice of Drug
Single-injection of neuraxial opioids is preferred over parenteral
opioids [31]. Single-injection neuraxial; fentanyl and sufentanil
are preferred over morphine and hydromorphone. Concomitant
administration of sedatives, hypnotics, or magnesium and
parenteral opioids, require therapeutic drug monitoring [31]. IV
PCA morphine is better than intramuscular morphine [12]. Various
modes of analgesia are often equi-analgesic but for the incidence of
Adverse drug reactions. It is a preferred strategy to use background
morphine when using IV PCA as it minimizes the dosage of
analgesic required [12]. In ambulatory patient’s morphine is not the
preferred post-operative analgesic [5,44]. Use of Fentanyl causes
minimal cortical depression, prolonged respiratory alteration with
minimal cardiovascular effects [29]. The clinical characteristics of
each opioid will be the consequence of the sum of all these types of
distribution as they dene its bio availability and spinal effect [31].
The dissipation of opioids following intrathecal administration has
been characterized in table 10.
Opioids have been combined with cannabinoids but optimal dose
combinations have not yet, been determined. Remifentanil can
be used in ICU patients for IV sedation [45]. Dexmedetomidine
accentuates the action of opioids by its action on the alpha 2
receptors. [41]. It is also used in ICU for sedation with analgesic
sparing. [46]. The biosocial nature of pain should be considered
when dealing with pediatric age group as they nd it difcult to
articulate quantum of pain [22]. Tramadol can be used for mild
to moderate pain, and morphine is the choice for severe and
intractable pain [12,47]. The higher plasma concentration of
oxycodone is due to greater clearance of morphine, in the study
where analgesics were given in ventilated patients [25]. Such
differential pharmacokinetics makes for optimal choice. The
parenteral routes are commonly used but it is beset with pain and
other adverse drug reactions.
Perioperative analgesics are provided in lower dosages in elderly
patients as they are more prone to adverse effects [5]. There are
Volume 1 | Issue 2 | 6 of 2J Anesth Pain Med, 2016
still lacunae in the optimal analgesic therapy in geriatrics as often
times they are undertreated [5].
Combination of Opioids
Better compliance can be fostered by using effective, rational
combinations (opioid+ NSAID/ GABA analogs), reducing pill
burden, dosing convenience and reduced adverse reactions
[30]. Synergistic analgesic benets have been noted with opioid
+NSAID (30-40%). GABA analogs combination, due to opioid
sparing effect that allows better analgesia at low doses of opioid
[30,48-53]. The investigators have arrived at the recommendations
which should be kept in mind in the choice of an optimal analgesic.
The guidelines for optimizing analgesic therapy
• Assessment of pain and therapy of pain should be in tandem.
• The pain assessment tools should correlate with the cognitive
abilities of the individual- i.e. Geriatric and paediatric.
• Analgesic dose titration is mandatory to optimise pain relief
and reduce adverse drug reactions.
• Pain being subjective, all measures in communication to be
set in place to prevent oversight.
• Consideration of comorbid conditions is mandatory in
analgesic decision making.
• Combination of analgesics having varied mechanisms of
action is advocated for optimising analgesic therapy.
• Vigilance of concomitant drugs with opioids is necessary to
wards off unwanted side effects and ensures the ability to
tolerate.
• Varying sensitivity of individuals to opioids is also a moot
point in analgesic selection.
• Genotyping for CYP2D6 metabolize status would help in
accurate dosing
• Clinical usage of opioids requires the right agent, optimization
of dose and at times rehabilitation and physiotherapy for
effective recovery.
• A multimodal approach to pain allows for lower doses of
opioids with risk reduction.
• The perioperative pain management could be achieved by
epidural or intrathecal opioids, systemic opioid PCA and
regional technique
• The choice of analgesic and its administration hangs on the
anesthetists’ competency.
• It is not enough to manage pain through pharmacotherapy,
but emotional and behavioral component should also be
addressed.
• The Concomitant use of alcohol and opioids lead to
dumping syndrome which is a pharmacokinetic phenomenon
characterized by unintended, rapid release (over a short period
of time) of the entire amount or a signicant fraction of the
drug contained in a modied-release dosage form.
• combination of opioids with NSAIDs require short duration of
therapy as deleterious effects of NSAIDs supervene.
Conclusion
A review of the published data focusing on the pharmacokinetics
of opioids brought forth pertinent variations that are critical
in making optimal analgesic choice. Analgesic dose titration
is mandatory to optimize pain relief and reduce adverse drug
reactions. Combination of analgesics having varied mechanisms
of action is advocated for optimizing analgesic therapy. Opioid
analgesics are widely used but ferreting out the appropriate dose,
route and agent is the crux in effect analgesic.
Acknowledgements
Special mention of acknowledgement to Mrs. Prathiba Kamble,
for her contribution of the classication of opioids- Vide table 3
to this article.
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