text:
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Volume 10, Number 6, 2007
© Mary Ann Liebert, Inc.
DOI: 10.1089/jpm.2007.9842
The Pharmacologic Management of Cancer Pain
The under treatment of cancer pain is still a major issue in both oncology and palliative medicine.
The initial availability of opioids is seen as an important philosophical step forward in the phar-
macological treatment of cancer pain, one for which there continues to be considerable barriers
within regulatory and medical domains. Knowledge of the key pharmacological properties of the
multiple opioids available will assist in both improved analgesia and side effects. Understanding the
mechanisms of pain is important in terms of treatment, especially in terms of the choice of co-anal-
gesic agents. Much of the work obtained from the study of cancer patients is applicable to the non
cancer populations, as is work performed in non cancer patients with neuropathic pain.
the extensive research done with cancer pain popula-
tion, this will be the primary topic of this review. How-
ever, much of the research on the use of coanalgesics
has been done in noncancer pain. Many of the rec-
ommendations are applicable in palliative care popu-
lations other than those with cancer. Many clinical
guidelines are available to assist in the management of
cancer pain (Table 1).
AIN IS A MAJOR PROBLEM in palliative care but given
its prevalence in those with advanced cancer and
Pain, both acute and chronic, is a commonly reported
symptom in our community. Many people experience
pain, and one third of those interviewed in a recent pop-
ulation-based survey described their pain as disabling.1
Pain is present in 24% to 62% of adult patients at the
time of cancer diagnosis2,3and in almost all patients in
the terminal stages of cancer.4Among children with
cancer, 75% experience pain at the end of life.5
While expert opinion estimates that 90% of patients
can achieve adequate pain control with current pain
management strategies, we still find a significant per-
centage of patients with cancer living with under-
treated pain. Undertreatment of pain may be, in part,
related to minority status and greater age. Many pa-
tients receiving care at Eastern Cooperative Oncology
Group (ECOG) centers were undertreated for pain,
with older African American females being most likely
to be undertreated.6
Furthermore, patients treated at minority Commu-
nity Clinical Oncology Program (CCOP) facilities
were even less likely to receive guideline recom-
mended therapy.7While Morrison and colleagues8
noted the lack of availability of opioids in "nonwhite"
metropolitan areas, the primary reason given by phar-
macists for not stocking opioids was a lack of pre-
scriptions presented to their pharmacies. In a recent
retrospective review of more than 7000 U.S. patients
with cancer receiving hospice-based palliative care,9
there was a highly significant inverse association be-
tween age group and opioid dose. Older patients re-
ceived less opioids with only 15% of those greater than
90 years receiving more than 120 mg/d of morphine
equivalents compared to 50% of those aged 40–49
years. Decreased drug clearance in the very old may
play some role in this lower dose but undertreatment
is an ongoing concern. At least 50% of patients with
Department of Medicine, University of Wisconsin, Madison Wisconsin.
Palliative Care Reviews
Feature Editors: Robert M. Arnold and Solomon Liao
Page 2
a cancer diagnosis living in U.S. nursing homes re-
ported persistent severe pain,10again suggesting un-
dertreatment. Long-term cancer survivors frequently
report chronic pain syndromes (e.g., neuropathic pain
following surgery, chemotherapy and radiation ther-
apy in head and neck cancer patients) that are both un-
derdiagnosed and undertreated.11The potential mag-
nitude of this problem is illustrated in one breast cancer
population in which 50% of patients continued to ex-
perience postmastectomy pain 9 years after surgery.12
The World Health Organization pain relief ladder
The World Health Organization (WHO) pain relief
ladder has been the longstanding educational tool and
guideline for the treatment of cancer-related pain. Es-
poused in 1986,13the ladder recommended that cancer
pain be managed in a stepwise progression, moving
from nonopioids and NSAIDs (Step 1) to "weak" opi-
oids (Step 2) and then to "strong" opioids (Step 3). A
number of studies have addressed the effectiveness of
this stepwise approach to pain treatment. An Italian
study demonstrated that pain management adminis-
tered according to the WHO guideline was effective in
71% of those treated.14However, effectiveness was not
achieved quickly and in close to one third of patients,
the prescribed pain medicines were not effective.
Nonopioids were prescribed for an average duration of
19 days; in 52% of the cases, treatment was discontin-
ued due to inefficacy and in 42% because of side ef-
fects. "Weak" opioids were administered on average
for 28 days with the shift to "strong opioids" due to in-
efficacy in 92% of cases and due to side effects in 8%.
A similar German study, involving 2000 patients,15
showed effective pain control in 76% of those treated
according to the WHO ladder but still a significant
number of patients spent time without adequate pain
relief. A similar retrospective study was performed in
8 pediatrics cancer centers in Germany addressing the
role of the ladder in the treatment of 224 children with
cancer.16During nonopioid and opioid combination
therapy, side effects were more frequent and average
pain scores higher than for opioid therapy alone, sug-
gesting that opioid therapy should be the choice for in-
patient pediatric patients with cancer. A systematic re-
view suggested that there was no proven clinical benefit
of the WHO ladder.17However, others have argued to
the contrary on the basis that the ladder has served as
both a major teaching tool for the treatment of cancer
pain and a political tool to ensure the availability of
opioids for cancer pain relief.18–20
The Agency for Health Care Policy and Research
(now Agency for Healthcare Research and Quality
AHRQ) released Cancer Pain Guidelines in 199421
with the recommendation that the choice of analgesic
agent should be based on a patient's pain severity rat-
ing. This approach was founded on the work of the Pain
Research Group22which documented the severity lev-
els of self-rated pain scales (1–4, mild; 5–6, moderate;
and 7–10, severe) based on interference with activities
of daily living. The guidelines recommended that mild
pain should be treated with acetaminophen and
NSAIDs, moderate pain with "weak" opioids and se-
vere pain with "strong" opioids. The recent revision of
these Cancer Pain guidelines by the American Pain So-
ciety23states that all patients with cancer should have
access to opioids for the treatment of cancer pain while
supporting an approach based on the mechanism of
pain. Ashby and colleagues24recommended a treat-
ment approach based on pain classification: superficial
somatic, deep somatic, visceral and neurogenic (mixed
or pure, i.e., nociceptive component present or absent).
In testing this model in a small number of patients, al-
most all had multiple mechanisms, suggesting the need
to use multiple therapy modalities (e.g., opioids,
coanalgesics, psychological support, etc.).
This approach has also been endorsed by the Na-
tional Cancer Center Network (NCCN) Cancer Pain
guideline.25A number of factors contribute to this
change in approach. First, the differentiation between
"weak" and "strong" opioids has been artificial and
defined more by the combination products (e.g., hy-
drocodone and acetaminophen, oxycodone, and acet-
aminophen) rather than the opioids themselves. Sec-
ond, the impact of pain on a patient's quality of life is
determined by the "pain worst" they endure each day
rather than average pain.22Severe pain causes major
interference with a patient's activities of daily living
American Pain Society Clinical Practice Guidelines
Management of Cancer Pain in Adults & Children, 2005
Academy of Hospice and Palliative Medicine
Clinical Practice Guidelines for Quality Palliative Care
World Health Organization (WHO)
Cancer Pain Relief and Palliative Care in Children, 1998
Cancer Pain Relief with a guide to Opioid Availability,
International Association for the Study of Pain
Core Curriculum for Professional Education in Pain, 2005
National Comprehensive Cancer Network Clinical Practice
Guidelines in Oncology
Adult Cancer Pain
Pediatric Cancer Pain
Page 3
(e.g., interacting with others, eating, sleeping), and the
patient should have appropriate medications, namely
opioids, available to treat such severe pain when it oc-
curs, as confirmed by Marinangeli and colleagues.26
In this randomized study of initial "strong" opioids
versus the WHO pain relief ladder, improved pain
management in the "strong" opioid group supported
the commencement of "strong" opioids as first-line
therapy. No differences were seen between the arms
(WHO ladder versus initial "strong" opioids) in terms
of quality of life. Patients in the "strong" opioid group,
in comparison to the WHO ladder group, reported bet-
ter pain relief and had fewer changes in therapy, a
greater reduction in pain when a change was initiated
and greater satisfaction with overall treatment.
The WHO ladder has served as simple yet effective
teaching tool while applying pressure on regulators to
allow opioids for the treatment of cancer pain. Most
of the Step 1 medications in the United States are avail-
able over the counter, and many patients have tried
these prior to seeking medical assistance. The same
however cannot be said of developing countries where
both nonopioids and opioids are often limited.27-30The
International Narcotic Control Board has recognized
that opioids are indispensable for the treatment of pain
and should be available in a balanced manner for the
treatment of pain while minimizing diversion.31
Pharmacologic agents are the mainstay of cancer
pain relief, and understanding the mechanisms of pain
is important in both the use of opioids, nonopioid anal-
gesics and coanalgesics. Pain is mediated through both
peripheral and central mechanisms. In nociceptive
pain, peripheral nociceptors are stimulated and trans-
mit pain through pain fibers to the dorsal horn of the
spinal cord through to the thalamus and cortex while
neuropathic pain results from direct injury to the pain
transmission fibers. The transmission of pain in the
dorsal horn is proposed to involve a complex series of
events that are modulated by a variety of receptors, ion
channels and neurotransmitter systems. Examples of
these include the serotonin, mu, and GABA receptors,
and sodium and calcium channels, with mediation by
the NMDA receptors and nitrous oxide, which may be
responsible for hyperalgesia.
Opioids are thought to exert their effect by action
with one or more subclasses of the three opiate re-
ceptors known as mu, delta, and kappa32–34with the
mu receptor being primarily involved in analgesia.
These three receptors share common properties—they
are 370–400 amino acid pairs, and all are negatively
coupled through Giprotein to adenylate cyclase.35Ag-
onist occupancy of the mu receptor leads to several
events that result in inhibition of neuron activation,
through (1) induction of membrane hyperpolarization
through the activation of an inwardly rectifying potas-
sium channel and (2) inhibition of the opening of volt-
age sensitive calcium channels that will subsequently
depress the terminal release of neurotransmitter from
the cell. These opioid receptors are located in the brain,
spinal cord and at peripheral afferent terminals. Opi-
oids acting primarily at the periaqueductal gray (PAG)
result in increased activity in descending pathways
with decreased firing of "on" cells and increased fir-
ing of "off" cells resulting in downward inhibition/
modulation of dorsal horn firing. Opioids also work at
the level of the amygdala, medial thalamus, and pre-
frontal cortex to block predominantly the affective
component of pain. In the spinal cord, opiates act in
the substantia gelatinosa, both at presynaptic and post-
synaptic sites. Presynaptically, they prevent release of
neurotransmitter via voltage-gated calcium channels,
while postsynaptically, they inhibit second order neu-
rons by stimulating inward rectifying potassium chan-
nels. Both these brain and spinal cord actions result in
analgesia. Peripheral action, through alteration of the
excitability in terminals located in the inflammatory
milieu, only blocks hyperalgesia.
Different opioids have different affinities to the mu
receptor (Table 2)32,33and other opioid receptors.34
The choice of opioid is dependent on both patient and
drug characteristics.9Most commonly used opioids are
pure agonists for the mu receptor; however, structural
differences may lead to differences in analgesia, al-
though this has not been confirmed in human studies.
Lemberg and colleagues36recently studied the phar-
macodynamics of different opioids (morphine, oxy-
codone and methadone and its racemates) in both acute
nociceptive and neuropathic pain models in the rat.
Rats were subjected to nociceptive pain stimulation
(tail flick, hot plate, and paw pressure) and neuropathic
pain stimulation (mechanical and cold allodynia in rats
subjected to spinal nerve ligation). Morphine, oxy-
Page 4
codone, methadone, and L-methadone produced anti-
nociception in a dose dependent manner and produced
antiallodynic effect for both mechanical and cold
allodynia. D-methadone had no impact in any of these
rat pain models. The challenge of confirming these
findings in patients with cancer remains.
Morphine continues to be considered the standard
medication for the treatment of cancer pain partly due
to familiarity with the product as well as cost effec-
tiveness. However it may not always be the ideal prod-
uct due to issues associated with metabolism and side
effect profile. Available morphine formulations are
oral, rectal and parenteral (administered through sub-
cutaneous, intravenous and intraspinal routes). Oral
formulations are available as immediate-release (IR)
or sustained-release (SR) products. A review of 14
comparative studies showed no difference in analge-
sia between the IR and SR products at the same daily
dose.37However, this result should not be surprising
as many of these studies were powered to show equiv-
alence (often for product registration) rather than to
detect an improvement in analgesia or improvement in
side effects. The SR formulations are administered on
schedules that range from once per day to three times
daily.38,39Granular SR releaese products can be ad-
ministered by oral route or by G-tube with retention
of the SR characteristics.
Oral bioavailability ranges from 15%–60% with the
most quoted figure being 30%.40There is little evi-
dence that morphine is absorbed sublingually; in fact,
sublingual administration results in delayed absorption
of morphine (tmax, 75 minutes) compared to oral ad-
ministration (tmax, 45 minutes).41When used on
wounds, there is no evidence of absorption systemi-
cally42; however, the mechanism of its local effect has
not been fully elucidated. It is suggested that opioid
receptors sited on sensory nerve terminals may be up-
regulated in inflammation.43Morphine is absorbed
rectally with bioavailability equivalent to oral admin-
Morphine is metabolized to morphine-3-glu-
curonide (M-3-G) and morphine-6-glucuronide (M-6-
G) in the liver.41Ten to 14% percent of morphine is
metabolized to M-6-G,45an active metabolite 10 times
more potent than morphine itself and a useful anal-
gesic in its own right.46Sixty percent of morphine is
metabolized to M-3-G, a compound that has no re-
ported analgesic properties47,48but a compound that
may contribute to side effects and has been suggested
to act as an opioid antagonist at higher doses.49Inter-
estingly, Penson's study of the administration of M-3-
G to healthy volunteers showed no neurotoxicity at the
delivered doses.48The half-lives of M-6-G (12 hours)
and M-3-G (16 hours) are significantly longer that the
half-life of morphine (2.5–4 hours). There is little cor-
relation with serum concentrations of morphine or its
metabolites with analgesia.50,51
Glucuronidation of morphine takes place predomi-
nantly in the liver52and continues to occur in all but
the most serious of liver disease.53Enterocytes of the
gastrointestinal tract may contribute significantly to
first pass extraction after the oral administration of
morphine.54In patients with severe cirrhosis with a
history of encephalopathy, the plasma clearance of
morphine was significantly lower, its terminal elimi-
nation half-life longer and its oral bioavailability
greater than in patients with normal liver function.55
Renal impairment results in the accumulation of glu-
curonides with increased side effects.56While mor-
phine is not a recommended opioid in those with re-
nal failure, the glucuronides are water soluble and
therefore cleared by dialysis but not hemofiltration.57
Codeine is an opioid that is available as a distinct
product in many parts of the world; however, in the
United States, it is primarily available as a combina-
tion product with acetaminophen. Despite being a Step
2 drug on the WHO ladder, codeine (as a discrete prod-
uct) is a DEA Schedule II product in the United States
with use limited by the requirement of a written pre-
scription. Two systematic reviews comparing acet-
aminophen-codeine combinations versus acetamino-
phen alone concluded that in single dose studies, the
addition of codeine to acetaminophen produced a com-
paratively small but statistically significant increase in
analgesic effect; however, there was an increased in-
cidence of side-effects with the combination.58,59
While available as an intramuscular injection, it is pri-
marily used in the oral formulation with a bioavail-
ability of approximately 50%.60Elimination half-life
ranged from 3.2–5.7 hours with a mean of 3.7 hours.61
Codeine is a prodrug whose analgesic activity is me-
diated through the mu receptor by its metabolite, mor-
phine. Repeated administration of codeine results in
the measurable serum concentrations of morphine.60
Ten percent of codeine is broken down to morphine
by cytochrome p450 (CYP) 2D6, an enzyme lacking
in 5%–10% of Caucasians populations.62The ob-
Page 5
served ceiling effect of codeine may be related to sat-
uration of CYP2D6 together with accumulation of
other metabolites, such as glucuronides.63In a clini-
cal study, 14 extensive metabolizers of CYP2D6 and
14 poor metabolizers were administered morphine,
codeine, and placebo and subjected to painful stim-
uli.64Poor metabolizers had good analgesia with mor-
phine and poor analgesia with codeine. Neither mor-
phine nor M-6-G was detected in poor metabolizers
administered codeine whereas both were detected in
extensive metabolizers. Another recent study exam-
ined the kinetics in ultrametabolizers of CYP2D6,
showing 50% higher plasma concentrations of mor-
phine and its glucuronides after the administration of
codeine.61More sedation was reported by a signifi-
cantly higher number of ultrametabolizers compared
to the extensive metabolizers. The role of inhibitors of
CYP2D6 on the analgesic effect of codeine has not
been well elucidated although a possible implication
is an alteration in its analgesic effect.65,66Quinidine
administration with codeine reduced morphine pro-
duction and codeine "drug effect" in Caucasians but
not in Chinese individuals suggesting the presence of
racial variability with CYP2D6.67While all of this data
suggests value in screening for CYP2D6 polymor-
phism if one is considering the use of codeine, the
overall clinical implications are uncertain. A clinical
study in children posttonsillectomy suggested that
analgesia from codeine was less reliable but neither
did it correlate well with phenotype or plasma mor-
phine concentrations.68With the formation of mor-
phine together with significant glucuronidation of both
codeine and morphine, codeine is not recommended
in renal failure.57,69
Tramadol is a widely used analgesic due partly to
the fact that it is not a scheduled DEA opioid in the
United States although the DEA classifies it as a "Drug
of Concern." It is a synthetic mu receptor agonist that
consists of two enantiomers. L-tramadol is a weak in-
hibitor of the reuptake of serotonin and R-tramadol a
weak inhibitor of norepinephrine, enhancing inhibitory
effects on pain transmission in the spinal cord.70The
oral bioavailability of tramadol is 75%. Tramadol is a
prodrug with its metabolite, M1 or O-desmethyl-tra-
madol, believed to produce more analgesic effect than
the parent compound.71Tramadol and the M1 metab-
olite have half-lives of 6.3 and 7.4 hours, respectively.
The formation of M1 and, hence, the analgesia of tra-
madol is influenced by CYP2D6.72More recent data
suggests that tramadol metabolism by CYP2D6 is
enantioselective with no (?)-M1, the active moiety of
M1, produced in poor metabolizers,73, raising the pos-
sibility of decreased analgesic response or increased
side effects in those with decreased CYP2D6 activity.
It has also been demonstrated that ondansetron, a 5HT3
anti-emetic agent, interferes with the analgesia of tra-
madol.74The interaction of tramadol and selective
serotonin reuptake inhibitors can result in the serotonin
syndrome, the clinical manifestations of which are a
triad of altered conscious state, autonomic dysfunc-
tion, and neuromuscular excitability.75
While originally suggested to have an analgesic ef-
ficacy equivalent to morphine and therefore classified
as a WHO Step 3 drug, tramadol is now most com-
monly thought of as a WHO Step 2 drug. In a non-
randomized study comparing low dose morphine with
higher dose tramadol, a conversion ratio of 10:1 was
proposed with tramadol doses of over 400 mg/d being
tolerated safely.76A meta-analysis suggests the prod-
uct is equivalent to codeine and aspirin with similar
side effects for acute postoperative pain.77In ran-
domized crossover studies, there is a suggestion that
tramadol may have an analgesic effect in neuropathic
pain.78,79It is calculated that 4.3 patients would have
to be treated for 1 patient to achieve a greater than
50% improvement in neuropathic pain,80a measure re-
ferred to as the number needed to treat (NNT). Direct
calculations for the treatment of neuropathic pain for
other opioids have not been performed. A risk of
seizures has been identified with tramadol81,82al-
though this is thought to be no different than idiopathic
seizures in an equivalent population.83A dose of
greater than 400 mg/d is often poorly tolerated in the
elderly and in those with renal impairment.
Hydrocodone products are commonly used within
U.S. health care when combined with acetaminophen.
Its labeling as a DEA Schedule III product (allowing
pharmacists in most U.S. states to dispense without a
written prescription and with telephoned prescriptions)
has probably facilitated its utilization by U.S. clini-
cians. The dose of hydrocodone is typically limited by
the amount of acetaminophen that a patient can have
each day. New formulations have seen an increase in
the dose of hydrocodone relative to acetaminophen al-
lowing for higher daily doses of the drug to be ad-
ministered (hydrocodone 2.5–10 mg). Hydrocodone
has a half-life of 3.8 hours with a tmaxof 1.3 hours.84
Hydrocodone is metabolized by CYP2D6 to hydro-
morphone85,86and by CYP3A4 to norhydrocodone.86
Some 40% of hydrocodone metabolism is through
Page 6
pathways other than the CYP450s.86The role of the
metabolite hydromorphone in the analgesic effect of
hydrocodone is uncertain but is suggested to play a
role.85Hydrocodone is a drug that continues to be used
for patients initially presenting with cancer-related
pain but much of the clinical research has been for
conditions such as low back pain.87In a recent dental
study of pain following molar extraction, hy-
drocodone/acetaminophen (7.5/500 mg combination)
had less analgesia and more side effects than oxy-
codone (5 mg) in combination with either ibuprofen
or acetaminophen.88An emergency department study
with repair of fractures showed no difference in anal-
gesia between similar doses of oxycodone and hy-
Hydromorphone is very similar in structure to mor-
phine and is available as parenteral and oral products.
It has been available only as an immediate release
product in the United States. While Canada has had a
SR hydromorphone product for some years,90approval
of such a product in the United States91had only re-
cently been finalized as a once daily capsule formula-
tion. However its approval was immediately with-
drawn, with both a shortening in Tmaxand an increase
in bioavailability when coadministered with alcohol.
Administered orally, hydromorphone has a bioavail-
ability of 50% and a plasma elimination half-life of
2.5 hours.92Hydromorphone is metabolized to hydro-
morphone-3-glucuronide,93a compound that has no
known analgesic properties but one that may contrib-
ute to the neuroexcitatory toxicity of the drug.94Hy-
dromorphone is commonly used in the treatment of
acute pain especially in those with renal impairment
where the use of morphine may result in increased ac-
cumulation of metabolites and increased side effects.95
While the clearance of hydromorphone-3-glucuronide
is delayed in renal failure, there is little information as
to its impact on both analgesia and side effects.96
In a Cochrane systematic review with 43 studies and
2725 patients with acute and chronic pain,97the ma-
jority of studies demonstrated that hydromorphone
was a potent analgesic, that the analgesic effects of hy-
dromorphone appeared to be dose-related, and that the
adverse effect profile of hydromorphone was similar
to that of other mu opioid receptor agonists. No clear
benefit of hydromorphone over morphine was identi-
fied. On a milligram basis hydromorphone is five times
as potent as morphine when given orally, and 8.5 times
as potent as morphine when given intravenously.98
Fentanyl, a lipid soluble synthetic opioid, is avail-
able as parenteral, transdermal, and transmucosal
products. Its lipophilicity allows it to cross both the
skin and oral mucosa.99It is metabolized to norfen-
tanyl,100under the influence of cytochrome 450
3A4.101The concomitant use of fentanyl with potent
cytochrome P450 3A4 inhibitors (e.g., ritonavir, keto-
conazole) may affect metabolism. It is one of the opi-
oids that can be administered safely to patients with
renal failure,57,96although it should not be used as the
initial opioid in an opioid naïve patient with renal im-
pairment. Uremia can induce CYP3A4 activity that
may lead to decreased metabolism and a prolonged
elimination half-life. In a study of transmucoal fen-
tanyl, there was no kinetic nor analgesic differences
found between younger (18–40 years) and older
(60–75 years) volunteers.102However in older patients
administered fentanyl transdermally, plasma concen-
trations took longer to double (4.2 versus 11 hours)
but mean plasma concentrations, time to maximum
concentration, and elimination half-life were not dif-
ferent, again suggesting no difference in overall fen-
tanyl kinetics between younger and older patients.103
The elimination half life of transdermal fentanyl is ap-
proximately 2–3 times greater than that of intravenous
P. fentanyl (3–6 hours).104
The oral transmucosal administration of fentanyl
has been extensively explored. In one study, 25% of
the delivered drug was absorbed transmucosally with
another 25% delivered through the gastrointestinal
tract.99Randomized controlled trials of oral transmu-
cosal fentanyl citrate (OTFC) have shown both in-
creased analgesic efficacy and patient preference over
placebo105and morphine.106The administration of
fentanyl is currently being explored through other
routes, that is, intranasally107and nebulized.108The
rapid intravenous administration of fentanyl in the
emergency room has resulted in a rapid improvement
in pain control,109an effect also seen with mor-
phine.110Eighteen patients were successfully treated
with this protocol with the average time to pain con-
trol approximately 11 minutes and without significant
adverse effects.
The pharmacology of the fentanyl delivered through
the transdermal therapeutic system is such that the fen-
tanyl passively passes down a concentration gradient
from a reservoir of fentanyl in the patch, across the
patch membrane into the stratum corneum from where
it diffuses slowly out into the blood. The surface area
of the patch determines the rate of diffusion. A newer
formulation is the matrix delivery system in which fen-
Page 7
tanyl is dissolved in a polyacrylate adhesive that to-
gether with the stratum corneum provides the rate con-
trolling element of the percutaneous absorption. This
formulation can be cut—a potential therapeutic bene-
fit. Both the reservoir and matrix based patches are re-
ported to have similar kinetics111and clinical effec-
tiveness.112The time to peak concentration is between
16 to 24 hours.113Improved steady-state kinetics is
one of attributes suggested for using the fentanyl patch,
but Portenoy's original study of repeated dosing
showed both significant interpatient and intrapatient
variation.113This has been confirmed in more recent
studies104with bioavailability independent of dose,
number of patches, and patch placement. One third of
patients absorbed less than 60% of fentanyl present in
a patch and less than 10% of patients absorbed more
than 84%.104There is little known about use in
cachexic patients with expert opinion varying from in-
creased flow into the blood system to decreased ab-
sorption due to the lack of fatty tissue.
The first line use of fentanyl is not documented in
any guidelines, and recommendations are to start with
oral opioids prior to switching to the fentanyl patch,114
and increasing the dose no more than every 48
hours.114If pain is controlled using oral opioids, there
is no need for the early use of the fentanyl patch. An
industry-sponsored study has suggested that starting
patients on fentanyl was a safe and effective mecha-
nism for pain control115with the same authors report-
ing their experience with fentanyl in over 1800 pa-
tients, 268 of who were opioid naïve and 1200 who
had been on WHO step 2 medications.116They re-
ported successful use of the fentanyl patch with a me-
dian dose of 50 ?g/hr. An 8-nation study of approxi-
mately 300 patients showed the safety of starting with
the fentanyl patch in patients who had not been stabi-
lized on oral opioids.117Reports of severe respiratory
depression and sedation with the use of transdermal
fentanyl118led the author to continue to follow the
guidelines of Payne114and to not use transdermal fen-
tanyl as first-line therapy, a view shared by others.119
In another industry-sponsored study, it was suggested
that the dose could be safely increased every 24
hours.120This study was performed in an inpatient set-
ting with much closer nursing interaction than one
would expect in the home setting. At equianalgesic
dosing, there is a suggestion of improved side effects
with fentanyl compared with morphine particularly
with constipation121–123but greater disturbance in
sleep with fentanyl.122
Other delivery methods of fentanyl are under de-
velopment together with the intranasally107and nebu-
lized108products. In the postoperative setting, fentanyl
delivered by a patient-controlled iontophoretic trans-
dermal system was suggested to have equivalency to
intravenous morphine delivered by patient-controlled
analgesia (PCA).124
In the United States, oxycodone has been primarily
used as a WHO Step 2 drug because of its availabil-
ity in combination products where the total daily dose
is limited by the acetaminophen content. It has also
been available as a distinct oxycodone product but the
formulation was commonly limited to 5 mg tablets,
despite usage of up to 60 mg (12 tablets) every 4
hours.40The SR product led to oxycodone's evolution
from an opioid for moderate pain alone to one for both
moderate and severe pain.
Oxycodone is a synthetic opioid developed in Ger-
many in 1916. It has a half-life of approx 2–4 hours
125and a bioavailability of 50-60% based on kinetic
data from Finland126where a parenteral formulation
is in common use. This compares with the relative
bioavailability of 87% quoted and used in the US Pack-
age insert 127, data based on a study performed in sep-
arate groups of patients with known metastatic liver
disease. This is not the usual methodology for a
bioavailability study (same subjects without disease)
particularly given the great variability in opioid me-
tabolism between individuals. It is also difficult to ap-
ply this relative bioavailability to clinical use. No dif-
ference in pharmacokinetics was seen in patients based
on age 128with similar kinetics seen in children when
compared to adults.129
Conversion ratios from morphine to oxycodone
have ranged from 2:1 to 1:1.130The most accurate con-
version ratios seem to come from a paper by Kalso's
group that showed conversions ratios of 1.2:1 to 1:0.8.
The variability in this conversion is based on the di-
rection of the conversion (morphine to oxycodone ver-
sus oxycodone to morphine).131Based on these results,
it is generally safe to assume that 10 mg of oral mor-
phine has equivalent analgesic effect of 10 mg of oral
oxycodone. Dose reductions in the process of conver-
sion may be necessary and should be considered be-
cause of incomplete cross-tolerance.
Oxycodone should be used cautiously in patients
with liver disease. Tallgren and colleagues132admin-
istered oxycodone to patients with cirrhosis prior to
and after liver transplant. The mean half-life of oxy-
codone in these patients was 13.9 hours prior to trans-
plant and 3.4 hours posttransplant. Side effects, in-
cluding the risk of respiratory depression, were greater
in the patients prior to transplant. Dean57proposes that
Page 8
there is insufficient data to make a recommendation
regarding the use of oxycodone in renal failure. There
is documentation of an increased half-life of oxy-
codone in renal failure (by 1 hour) and suggestions
that the metabolite oxymorphone may accumulate in
renal failure.133There is evidence from a single case
report that it may be removed by dialysis.134
Oxycodone is metabolized in the liver to oxymor-
phone,135a potent analgesic with 40 times greater
affinity for the mu receptor than oxycodone. It is sug-
gested that the small quantities of oxymorphone
formed play a significant role in oxycodone metabo-
lism.136Cytochrome P450 plays an important role in
the metabolism of oxycodone with CYP3A4 and
CYP3A5 contributing to N-demethylation to noroxy-
codone and CYP2D6 contributing to the O-demethy-
lation to oxymorphone. In human microsomal enzyme
studies,137inhibition with ketoconazole showed that
CYP3A4 is the high-affinity enzyme for oxycodone
N-demethylation, inhibiting greater than 90% of
noroxycodone production. Inhibition with quinidine,
an inhibitor of CYP2D6, resulted in a 75%–90% re-
duction in oxymorphone production. On average, the
total intrinsic clearance for noroxycodone formation
was 8 times greater than that for oxymorphone for-
mation across the five liver microsomal preparations.
Volunteer studies suggest that oxymorphone does
not contribute to the analgesic effects of oxycodone,
although reduced oxymorphone production was seen
in extensive metabolizers given oxycodone following
pre-medication with quinidine, a CYP2D6 inhibi-
tor.135However, no change was seen in the psy-
chomotor or subjective drug effects of oxycodone.
Analgesic effect was not measured, as pain was not
present, nor induced in these volunteers. Lalovic and
colleagues138demonstrated that the time course of the
central opioid effects of oxycodone could be explained
by the pharmacokinetics and dynamics of oxycodone
alone. Although noroxymorphone, a potent active me-
tabolite, was present at relatively high concentrations
in circulation, it did not appear to penetrate the blood-
brain barrier to a significant extent. Other metabolites
either demonstrate low potency (noroxycodone and ?-
noroxycodol) or are present in circulation at very low
levels (oxymorphone and ?- and ?-oxycodol). In ad-
dition, all metabolites demonstrate restricted brain
penetration as compared with the parent drug,138sug-
gesting that oxycodone is responsible for its own anal-
gesia. However the formation of these metabolites
within the brain has not been excluded. A continuing
paradox remains that oxycodone has high analgesic
potency despite a relatively low affinity for mu re-
ceptors compared to morphine.
Oxymorphone, a product of oxycodone metabolism,
is another semisynthetic opioid. It has been available
in the parenteral form since the 1950s and continued
to be used for obstetric pain.139New IR and SR oral
formulations have recently been used with analgesia
and tolerability similar to morphine and oxycodone.140
The bioavailability of immediate release oxymorphone
is considered to be approximately 10%141with a tmax
of 30 minutes and a terminal elimination half-life of
approximately 8 hours. Metabolism is through glu-
curonidation to oxymorphone-3-glucuronide as well as
through CYP3A4 to noroxymorphone, both occurring
in the liver. Oxymoprhone-3-glucuronide accounts for
a third of metabolites collected in the urine. In an in-
dustry-sponsored comparative study with oxycodone,
it was suggested that an oxymorphone dose, half that
of a successful oxycodone dose is effective in cancer
patients.142The use of intramuscular oxymorphone
and morphine was compared in cancer pain patients,
and oxymorphone was found to be approximately 8
times as potent as morphine in terms of total analgesic
effect and 13 times as potent in terms of peak effect.143
However, with an oral bioavailability of only 10%, re-
cent comparisons have found extended release (ER)
oxymorphone to morphine SR to be 1 to 1.8 in terms
of equianalgesic effect.144The addition of oxymor-
phone to the cancer pain armamentarium should be
useful in the context of opioid rotation. The plasma
levels of oxymorphone administered as an ER tablet
were about 40% higher in elderly than in younger sub-
jects. Hepatic and renal impairment increased the
plasma concentration of ER oxymorphone and con-
current alcohol administration increases the bioavail-
ability of oxymorphone.144
Methadone is a long-acting opioid that has been
available for the treatment of pain since its synthesis
in the 1930s in Germany. Its use in the treatment of
cancer pain fell away with the introduction of the
newer "sustained release" products. Methadone has
similar adverse effects to the other opioids and has a
rapid onset of action with approximately 70%–80%
bioavailability when administered either orally or rec-
tally.145,146Ferrari and colleagues147have recently re-
viewed the pharmacokinetics of methadone. It has an
initial distribution half-life of 2–4 hours with a Tmax
of 1–6 hours in which time methadone exerts analgesic
activity as it is distributed throughout tissues in the
body including the liver and peripheral tissues with a
volume of distribution of 3.L/kg.148It is from this
Page 9
store, in particular, that methadone is slowly released
into the circulation for use as an analgesic. The large
volume of distribution and long half-life make the
pharmacokinetics of methadone unpredictable. The
titration of methadone is difficult, contributing to the
difficulty in converting from other opioids to
methadone. It has a long duration of action with
chronic use and as with most pure opioid agonists has
no ceiling dose. The long duration of action is due in
part to its long elimination half-life ranging from
15–60 hours.148,149
Methadone is not believed to have active metabo-
lites but is metabolized by hepatic CYP3A4150,151by
CYP2D6 and by both hepatic and intestinal CYP2B6
and CYP3A4145with CYP2B6 metabolizes the non-
opioid binding d-methadone enantiomer. The work of
Kharash et al.145is significant because the clinical
finding—especially for those with HIV and who are
using methadone—that drugs that inhibit CYP3A4
(such as fluconazole) and promote CYP3A4 upregu-
lation (carbamazepine) can promote side effects or in-
duce withdrawal respectively.152Kharash et al.145
found no evidence that CYP3A4 induction or inhibi-
tion changed methadone clearance but suggested that
the impact on drug levels by rifampacin may be on in-
testinal transporters that affect the absorption.
Findings show that methadone may have a poten-
tial role in the treatment of neuropathic pain,153,154al-
though other data suggests that NMDA receptor inhi-
bition is not important. A number of studies from
Bruera and colleagues155,156have not confirmed this
finding in a subset of cancer patients with neuropathic
pain. Methadone is a racemic mixture and L-
methadone is the active isomer for analgesia although
both racemates may be necessary for interaction with
the NMDA receptor.157. NMDA receptor antagonism
does not appear to contribute to the mechanism of d-
methadone antinociception.158The broad scope of its
analgesic properties together with its lower cost are
two reasons why methadone has undergone a renais-
sance in cancer pain treatment.
Methadone has been found to be highly effective as
an alternative to other opioids but difficulty with the
conversion ratio make this process both a challenge
and barrier to its use. The classic ratio commonly seen
in conversion charts is a 3:2 conversion. This conver-
sion is in fact true for single dose conversion namely
that 30 mg of morphine is equal to 20 mg of
methadone. This conversion is however incorrect for
long-term dosing. Different methods of conversion
have been proposed. The Edmonton Group has used a
simple 10:1 conversion ratio.159Other methods are
outlined in Tables 3 and 4 using suggestions from Ri-
pamonti et al.159and Morley et al.160Occasionally pa-
tients with a component of neuropathic pain may have
a dramatic improvement in pain when administered
much smaller doses of methadone than predicted. Not
only is the conversion ratio complex but the rate of
conversion to methadone can also be a somewhat com-
plicated process. Morley et al.160suggested stopping
Morphine doseMethadone dose (q8h)
Day 1 2/3 of dose4?1 if OME 30–90 mg/d
8?1 if OME 90–300 mg/d
12?1 if OME ?300 mg/d
Continue methadone
Increase dose if moderate–severe pain
Breakthrough with short-acting opioids
Maintain q8h methadone
10% of daily dose as breakthrough.
Assess methadone titration daily
Day 2 1/3 of dose
Day 3None
OME, oral morphine equivalents.
Day 1Stop morphine
Commence fixed-dose of methadone q 3h prn
Methadone dose ? 1/10 of daily oral morphine equivalent (max 30 mg)
Calculate average daily methadone dose for days 4 and 5.
Administer as bid dosing with breakthrough dose, q3h prn.
Increase dose as needed every 4–6 days by 30–50%.
Day 6
Page 10
morphine at the same time as methadone is started
while Ripamonti et al.,159suggested titrating down on
the morphine over 3 days. In a recent kinetic study of
the conversion from morphine to methadone,
methadone reached steady state within 1–2 days sug-
gesting a need to reduce the morphine dose more
rapidly than 3 days.161It is important for a clinician
to become familiar and gain experience with one con-
version methodology.
Many are beginning to use methadone as the pri-
mary analgesic agent. Dunlop162has suggested a
method for methadone as the initial opioid for the treat-
ment of pain. The suggested regimen was to prescribe
2.5 mg orally every 30 minutes as needed. Patients will
establish an effective dose for themselves as well as
an effective dosing interval with the continued ad-
ministration of the drug. Using this method of "as
needed dosing," patients should have maximal anal-
gesia while reducing the risk of overdosing and tox-
icity. Outcomes in terms of the analgesia and safety
of this method have not been reported. Others have
also started analgesia with methadone both effectively
and safely.163Once methadone has been commenced
and patients have reached a steady state, with satura-
tion of the peripheral tissue, methadone can be titrated
in the same manner as other opioids. An ongoing con-
cern is the interval between dose increases. Under-
standing that steady state would not be achieved for
4–5 half-lives, ideally the dose would be adjusted no
more than every 5–7 days, somewhat at odds with the
work of Mercandante161that suggested methadone
reached steady state in 1–2 days for methadone. From
experience, the dose of methadone may be adjusted
every 2–3 days with careful observation. Methadone
is another opioid reasonable for use for patients with
renal failure.57,146
One of the increasing concerns with methadone is
the documentation of arrhythmias in patients adminis-
tered methadone at higher parenteral doses.164–167QTc
interval prolongation has also been seen in patients re-
ceiving oral methadone at higher doses. In a recent
study of 138 patients on long term stable methadone
maintenance,1683 were found to have a prolonged QTc
interval and 19 had possibly prolonged QTcintervals.
Of note, after 2 years of follow-up, 2 patients had died,
both of whom had prolonged QTc intervals (their
causes of death were determined to be non cardiac).
There was no correlation with methadone plasma lev-
els and QTcintervals. No case of QTcprolongation
was reported in the M. D. Anderson experience with
patients with cancer who received considerably lower
doses of methadone than reported in other series.169
While the Food and Drug Administration (FDA) has
included a Black Box warning regarding QTcinterval
prolongation and methadone, and patients need to be
monitored, the role of other drugs that may cause QTc
prolongation in interaction with methadone needs to
be considered.
Buprenorphine is an opioid that is currently avail-
able in the United States as parenteral and sublingual
formulations approved for the treatment the treatment
of addiction. A transdermal formulation is now avail-
able in Europe and is under development in the United
States, and may be useful in the palliative care set-
ting,170hence, its discussion here. The primary actions
of buprenorphine in humans are as a partial agonist at
the mu-opioid receptor171and as an antagonist at the
kappa receptor. A partial agonist is a compound, which
possesses affinity for a receptor, but unlike a full ag-
onist, will elicit only a small degree of the pharmaco-
logical response of the receptor involved, even if the
compound occupies a high proportion of receptors.
Partial opioid agonists (e.g., buprenorphine) have less
intrinsic activity than full agonists and are character-
ized by a shallower dose response curve and a lower
maximum effect compared with a full agonist.
The effects of binding at mu-opioid receptors in-
clude supraspinal analgesia, respiratory depression,
and miosis while the antagonist effects at the kappa
receptor are associated with limited spinal analgesia,
and dysphoria and psychomimetic effects. Buprenor-
phine, being a partial mu-opioid agonist, may have a
wider safety profile compared to full mu agonists, es-
pecially with regard to respiratory depression.
Buprenorphine has a ceiling for respiratory depres-
sion172and should this occur, reversal may require
higher doses of infused nalaxone. Furthermore, the
slow dissociation of buprenorphine from the receptor
may result in fewer signs and symptoms of opioid
withdrawal upon termination of buprenorphine ther-
apy than those that occur with full mu-opioid agonists,
such as morphine, heroin, and methadone. The kappa
antagonist properties may in fact occur at doses above
those that are clinically relevant for analgesia. How-
ever, patients maintained on buprenorphine for addic-
tion who were given extra doses, experienced dys-
phoria and sleepiness while euphoria and drug liking
decreased.173There are suggestions that buprenor-
phine has a prolonged antihyperalgesic effect.174There
are also concerns with the coadministration of pure mu
agonists with buprenorphine; however, recent studies
Page 11
have shown that the combination does not result in re-
versal of analgesia or the onset of symptoms of with-
Buprenorphine is 25–50 times more potent than an
equivalent dose (by weight) of morphine (0.3 mg
equals 10 mg morphine). It has a low oral bioavail-
ability (10%) but its administration by the sublingual
and transdermal routes can avoid significant first pass.
Bioavailability after sublingual administration was
58% with analgesic effect some 20 minutes after dos-
ing.174After intravenouse administration, it has a peak
plasma concentration 5 minutes after dosing. There
was no increase of buprenorphine plasma levels in pa-
tients with renal impairment, suggesting its safety in
patients in renal failure.175,176The half-lives of
buprenorphine-induced analgesic and anti-hyperal-
gesic effects were 171 and 288 minutes, respec-
There are now a number of European studies that
have confirmed the role of buprenorphine in the man-
agement of both cancer and noncancer pain through a
patch every 3 days with dosage strengths of 35, 52.5,
and 70 ?g/hr.170, 177The patches currently under de-
velopment in the United States are 10 and 20 ?g/hr
with patches changed every 10 days, reducing the po-
tential role of this medication in the treatment of can-
cer pain.
Comparison of opioids
In a systematic review of opioid equianalgesic dos-
ing ratios, Pereira et al.178found a general paucity of
data related to equianalgesia and long-term dosing.
The studies were heterogeneous in nature and exhib-
ited extremely wide ranges that may change accord-
ing to the direction of the opioid switch; these dis-
crepancies clearly exist with respect to both oxycodone
and fentanyl. At equianalgesic dosing, fentanyl com-
pared favorably with morphine with regard to im-
proved side effects, particularly with respect to con-
stipation121–123; however, the use of fentanyl resulted
in greater disturbances in sleep.122
also reviewed the situation with
methadone and concluded that the drug is more potent
than previously appreciated and that its conversion ra-
tios are highly correlated with the dose of the previ-
ous opioid, data confirmed by a Cochrane review.180
Bruera and colleagues156conducted a double blind
randomized controlled study with morphine and
methadone and found no differences in analgesic effi-
cacy or side effects between the two.
The importance of equianalgesic dosing is related
mainly to the concept of opioid switching or rotation.
While commonly used in practice for many years, it
was first described in the literature by Bruera and col-
leagues181in the treatment of agitation and has become
a important principle of cancer pain management. The
absence of randomized controlled trials, however, lim-
its the available evidence to support this. In a Cochrane
review, Quigley182identified 52 reports (23 case re-
ports, 15 retrospective studies/audits and 14 prospec-
tive uncontrolled studies), the majority using morphine
as the first-line opioid and most frequently switching
to methadone. All but one report concluded opioid
switching to be a useful clinical maneuver for im-
proving pain control and/or reducing opioid-related
side effects. Prospective randomized trials to establish
true effectiveness and standardize conversions ratios
are needed.
Comparison of routes
Oral. The preferred method for opioid administra-
tion is still the oral route as suggested by the WHO.
This is related somewhat to available products and the
later development of other routes of delivery, such as
transdermally and transmucosally administered prod-
ucts. The time for peak absorption of IR products is
in the order of 30–45 minutes. The time to peak con-
centrations of sustained release products is variable.
Morphine SR tablets reaches a peak at 2–4 hours,40
while oxycodone SR has a reported bimodal distribu-
tion system with a peaks at 45 minutes and 6 hours.128
The once-per-day morphine products reach a peak at
6–8 hours.38
Other approaches to the oral administration of opi-
oids are the sublingual and transmucosal routes. While
morphine is not absorbed sublingually,56fentanyl is
absorbed sublingually with the rapid absorption of
25% of the delivered drug.100New products with an
effervescent mechanism that, through alteration of the
pH of the oral mucosa, further increases the absorp-
tion of fentanyl have become available in the United
States. The buccal administration of oxycodone in
children resulted in an estimated bioavailability of
50%.129Methadone has also been proposed for sub-
lingual administration.183
Rectal. The rectal administration of opioids is an-
other alternative either with suppository formulations
or the oral formulations, although there can be a de-
gree of variation based on the placement of the sup-
pository. Lower placement would result in diffusion
to the inferior and middle hemorrhoidal veins that by-
Page 12
pass portal flow and hence decrease hepatic first-pass
metabolism. Compared to oral morphine tablets, mor-
phine suppositories had similar pain control and side
effect profiles and demonstrated a 1:1 dosing ratio.44
Decreased levels of morphine glucuronides were
found, supporting the concept that the rectal absorp-
tion may be associated with significant avoidance of
hepatic biotransformation. The rectal administration
of oxycodone tablets resulted in greater absorption
than seen with the same tablets administered orally.184
The rectal administration of methadone resulted in a
shorter time to maximum concentration (1.4 versus
2.8 hours) compared to oral administration.146Bio-
availability was similar to that of orally administered
Intravenous. Understanding the pharmacokinetics
of opioids is essential for the effective administration
of parenteral opioids. Opioid infusions are often inap-
propriately initiated for the management of severe
pain. It requires 4–5 half-lives to reach steady state
and effective drug levels for analgesia. Taking a mor-
phine infusion as an example (half-life of 2–3 hours),
steady-state levels would be reached in 10–15 hours,
clearly not an effective outcome in terms of analgesia
for acute severe pain. Based on these pharmacologi-
cal principals, increasing the infusion rate every 2–4
hours is not a safe method of managing pain. The in-
fusion rate of opioids should not be increased more
than every 12 hours. Many patients are started with an
infusion and patient controlled analgesia, an effective
delivery mechanism for only those patients who have
the ability to use such a pump. In the palliative care
setting, many patients do not have this ability and their
families are often relied upon to administer boluses
(family controlled analgesia [FCA]). This may be to
the detriment of the patient with increased side effects,
particularly sedation and myoclonic jerking resulting
from the accumulation of both the parent drug and/or
Based on expert opinion, the most productive way
to ensure maximum analgesia is with a loading
dose.185A review of a number of studies showed in-
adequate methodology to document the application of
these pharmacological principals to clinical prac-
tice.110Of interest, no respiratory depression was re-
ported in the nine studies where a loading dose was
used. Fentanyl administered intravenously has been
shown to be effective in the treatment of severe pain
in an emergency department.109After a loading dose,
an infusion can be commenced together with patient
controlled analgesia. Clinician boluses can also be
given to ensure pain relief prior to increasing the rate
of infusion.
Intramuscular. Intramuscular injection is not an ef-
fective route of opioid administration with time to peak
effect longer than with intravenous administration and
not much shorter than for oral opioids. The intramus-
cular injection of opioids effectively creates a depot of
opioids that slowly diffuse into systemic circulation.
It is the use of intramuscular injections that has led to
the common practice of not administering opioids to
patients being investigated for an acute abdomen. Re-
cent studies have shown that the use of intravenous in-
jections of opioids in this situation does not compro-
mise the diagnosis of acute appendicitis compared to
Subcutaneous. The subcutaneous administration of
opioids is a common way of delivering opioids pri-
marily by direct subcutaneous infusion. Water-soluble
products are usually administered by a subcutaneous
injection or infusion. The bioavailability of subcuta-
neous morphine administered in this way is in the or-
der of 70%–100% of the intravenous dose.187Day to
day variations of the concentrations of morphine and
its metabolites were less with subcutaneous adminis-
tration than with orally administered morphine.188
Intraspinal. Intraspinal opioids are necessary in 2%
of those with cancer pain.189Epidural or intrathecal
infusions deliver drugs directly to opioid receptors,
limit systemic exposure, and by decreasing the opioid
dosage required for pain relief, may reduce side ef-
fects. One tenth of the intravenous dose can be ad-
ministered epidurally and one hundredth intrathecally,
illustrating the potential high oral and intravenous
doses that are avoided through the use of these deliv-
ery routes. No direct comparisons of the epidural and
intrathecal routes of administration have been per-
formed. While the epidural route is more convenient,
proponents of intrathecal drug administration argue
that this route optimizes the chance for uniform drug
Preservative-free morphine sulfate, a sterile hy-
drophilic compound that circulates throughout the ce-
rebrospinal fluid (CSF), is the only compound ap-
proved by the FDA for intraspinal administration.
Compared to those with noncancer pain, initial doses
in cancer patients were higher but increased only
twofold after 3 months of therapy from 6.84 ? 0.65
mg/d to 13.19 ? 1.76 mg/d at 24 months. Other opi-
oids, e.g., fentanyl, can also be administered by the in-
Page 13
traspinal route. It is suggested that the site of action of
epidural fentanyl (intraspinal versus supraspinal) is de-
pendent on both the concentration of the administered
dose and the method of delivery (bolus versus infu-
The addition of bupivacaine to patients not achiev-
ing adequate analgesia with intrathecal morphine re-
sulted in improved pain relief in 14 of the 17 pa-
tients.192The addition of intraspinal clonidine, an
?-adrenergic agonist can make a significant difference
to analgesia.193In a subset analysis of those with neu-
ropathic pain, 55% receiving clonidine reported ade-
quate analgesia compared to 5% of those with placebo.
In an industry supported randomized study com-
paring intraspinal opioids with usual medical care,
Smith and colleagues194found both an improvement
in pain and quality of life with the intraspinal admin-
istration. While concerns have been raised as to the
general applicability of this study, there may be a se-
lect population of patients for whom intraspinal opi-
oids are particularly appealing (e.g., pelvic recurrence
in patients with rectal and cervical cancer).
Acetaminophen is an analgesic used commonly as
initial therapy for mild pain and as a continued med-
ication for cancer pain management in the elderly. It
is a drug with little clinical anti-inflammatory activ-
ity.195A recent randomized controlled trial in cancer
patients has shown that the addition of acetaminophen
to opioids used in the treatment of severe pain results
in a small but added analgesic effect.196Safety con-
cerns about the effects of high and continued dosing
of acetaminophen on the kidney and liver are well es-
tablished. Hepatotoxicity with associated liver fail-
ure197can also occur at doses below the daily recom-
mended dosage.198Kidney damage can be due to both
the acute and chronic administration of acetamino-
Nonsteroidal anti-inflammatory drugs
NSAIDs are traditional WHO Step 1 opioids and
are effective in the treatment of mild pain as well as
having an opioid-sparing effect for moderate to severe
pain.200Many NSAIDs in the United States have both
prescription and nonprescription formulations; these
are generally equally effective when equivalent doses
are given. NSAIDs may be most useful in the treat-
ment of cancer-related pain when the pain is associ-
ated with inflammation, for example, in patients with
pain from bone metastasis. Although a dose-response
relationship exists with both nonselective and COX-2
selective NSAIDs, each individual drug has a maxi-
mum therapeutic dose above which there is no addi-
tional analgesic effect but for which there is an in-
creased risk of toxicity. This pharmacologic property
is known as a ceiling effect. Mercandante and col-
leagues200have confirmed the opioid sparing nature
of NSAIDs. The addition of 60 mg daily of ketorolac
resulted in a significant reduction in opioid dose. The
patients receiving ketorolac had less constipation but
more gastric discomfort. However ketorolac has a lim-
ited duration of use (usually 5 days) due its gastroin-
testinal toxicity.201Prolonged usage may also result in
nephrotoxicity.202A recent Cochrane review assessed
the effects of NSAIDs, alone or combined with opi-
oids, for the treatment of cancer pain.203NSAIDs had
a clear benefit over placebo but no difference in side
effects while some studies showed improved efficacy
of different NSAIDs over others, even in a single in-
dividual. In terms of the combined therapy of opioids
and NSAIDs, there was a statistical advantage dem-
onstrated in 9 of 23 studies. Most of the studies were
less than 7 days, making their applicability to the can-
cer population questionable. Rodent studies suggest a
selective potentiation of opioid analgesia by NSAIDs,
an effect that is variable among drugs within each
class.204Most clinicians continue to recommend
NSAIDs especially for patients with bone pain. The
potential cardiac risk of NSAIDs may be a factor in
the treatment of cancer pain in the palliative care set-
ting but should be discussed with the patient. There
appears to be no published benefit of COX-2 selective
inhibitors for the treatment of cancer pain or the re-
duction of major detriments (renal, cardiovascular).
The term coanalgesic has become the more com-
mon term to describe adjuvant analgesics, that is, those
nonopioid drugs that may have some pain relieving ef-
fects, although pain relief may not be their primary in-
dication in medicine.23On some occasions, these
agents may be first-line therapy for neuropathic pain
and not as adjunctive therapy to opioids. It is more
correct to classify these medications based on a drug
class and physiologic effect (e.g., anticonvulsants, an-
tidepressants, oral antiarrhythmias, NMDA antago-
nists, sympatholytic agents). Much of the evidence for
Page 14
efficacy and safety of these drugs comes from studies
in nonmalignant neuropathic pain rather than cancer
pain. However, since the pathophysiologic mecha-
nisms underlying neuropathic pain syndromes are as-
sumed to be similar whether a patient has cancer or
not, these studies are used, with some success, to guide
treatment of neuropathic pain in patients with cancer.
The clinical use of these medicines is often based on
trial and error in individual patients, weighing both the
mechanism of the pain together with the likely effec-
tiveness and expected side effect profile. The current
model for treating neuropathic pain is largely based
upon the treatment of peripheral neuropathic pain but
there are limited data on the treatment of central neu-
ropathic pain.205Many of the studies with coanalgesics
report response in terms of the NNT to achieve a re-
sponse in a single patient206and also the numbers
needed to harm (NNH).205
Anticonvulsants are commonly used for the treat-
ment of cancer pain with little evidence as to their
overall effect.207In a Cochrane Systematic review, 23
studies were considered for analgesic effectiveness 80.
The primary measure used, allowing comparison of the
effectiveness, in these studies in over 1000 patients
with nonmalignant conditions was NNT. Carba-
mazepine, phenytoin and gabapentin have been shown
to have some analgesic efficacy. A single study with
sodium valproate showed no analgesic effect. Newer
anticonvulsant medications have also been studied. It
is important to remember that many classic antiseizure
medications, including carbamazepine, are associated
with drug interactions through CYP3A4 and may in-
teract with opioid metabolism.208
Carbamazepine has commonly been used in the
treatment of trigeminal neuralgia. The Cochrane re-
view included three placebo-controlled trials of car-
bamazepine in patients with trigeminal neuralgia. This
showed a NNT of 2.5 (confidence interval [CI]
2.0–3.4) patients to achieve a response in a single pa-
tient. While small controlled trials have demonstrated
the efficacy of carbamazepine for painful diabetic neu-
ropathy (NNT ? 2.3), there is little evidence to sup-
port its role in cancer neuropathic pain with only one
study in this population. It is a difficult drug to use in
patients receiving chemotherapy as it is contraindi-
cated in patients with leukocyte counts below 4000 or
absolute neutrophil count of 1500 or less. Regular
complete blood counts (CBC) are usually recom-
mended (2 weeks, 1 month, and then every 3 months)
creating considerable burden in the palliative care set-
ting. When studies of the different conditions were
combined, carbamazepine was found to have increased
side effects. Oxcarbazepine is a derivative of carba-
mazepine that has been shown to have analgesic ac-
tivity in painful diabetic neuropathy.209
Small controlled trials have demonstrated the effi-
cacy of phenytoin for painful diabetic neuropathy.80
While serum concentrations can be monitored, its poor
efficacy and high incidence of intolerable side effects
(e.g., confusion, ataxia, nystagmus, nausea), makes the
burden outweigh any benefit. This poor burden to ben-
efit ratio has resulted in its minimal clinical use.
The anticonvulsant, gabapentin, has found many
uses within medicine, including the treatment of neu-
ropathic pain. Randomized controlled trials (RCTs)
with placebo have demonstrated the efficacy and tol-
erability of gabapentin for the treatment of posther-
petic neuralgia210,211and painful diabetic neuropa-
thy.212For postherpetic neuralgia, the NNT is 3.2 (CI
2.4–5.0) while for diabetic neuropathy the NNT was
3.8 (CI 2.4–8.7). Two small open-labeled studies213,214
have suggested that gabapentin may be effective in the
management of neuropathic pain associated with can-
cer and cancer treatment. A systematic review showed
that smaller non-randomized studies supported the
randomized controlled studies.215In a later random-
ized controlled study, the addition of gabapentin
showed an improvement in analgesia in patients al-
ready receiving opioids for cancer pain.216Patients
with dysesthesia were more likely to be responsive to
gabapentin. Other pain qualities are often alleviated
with gabapentin, including lancinating, burning, and
aching pain, as well as allodynia, confirming the need
for a careful assessment. Gabapentin is well tolerated
with the majority of patients experiencing few intol-
erable side effects. The most common side effects are
infrequently occurring sedation, dizziness with nausea,
confusion, and lower extremity edema. Although stud-
ies and clinical experience have suggested that the ef-
fective dose appears to be in the order of 2700 mg/d,
randomized controlled trials have not established a
clear benefit with doses above 1800 mg/d (adminis-
tered in three divided doses) but individual dose titra-
tion is important. Doses should be reduced in patients
with renal insufficiency. In a retrospective review of
insurance claim data, the addition of gabapentin to
morphine used in the treatment of postherpetic neu-
ralgia resulted in a reduction in the required morphine
dose.217This was confirmed in a randomized study of
patients with either post-herpetic neuralgia or diabetic
peripheral neuropathy.218
Other newer antiseizure medicines have also been
studied with suggestions that they may be useful in
Page 15
the treatment of neuropathic pain. Research has
shown that pregabalin provides effective, safe, and
lasting relief from neuropathic pain associated with
diabetic pain.219,220Forty percent of 70 patients re-
ceiving pregabalin had pain reduced by more than
half compared to 13% of the patients receiving
placebo.221Lamotrigine has been shown to be effec-
tive in the treatment of central post stroke pain222and
in a small randomized study of human immunodefi-
ciency virus (HIV)-associated distal sensory poly
neuropathy in which 9 patients received lamotrigine
and 20 placebo, the study group achieved an im-
provement in average pain but no difference in worst
pain compared to placebo.223
A variety of tricyclic antidepressant (TCA) drugs,
including amitriptyline, nortriptyline, desipramine,
doxepin, and imipramine, have proven pain relieving
effects independent of their antidepressant ef-
fects.206,224Serotonin and norepinephrine are thought
to inhibit pain through interaction with descending
pain pathways. Therefore, drugs that inhibit the reup-
take of these compounds have been proposed as agents
in the treatment of neuropathic pain. Animal studies
suggest that drugs that inhibit norepinephrine reuptake
are more effective than the serotonin reuptake inhibi-
tors.225Randomized controlled trials have demon-
strated the efficacy of TCAs for the treatment of post-
mastectomy pain, postherpetic neuralgia (PHN), and
painful diabetic neuropathy.226Typically, the doses
needed for pain relief are significantly lower than the
therapeutic antidepressant doses. In patients with can-
cer pain, TCAs are frequently used to treat neuropathic
pain associated with surgery, radiation therapy, che-
motherapy, or caused by malignant nerve infiltration.
A baseline ECG may be necessary to exclude patients
with conduction abnormalities (e.g., bundle branch
block, AV block) that may be worsened by TCAs. This
risk may be higher in patients who have received an-
thracycline chemotherapy. Amitriptyline has the best-
documented analgesic effects but is also the least well
tolerated because of its potent anticholinergic effects;
for this reason it is not recommended in patients over
the age of 65. Many clinicians prefer nortriptyline or
desipramine to amitriptyline because they cause less
sedation and fewer anticholinergic effects. Adminis-
tration of the entire dose of amitriptyline at bedtime
promotes sleep and minimizes daytime side effects. A
comparative crossover study of opioids (morphine or
methadone) versus TCAs (nortriptyline or de-
sipramine) showed a trend favoring opioids in terms
of pain relief with patients preferring opioids despite
some increased side effects.227
The newer antidepressants, the selective serotoner-
gic reuptake inhibitors (SSRIs), have produced mixed
results in controlled clinical trials. Fluoxetine failed to
demonstrate efficacy in a randomized controlled trial
of diabetic neuropathy,228while paroxitene showed ef-
ficacy in several small controlled trials.224Venlafax-
ine and duloxitene that combine the properties of the
TCAs and SSRIs have also been studied.
Venlafaxine is an antidepressant classified as a sero-
tonin and weak norepinephrine reuptake inhibitor.
Rowbotham and colleagues229evaluated the efficacy
and safety of venlafaxine ER (75 mg and 150–225 mg)
administered for 6 weeks to patients with painful dia-
betic neuropathy. With 244 adult outpatients enrolled
in this multicenter, double-blinded, randomized,
placebo-controlled study, the NNT for 50% pain in-
tensity reduction with venlafaxine ER 150–225 mg
was 4.5 at week 6. There was a significant percentage
reduction from baseline in pain intensity measures be-
tween placebo and venlafaxine but not between the
two doses of venlafaxine. Seven patients had signifi-
cant ECG changes, and the predominant side effects
were nausea and sedation. The authors suggest that
venlafaxine appeared to be equivalent to TCAs in the
treatment of neuropathic pain. Venlafaxine has been
compared directly with imipramine.230Twenty-nine of
40 patients completed a double-blinded placebo con-
trolled study with a three-way crossover. The sum of
the individual pain scores during treatment week four
was lower on venlafaxine (225 mg, 80% of baseline
score; p ? 0.006) and imipramine (150 mg, 77%; p ?
0.001) than on placebo (100%) with no statistical dif-
ference between venlafaxine and imipramine (p ?
0.44). The numbers needed to treat to obtain one pa-
tient with moderate or better pain relief were 5.2 for
venlafaxine and 2.7 for imipramine questioning the ef-
ficacy of venlafaxine when compared with a TCA. In
a placebo-controlled crossover study in a small group
of patients with established postmastectomy pain, ven-
laxafine showed no difference in the primary end point
(average daily pain intensity) but some improvement
in the secondary measures of maximum pain relief and
maximum pain intensity.231These authors included
Kinetics in the study and found that the two poor re-
sponders had low drug levels and suggested that a dif-
ference in metabolism may account for the difference
in response. Rather than administering these agents
when pain becomes a problem, some have suggested
that their preemptive use may prevent pain syndromes
as demonstrated with the preemptive use venlafaxine
in postmastectomy pain.232Patients administered 2


text:
Recently heard rhyming alongside Brooklyn mic-murderer Nino Bless on mixtape single The Watchmen, Cambatta returns to make his solo DJBooth debut with a cut that'll have listeners shouting "Lawdamercy!" On this freshly-released mixtape inclusion, Pryme & Keyz' gospel samples set the mood as the Connecticut rhymesayer preaches a gospel of hard work and self-determination. In the record's final seconds, he drives the point home: "Now stop asking what God would do, when the only god you need is the god in you… church!" Craving more? You'll find what you seek on Cambatta's Smoke & Mirrors: The Porch LP, released to the 'net in mid-January.
Cambatta DownloadsIndieStreet Banger
Written by richard on 02/1/13
Submit your Rating
First DJ Booth Appearance:
"The Watchmen" (2013)
Total DJ Booth Features:
2 Songs
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subset: commoncrawl


text:
Veterans Field Guide to Government Shutdown
In the event of a federal shutdown, most VA services will still be available. For the full list, check out VA's Veterans Field Guide. VA will continue to deliver medical care.
Veterans Crisis Line:
1-800-273-8255 (Press 1)
Social Media
Complete Directory
U.S. Department of Veterans Affairs | 810 Vermont Avenue, NW Washington DC 20420
Last updated May 22, 2013


text:
Howard Johnson Valdosta
No availability found through our partners. Please contact the business directly or check some of our recommended alternatives.
- Free High-Speed Internet
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TripAdvisor Reviews Howard Johnson Valdosta
Travel Blogs from Valdosta
We have a house!
... I said goodbye to my car, cat, and family in one day, so you know I was crying a lot.
Tomorrow the packers come. Apparently they have to put a sticker on every single item. As soon as they are done we get to hit the road! YAY! A lady came Friday to do a generalized listing of what the packers should expect to box up. She told ...
Getting ready to go!
... El Paso, TX (overnight stay, then back on the road) Flagstaff, AZ (2 nights stay while at the national park) Grand Canyon National Park (1 day) Hoover Dam (short visit) Las Vegas, NV (2-3 days stay) Twin Falls, ID (overnight stay) Seattle, WA (2-3 days stay) Then on into Canada and finally into Anchorage! I haven't gotten to planning the last leg of our trip yet. The whole trip should take about 3 weeks. Maggie (my dog) will be ...
6th State
Today was a short day, only 189 miles, but for some reason it was a very tiring drive. We wanted to depart Deland by 9 am, but we didn't make it. I woke up at 8 and found Bob asleep on the couch. So it was almost 10 by the time we departed Deland. We did not return to I-75 the way we went into Deland, so the ride was better. We didn't really stop like we normally do, so we made it to Grassy Pond about 2 pm. Grassy Pond is the ...
... and headed towards Pembroke Pines. Husb had spent some time researching safe neighborhoods in that area, and decided on this particular Wal Mart based on his research. Needless to say, I think all Wal Marts are the same at this point. A lot of the late night clientele is sketchy, but it's a free place to sleep and we will continue to take advantage of it... it was just a one night stop en route to the Keys anyhow!
Los Tres Amigos - The Three Amigos
... me haya comportado como una fanática adolescente, pero hice lo posible para no avergonzarme frente a mis ídolos. Por suerte, pude disfrutar de su compañía por unos días antes de que viajen a Paraguay. Y yo que hice después? Pues mi humana me dijo que nosotras también iríamos a Paraguay pero que tomaríamos la ruta panorámica. Y fue entonces que nos embarcamos hacia el sur. Por el camino ...


text:
People's journalism isn't 'citizen journalism'
In the past week we've seen an uprising of angry people, mostly women, offended by the Susan G. Komen Foundation cutting off funding for breast cancer exams at Planned Parenthood clinics. It's just the latest example of how the global news conversation is in the hands of people, not just "the media." And it's what I had in mind over a dozen years ago when I talked about the rise of a new kind of people's journalism.
- Read more about People's journalism isn't 'citizen journalism'
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Stephen King has 1 upcoming event.
Filter: featured, adult only
Stephen King
Barnes & Noble Booksellers - Union Square, Wednesday, November 11 at 12pm
Stephen King is the author of more than fifty books, all of them worldwide bestsellers. His recent work includes Mr. Mercedes, Doctor Sleep, and Under the Dome, now a major TV miniseries on CBS. His novel 11/22/63 was named a top ten book of 2011 by The New York Times Book Review and won the Los Angeles Times Book Prize for Mystery/Thriller as well as the Best Hardcover Book Award from the International Thriller Writers Association. He is the recipient of the 2003 National Book Foundation Medal for Distinguished Contribution to American Letters. He lives in Bangor, Maine, with his wife, novelist Tabitha King. (added from Simon & Schuster)… (more)
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Calories in Gluten Free Muffin Mix
Wondering how many calories are in Gluten Free Muffin Mix?Manufactured by King Arthur Flour
Gluten Free Muffin Mix
Vanilla Base
A- Grade
130 Calories
Nutrition Facts
Serving Size 4 tbsp mix (38 g)
Per Serving % Daily Value*
Calories 130
Calories from Fat 0
Total Fat 0g 0%
Saturated Fat 0g 0%
Cholesterol 0mg 0%
Sodium 125mg 5%
Carbohydrates 32g 11%
Dietary Fiber 3g 12%
Sugars 15g
Protein 1g
Vitamin A 0% · Vitamin C 0%
Calcium 20% · Iron 15%
*Based on a 2000 calorie diet
Gluten Free Muffin Mix Calories and Health Benefits
- No saturated fat
- No cholesterol
- High in calcium
- High in iron
- High in thiamin
- Very high in sugar
Get Nutritional Facts and the Health Benefits for Gluten Free Muffin Mix
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Allergy Remedies
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The side effects of allergy medications keep some people from using them. Natural remedies can be a great alternative, but some are more effective than others.
The side effects of allergy medications keep some people from using them. Natural remedies can be a great alternative, but some are more effective than others.


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Our star species are some of the most interesting birds you may see on your visit to the reserve.
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Look for dippers feeding around the edges of the lake and feeder stream. They can even walk underwater!
Golden eagles are resident here, but visit between April and August when the viewpoint is open and experts will show you the birds. When a pair is present, you can witness nesting activity.
Peregrines nest on the rocky crags here. Spend time scanning the skies and you may see these powerful falcons passing overhead.
Several pairs of redstarts nest in the birch, ash and oak woodland here. They can be seen between late April and August.
Note: Some reserves are not served directly by public transport and, in these cases, a nearby destination (from which you may need to walk or take a taxi or ferry) may be offered.


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Hotel Grand Gardenia (Kannappa),
Mannarpuram Junction,
Tiruchi- 620 020
Ph: 0431- 4045000
This tempting hors d'oeuvre is the chef's signature recipe. Macaroni pasta artfully stuffed with minced lamb, deep fried to perfection and dipped in mayonnaise sauce makes for a simply delectable starter. Available only at the hotel's new roof top restaurant, this is the best bet to begin dinner with.
Price: Rs. 125
More In: METRO PLUS | FEATURES


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Congratulations are due …
Congratulations are due …
By Bill Beard, Theater Critic
I have been a newspaper theater critic for more than 30 years and have always made it a policy not to review community, college or high school productions. But once in awhile, I happen to see a show that is outstanding enough within its genre that it deserves attention. This show was one of those occasions. I attended the opening night of Rodgers and Hammersteins old chestnut, Oklahoma!, presented by the high school at First Assembly Church at Spring Creek and Mulford.
It was stunning. It had all elements of musical theater excellence, at levels not often reached by such young amateurs, and with a balance that showed detailed attention to each and every element. This high level of accomplishment is due to the vision and work of the director, Jody Beach. Jody is well known and loved throughout the area for her much-in-demand Jody Beach Trio, whose recently released CD is terrific. But she is to be highly commended for her dedication to her teaching and development of young performers, whose product always surpasses our expectations and whose love and sincerity shines through every performance.
Beach has gathered a group of parents, friends and artists around her whose combined talent, devotion and labor lift this production to such a high level. The set, designed by Beach and built and painted by Steve and Ann Humphreys, is a realistic, life-size farmhouse and barns, with fence, hay bales and all. Costumes for some 36 female and 15 male singer-actor-dancers were perfectly executed by Becky Nelson and Kris Eckburg and crew. Lighting and sound each complemented the whole performance.
The directors most important choice of colleagues was in her selection of the choreography team of Doug and Jill Beardsley, so well remembered for their superb dancing in last years Coronado production of Musicals II. These two exquisite dancers have proven once again that they are also wonderful teachers of dance. In this case, they have taken some 50 teen-age non-dancers and turned them into a troupe of enthusiastic musical performers. With the help of several dance-trained members of the ensemble, and especially with the marvelous dancing of leading lady, Sarah Humphreys, as Laurey, the overall dance performance was better than almost any high school work I have seen in the Stateline. Again, part of a terrific artistic team.
Miss Humphreys singing and acting were also excellent, and she was perfectly matched by the confident and charming performance of her leading man, Adam Layman, as the impetuous cowboy hero, Curley. Both of these performers show significant potential as future stage personalities, as do all of the actors playing the other major characters in this cast. Congratulations to Jody and the company! I only wish that the show could have been seen by all theater goers in Rockford.


text:
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|Great isn't it!
#9185591, By Help_me Need for Speed Most Wanted Vita
Help_me 943 posts
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Bloodborne guide: bosses, areas and secrets Our essential guide to Miyazaki's latest dark adventure.
Pillars of Eternity walkthrough Our guide to the long-awaited RPG from Obsidian.
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"I don't know what the others are complaining about. I found the place to be very friendly and not seedy at all, at least compared to other "gentleman's ..."
"I tried to work in this club last night. One client got very drunk and didn't want to pay for his dances. He didn't want me to talk ..."
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