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International Journal of Biomedical and Advance Research
7
TRAMADOL SAFER AND EFFECTIVE ANALGESIC TO TREAT CHRONIC PAIN:
A REVIEW
Gulshan Pandey*
Department of Pharmacy Barkatullah University Bhopal (M.P.)
E-mail of Corresponding Author: [email protected]
Abstract
Pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant
sensory and emotional experience associated with actual or potential tissue damage, or described in
terms of such damage". Pain has now been equated to a “fifth vital sign” highlighting the significance
of pain management in patient care. Tramadol is a centrally acting analgesic, structurally related to
codeine and morphine .It is effectively used to treat moderate-to-severe acute and chronic pain in
diverse conditions. Tramadol is placed on the second step of WHO analgesic ladder and in contrast to
traditional opioids, exerts its analgesic activity, a dual mechanism of action inhibiting transmission as
well as perception of pain. Tramadol is more suitable than NSAIDs and coxibs for patient with GI,
renal and cardiovascular problems. Combined with low dependence/abuse potential, it has proven to
be of significant advantage over other agents, especially in the elderly.
Keywords: Tramadol; analgesic; pain; cyclooxygenase
1. Introduction
Pain is part of the body's defense system;
triggering mental and physical behavior to end
the painful experience.Pain perception is the
sum of complex sensory, emotional and
cognitive processes1. The international
Association for the study of pain (IASP)
defines pain as “unpleasant sensory and
emotional experience associated with actual or
potential tissue damage or described in terms
of such damage” 2,3. In contrast to acute pain,
chronic pain is not a protective response and is
no longer linked to a stimulus. Remodeling
within the central nervous system results in
persistent pain, hyperalgesia (lowered pain
threshold), allodynia (perception of pain
caused by the usually non-painful stimuli) and
spread of pain to areas other than those
involved with initial pathology. The most
common etiology of chronic non-malignant
pain is musculoskeletal such as arthritis,
cancer; peripheral nerve disorders and diabetes
are other conditions that cause chronic pain.
Pain has been acknowledged as the “fifth vital
sign” by the American Pain Society (APS) and
pain assessment and treatment much now be
integrated into overall patient management 2,3.
The 3-step analgesic ladder, originally
proposed for cancer pain relief by the WHO is
useful and now widely employed for all types
of pain, including the chronic pain of
musculoskeletal diseases (Figure 1) 4.
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Figure 1: WHO 3 step analgesic ladder
2. Current pharmacotherapy for pain:
NSAIDs,
opioids
and
co-analgesic
(antidepressants, anticonvulsants and calcium
channel blockers) form the mainstay of
pharmacotherapy for chronic pain. But, their
use is often limited by side effects4.
2.1.Non-steroidal anti-inflammatory drugs:
Usually abbreviated to NSAIDs, are drugs
with analgesic, antipyretic and, in higher
doses, with anti-inflammatory effects. The
term "non-steroidal" is used to distinguish
these drugs from steroids, which have a similar
eicosanoid-depressing,
anti-inflammatory
action. As analgesics, NSAIDs are unusual in
that they are non-narcotic5.
2.1.1. Mode of Action: Most NSAIDs act as
non-selective inhibitors of the enzyme
cyclooxygenase,
inhibiting
both
the
cyclooxygenase-1
(COX-1)
and
cyclooxygenase-2
(COX-2)
isoenzymes.
Cyclooxygenase catalyzes the formation of
prostaglandins
and thromboxane
from
arachidonicac id (itself derived from the
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Gulshan Pandey
cellular phospholipid bilayer by phospholipase
A2). Prostaglandins act as messenger
molecules in the process of inflammation 5,6.
This mechanism of action was elucidated by
John Vane, who later received a Nobel Prize6.
2.1.2. Adverse Effects: The widespread use of
NSAIDs has meant that the adverse effects of
these relatively safe drugs have become
increasingly prevalent. These effects are dosedependent, and in many cases severe enough
to pose the risk of ulcer perforation, upper
gastrointestinal bleeding, and death, limiting
the use of NSAID therapy. An estimated 1020% of NSAID patients experience dyspepsia,
and NSAID-associated upper gastrointestinal
adverse events are estimated to result in
103,000 hospitalizations and 16,500 deaths per
year in the United States, and represent 43% of
drug-related emergency visits. Many of these
events are avoidable; a review of physician
visits and prescriptions estimated that
unnecessary prescriptions for NSAIDs were
written in 42% of visits6.
2.1.3. Cardiovascular Risk: A recent metaanalysis of all trials comparing NSAIDs found
an 80% increase in the risk of myocardial
infarction with both newer COX-2 antagonists
and high dose traditional anti-inflammatories
compared with placebo7.
NSAIDs aside from aspirin are associated with
a doubled risk of symptomatic heart failure in
patients without a history of cardiac disease. In
patients with such a history, however, use of
NSAIDs (aside from low-dose aspirin) was
associated with more than 10-fold increase in
heart failure. If this link is found to be causal,
NSAIDs are estimated to be responsible for up
to 20 percent of hospital admissions for
congestive heart failure8.
2.1.4.Gastrointestinal ADRs: The main
ADRs (adverse drug reactions) associated
with use of NSAIDs relate to direct and
indirect irritation of the gastrointestinal tract
(GIT). NSAIDs cause a dual insult on the
GIT: the acidic molecules directly irritate the
gastric mucosa, and inhibition of COX-1
reduces
the
levels
of
protective
prostaglandins9,10,11.
Common gastrointestinal ADRs include:
(Rossi, 2006)
 Nausea/Vomiting
 Dyspepsia
 Gastric ulceration/bleeding.
 Diarrhea
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2.1.5. Renal ADRs: NSAIDs are also
associated with a relatively high incidence of
renal adverse drug reactions (ADRs). The
mechanism of these renal ADRs is due to
changes in renal hemodynamics (blood flow),
ordinarily mediated by prostaglandins, which
are affected by NSAIDs. Prostaglandins
normally cause vasodilation of the afferent
arterioles of the glomeruli. This helps maintain
normal glomerular perfusion and glomerular
filtration rate (GFR), an indicator of renal
function. By blocking this prostaglandinmediated effect, NSAIDs ultimately may cause
renal impairment. Common ADRs associated
with altered renal function include12,13:
 Salt and fluid retention
 Hypertension (high blood pressure)
These agents may also cause renal impairment,
especially in combination with other
nephrotoxic agents. Renal failure is especially
a risk if the patient is also concomitantly
taking an ACE inhibitor and a diuretic - the socalled "triple whammy" effect14.
In rarer instances NSAIDs may also cause
more severe renal conditions15:
 Interstitial nephritis
 Nephrotic syndrome
 Acute renal failure
 Acute tubular necrosis
2.1.6. Photosensitivity: Photosensitivity is a
commonly overlooked adverse effect of many
of the NSAIDs16. It is somewhat ironic that
these
anti-inflammatory
agents
may
themselves
produce
inflammation
in
combination with exposure to sunlight. The 2arylpropionic acids have proven to be the most
likely to produce photosensitivity reactions,
but other NSAIDs have also been implicated
including
piroxicam,
diclofenac
and
benzydamine.
Benoxaprofen, since withdrawn due to its
hepatotoxicity, was the most photoactive
NSAID observed. The mechanism of
photosensitivity, responsible for the high photo
activity of the 2-arylpropionic acids, is the
ready decarboxylation of the carboxylic acid
moiety. The specific absorbance characteristics
of the different chromophoric 2-aryl
substituents, affects the decarboxylation
mechanism. While ibuprofen is somewhat of
an exception, having weak absorption, it has
been reported to be a weak photosensitizing
agent17.
2.1.7. During Pregnancy: NSAIDs are not
recommended during pregnancy, particularly
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Gulshan Pandey
during the third trimester. While NSAIDs as a
class are not direct teratogens, they may cause
premature closure of the fetal ductus arteriosus
and renal ADRs in the fetus. Additionally,
they are linked with premature birth 18,19,20.
2.1.8. Erectile Dysfunction Risk: A 2005
study linked long term (over 3 months) use of
NSAIDs, including ibuprofen, with a 1.4 times
increased risk of erectile dysfunction.21The re­
port by Kaiser Permanente and published in
the Journal of Urology, considered that "regu­
lar non-steroidal anti-inflammatory drug use is
associated with erectile dysfunction beyond
what would be expected due to age and other
condition".22,23
2.1.9. Other ADRs: Common ADRs, other
than listed above, include: raised liver
enzymes, headache, and dizziness. Uncommon
ADRs include: hyperkalemia, confusion,
bronchospasm and rash. Rapid and severe
swelling of the the face and body. Ibuprofen
may also rarely cause irritable bowel
syndrome symptoms. In very rare cases,
ibuprofen can cause aseptic meningitis24.
2.2. Paracetamol:
Paracetamol
or
acetaminophen is a widely used over-thecounter analgesic (pain reliever) and
antipyretic (fever reducer). It is commonly
used for the relief of fever, headaches, and
other minor aches and pains, and is a major
ingredient in numerous cold and flu
remedies25. In combination with non-steroidal
anti-inflammatory drugs (NSAIDs) or opioid
analgesics, paracetamol is used also in the
management of more severe pain (such as
cancer pain)26.
2.2.1. Adverse Effects: In recommended
doses, paracetamol does not irritate the lining
of the stomach, affect blood coagulation as
much as NSAIDs, or affect function of the
kidneys. However, some studies have shown
that high dose-usage (greater than 2,000 mg
per day) does increase the risk of upper
gastrointestinal complications such as stomach
bleeding. Paracetamol is safe in pregnancy,
and does not affect the closure of the fetal
ductus arteriosus as NSAIDs can. Unlike
aspirin, it is safe in children, as paracetamol is
not associated with a risk of Reye's syndrome
in children with viral illnesses29.
In 2008 the Lancet published the largest study
to date on long term side effects of
paracetamol in children. Conducted on over
200,000 children in 31 countries, the study
determined that use of paracetamol for fever in
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the first year of life was associated with a 46%
increase in the risk of developing asthma
symptoms when aged 6–7 years. Higher doses
and more regular use of the drug are associated
with a greater risk of developing asthma; up to
a three-fold increase for heavy use.
Furthermore, paracetamol use, both in the first
year of life and in children aged 6–7 years,
was associated with an increased risk of
symptoms of rhinoconjunctivitis and eczema.
In that article the authors acknowledged that
"our findings might have been due to
confounding by indication", i.e. that the
association they found was not causal but
rather due to the disease being treated with
paracetamol, and emphasized that further
research is needed30.
Excessive use of paracetamol can damage
multiple organs, especially the liver and
kidney. In both organs, toxicity from
paracetamol is not from the drug itself but
from one of its metabolites, N-acetyl-pbenzoquinoneimine (NAPQI). In the liver, the
cytochrome P450 enzymes CYP2E1 and
CYP3A4 are primarily responsible for the
conversion of paracetamol to NAPQI. In the
kidney, cyclooxygenases are the principal
route by which paracetamol is converted to
NAPQI. Paracetamol overdose leads to the
accumulation of NAPQI, which undergoes
conjugation with glutathione. Conjugation
depletes glutathione, a natural antioxidant.
This in combination with direct cellular injury
by NAPQI, leads to cell damage and death31,32.
2.3. Opioid analgesic: An opioid is a chemical
substance that has a morphine-like action in
the body. The main use is for pain relief. These
agents work by binding to opioid receptors,
which are found principally in the central
nervous system and the gastrointestinal tract.
The receptors in these two organ systems
mediate both the beneficial effects, and the
undesirable side effects. There are a number of
broad classes of opioids33,34.
2.3.1. Infrequent adverse reactions in
patient taking opioids for pain relief: These
include: dose-related respiratory depression,
confusion, hallucinations, delirium, urticaria,
hypothermia,
bradycardia/tachycardia,
orthostatic hypotension, dizziness, headache,
urinary retention, ureteric or biliary spasm,
muscle rigidity, myoclonus (with high doses),
and flushing (due to histamine release, except
fentanyl and remifentanil)35.
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2.4.Tramadol: Tramadol is a CNS depressant
and analgesic, used for treating moderate to
severe pain. It is a synthetic agent, and it
appears to have actions at the μ-opioid
receptor as well as the noradrenergic and
serotonergic
systems.
Tramadol
was
developed by the German pharmaceutical
company Grunenthal GmbH in the late 1970s
and marketed under the trade name Tramal36.
Many other pharmaceutical companies market
it under various names.
Tramadol is a centrally acting, synthetic
analgesic of the aminocyclohexanol group,
which has opioid-like effects 37.It has been in
clinical use in Europe since the late 1970s
38
.Its mode of action is not completely
understood but it appears to have a dual
mechanism of action, which involves
inhibition of re-uptake of serotonin (5-HT)
and/or noradrenaline as well as weak affinity
for opioid (mu) receptors39.Since tramadol
does not affect prostaglandin synthesis, it does
not have antipyretic or anti-inflammatory
effects40.
Tramadol has high oral bioavailability. Its
absorption is not affected by food 39.The two
oral dosage forms (50mg capsules 4 times
daily and 100mg sustained-release tablets
twice daily) have been reported to be
equivalent in terms of analgesic efficacy and
tolerability41.
2.4.1. Clinical Use: Publications reporting the
clinical use of tramadol are numerous. A num­
ber of reviews of the clinical use of tramadol
have also been published42,43,44.
2.4.2.Comparison with Placebo: A pooled
analysis of 9 single-dose, double-blind, ran­
domized, placebo-controlled studies18 in­
cluded a total of 1594 patients with post-oper­
ative pain following caesarean section or
general surgical procedures. Analysis
showed that analgesic efficacy of tramadol at
doses equal to or greater than 50mg was super­
ior to that of placebo (statistical value not re­
ported). Likewise, pooled analysis of 9
double-blind, randomized studies involving
1859 patients with dental extraction pain
evaluated single oral doses of tramadol ran­
ging from 50mg to 200mg 45. Analysis demon­
strated a significantly greater efficacy for tra­
madol than for placebo at all doses evaluated.
(The majority of these studies have not been
published.) A subsequent meta-analysis of
these 18 studies confirmed the effectiveness of
tramadol in comparison with placebo and
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demonstrated a significant dose response19.
Multi-dose studies have also demonstrated a
superior effect of oral tramadol over placebo in
both pains after dental extraction and pain
after orthopaedic surgery45.
2.4.3. Comparison with Morphine: Tramadol
(up to 3 doses of 50mg iv) was compared with
morphine (up to 3 doses of 5mg iv) over 6
hours in a double-blind, randomised study of
150 patients after gynaecological surgery46. In
those patients who reported moderate pain, the
two drugs were equally effective. However,
morphine was superior in patients starting with
severe pain. Respiratory depression (as meas­
ured by oxygen desaturation) occurred in 13%
of the morphine group but not at all in the tra­
madol group. Sedation and nausea were also
more common in the morphine group.
In a multi-centre, double-blind, randomised
study involving 523 patients47, the analgesic
efficacy of tramadol and morphine given in
repeated intravenous boluses as required to
control post-operative pain over 24 hours
following abdominal surgery was compared.
There was no substantive difference in
analgesia between tramadol (100mg iv then
100-125mg iv or im as needed) and morphine
(5mg iv then 5-20mg iv or im as needed). The
time between the first and second dose of
study medication was longer in the tramadol
group than in the morphine group, probably
due to the lower comparative starting dose of
morphine (5mg) compared with tramadol
(100mg). However, the intervals between all
subsequent doses were comparable. A high
incidence of gastrointestinal
adverse events were observed with both
treatments, mostly consisting of nausea and
symptoms such as dry mouth, vomiting,
dyspepsia and hiccups. Constipation was not
reported in either group. Similar efficacy has
been observed in more recent studies in this
surgical group48.
Scott et al49 reviewed the literature (since
1993) where effectiveness of tramadol in
perioperative pain was assessed using standard
visual analogue scales. On the basis of
percentage change in pain scores from
baseline, they concluded that tramadol
effectively relieved moderate to severe
postoperative pain associated with several
types of surgery, including abdominal,
orthopaedic and cardiac surgery. Pain
scores with tramadol were reduced by
approximately 57% within 4 to 6 hours,
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Gulshan Pandey
compared to a reduction of approximately
70% with morphine
2.4.4. Comparison with NSAIDs: In
comparative studies of tramadol and ketorolac
in nasal surgery50 and orthopaedic surgery51,
improvements in postoperative analgesia and
quality of sleep were similar with
intramuscular tramadol or ketorolac49.
2.4.5. Comparison with oral analgesics:
single dose studie: The analgesic efficacy of
single dose, orally administered tramadol
75mg or 150mg was compared in a double
blind, placebo controlled trial with a combina­
tion of paracetamol 650mg and dextropro­
poxyphene napsylate 100mg in 161 patients
with severe post operative pain after
caesarean section52. Both tramadol and the
combination analgesic were statistically super­
ior to placebo. Tramadol 150mg was signific­
antly more effective than both tramadol 75mg
and combination paracetamol/ dextropro­
poxyphene. No serious adverse effects were
observed, but dizziness was more frequently
reported with 150mg tramadol.
On the other hand, Stubhaug et al53compared
oral tramadol 50mg or 100mg with a
combination paracetamol/codeine analgesic
(1000mg/60mg) or placebo in a single-dose
study in 144 patients after total hip
replacement. In this study the combination of
paracetamol/codeine was superior to both
doses of tramadol. There was no difference in
efficacy between either dose of tramadol and
placebo. Adverse effects were more common
with tramadol than with the combination,
particularly nausea.
Single oral doses of tramadol 75mg or 150mg
have been compared with codeine phosphate
60mg and paracetamol/propoxyphene HCl
(650mg/65mg) in 239 patients with pain after
dental extraction54. Tramadol 75mg was more
effective than codeine. Although 150mg of
tramadol was superior to the combination
analgesic, 75mg of tramadol was not. In
another double-blind, single dose parallel
study in 206 patients after dental extraction55,
tramadol 100mg was judged to be more
effective than codeine 60mg but only tramadol
200mg was statistically so.
2.4.6. Paediatric Surgery: In paediatric sur­
gery (in patients over the age of 12 months),
tramadol has been used effectively for moder­
ate to severe pain in im or IV doses of 12mg/kg42.
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2.4.7. Chronic Pain: Tramadol has been in­
cluded as a step 2 analgesic in the second edi­
tion of the World Health Organization’s re­
commendations for treatment of cancer pain56.
Twenty cancer patients with strong pain
unresponsive to previous pain treatment were
randomized to receive oral tramadol or
morphine solution in a randomized, doubleblind, cross-over study57. Doses were
individually titrated and cross-over occurred
on day 4. Pain scores were similar on day 4,
although pain scores were higher in the
tramadol group on days 1 and 2. There was a
statistically significant reduction in sideeffects (particularly nausea and constipation)
with tramadol.
Efficacy and safety of high dose oral tramadol
(300-600mg/day) compared with low dose oral
morphine (10-60mg/day) was evaluated in a
non-blinded, non-randomized study involving
a total of 1658 patients with cancer pain58.
There was no significant difference in
analgesic efficacy between the two groups.
Antiemetic’s, laxatives, neuroleptics and
steroids were prescribed significantly more
frequently in the morphine group; the use of
other adjuvants was similar in both groups.
Constipation, neuropsychological symptoms
and pruritus were observed significantly more
frequently with low dose morphine. Other
symptoms had similar frequencies in both
groups.
Oral tramadol was evaluated in a double-blind
study over a 4 week period in 390 patients
over 65 years of age with chronic pain due to
a variety of conditions59. Patients were
initially treated with either tramadol 50mg
orally or paracetamol/codeine 300mg/30mg
and were then allowed to titrate the dose
according to pain severity to a total of eight
capsules per day. Mean pre-treatment pain
intensities were moderate for both groups. At
the end of the study, average daily doses were
244mg of tramadol and 1,407mg/140.7mg of
paracetamol/codeine. Both treatments were
rated as good,
very good or excellent by 55% of patients in
each group. There was no significant
difference in the incidence of adverse effects
in each group, but adverse effects resulted in
discontinuation in a significantly higher
proportion of patients taking tramadol (18.8%
vs 9.6%, p<0.05).
Oral tramadol (100mg eighth hourly) was
compared with a fixed dose combination of
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Gulshan Pandey
paracetamol/codeine (1000mg/60mg eighth
hourly) in a randomized, double-blind crossover study in 55 patients suffering from
refractory chronic back pain60. Efficacy was
similar in the two arms. Although the
combination analgesic was reported by the
authors as better tolerated than tramadol, the
difference was not statistically significant. A
multicenter,
randomized,
double-blind,
parallel group study compared the analgesic
efficacy and tolerability of immediate release
tramadol (50mg four times daily) and
sustained-release tramadol (100mg twice
daily) in 205 patients with chronic refractory
low back pain. There was no difference in
pain relief, the course of pain intensity or
adverse events between the two groups6.
Those continuing beyond the first week
became more tolerant of the adverse effects.
The efficacy of tramadol in osteoarthritis has
been evaluated in patients who experienced
breakthrough pain while being treated with
NSAIDs61. After an open label phase, forty
two patients were randomized to receive
tramadol or placebo for a two week period;
NSAID therapy was continued. Significantly
more tramadol-treated patients completed the
study. An average daily dosage of 245mg was
significantly more effective than placebo in
reducing the severity of pain at rest. In
naproxen-responsive patients with painful
osteoarthritis of the knee, the addition of
tramadol 200mg/day allowed a significant
reduction in NSAID dosage (by 78%) without
compromising pain relief40. Fifty eight
percent were able to discontinue naproxen
with the addition of tramadol. Tramadol may
have a role in treatment of neuropathic pain
of diabetic or other origin and has been
estimated to be similar in efficacy to tricyclic
antidepressants in such conditions 62. Tramadol
has been reported to be effective across a wide
range of chronic pain conditions, including
chronic pancreatitis, fibromyalgia, and
scleroderma10, 17. It should be noted,
however, that controlled studies in chronic
pain conditions have been of relatively short
duration (4-8 weeks)63 and studies of longerterm use are required.
2.4.8. Adverse Effects: The adverse effects of
tramadol are similar to other opioids and
include nausea, vomiting, constipation,
headache, dizziness, dry mouth, sedation,
asthenia, fatigue and sweating64. Less common
effects include skin reactions and pruritus.
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Titrating the dose slowly may improve
tolerability65, and intra-operative loading may
reduce post-operative nausea and vomiting 66.
With the exception of sweating, constipation
and dry mouth, most adverse effects appear to
decrease with prolonged use67. Tramadol is
unlikely to produce clinically relevant
respiratory depression at recommended doses
but respiratory depression may occur if
recommended doses are exceeded67. The abuse
and/or dependence potential for tramadol is
low, provided it is dosed within recommended
ranges68. However, reports of drug dependence
and withdrawal have occurred16. Tramadol
has very low affinity for opioid receptors (10
times less than codeine, 60 times less than
propoxyphene and 6000 times less than that of
morphine)12. Low abuse potential has been
confirmed in a randomised, double-blind,
placebo-controlled, crossover trial. However, a
number of case reports have been published
which highlight the potential for dependence,
abuse and withdrawal syndrome after longterm treatment68,70-72
Conclusion
Tramadol has a dual mechanism of action that
explains its effectiveness in those types of pain
that are refectory to conventional opioids, and
its better tolerability profile. At therapeutic
doses, Tramadol has weak/no effects on
respiration, cardiovascular system and
intestinal motility. Compared with traditional
NSAIDs, Tramadol lacks serious GI renal
toxicity, which are major concerns in the
elderly. These side effects are generally
mediated by prostaglandins, and so are not
seen with Tramadol. Even though the new
COX-2 specific NSAIDs may demonstrate
greater GI safety than the older NSAIDs,
Tramadol has a superior safety profile.
Hepatotoxicity consider to be a class
characteristic of NSAIDs that has not been
reported to date with Tramadol. Unlike
acetaminophen, Tramadol has no antipyretic
activity. So it does not mask any possible
infective
and/or
phlogistic
processes.
Tramadol can be used safely even in patients
with hypertension, congestive heart failure, or
renal insufficiency, because such patient such
patients may not tolerate the renal side effects
of NSAIDs. It is safer in patients with asthma
and GI ulcers. Tramadol has every low affinity
for opioid receptors (10 times less than
codeine, 60 times less than propoxyphene and
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Gulshan Pandey
6000 times less than that of morphine).
Consequently, constipation and respiratory
depression are less frequent with Tramadol at
therapeutic doses as compared to conventional
opioids. There is also less risk of abuse and
dependence with Tramadol and may result in
lack of compliance. Noncompliance with high
–frequency dosing regimens results in
inconsistent analgesia.
Tramadol maintains a good profile of
tolerability in every old patients (mean age 85
years) and in long term treatments with
reduced
pharmacological
interactions.
Tramadol represents a solution to the dilemma
posed by the unfavorable side effects profiles
of other analgesic typically used for unrelieved
chronic pain.
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