Pain Management

Content
• Understanding pain

• Chronic pain

• Pain assessment

• Pain pharmacotherapy

• Need for multimodal pain management

• Tramadol/ Paracetamol combination

• Clinical trial evidence

• Conclusion
Pain

“ An unpleasant sensory and emotional experience

associated with actual or potential tissue damage,
or described in terms of such damage”

IASP – International Association for the Study of Pain

Pain

‘Pain increases cardiac work, Increases metabolic rate,

Interferes with blood clotting, Leads to water retention,

Impairs wound healing, Alters immune function and

Creates negative emotion’

Thienhaus O, Cole BE.’Pain management: A practical Guide for

Clinicians.’5th Edition, Boca Raton,FL:CRC Press LLC;1998:19-26
 Pain

• Pain alerts body that something is wrong

• Nervous system communicates this information almost

instantaneously via nerve impulses

• The primary functional unit of this system is neuron

Pain transmission

Neuron
Pain transmission
 Pain transmission

Synapse
It is a junction between two neurons or a neuron and a tissue
 Pain transmission

Receptors

• Any substance that binds to the receptor is called a ligand

• A substance which acts in accordance with receptor

function, activating it to exert its effect is called an agonist

• A substance which counteracts receptor function by

blocking its effect is called an antagonist

•  neurotransmitter → downregulation →  response

•  neurotransmitter → upregulation →  response

Nervous system

Major types of neuron

• Afferent or sensory neurons

• Efferent or motor neurons

• Interneurons
 Pain transmission

Central Pain Pathways

Nociceptor → dorsal root → spinal cord (substantia

gelatinosa) → spinothalamic tract → brainstem & thallamus

→ cortex and limbic system

Pain transmission

Nociception consists of 4 stages

• Transduction

• Transmission (conduction)

• Modulation

• Perception
Pain transmission

Perception

Modulation
Transduction

Transmission
Pain transmission

Perception

Modulation
Transduction

Transmission
Pain transmission

Perception

Modulation
Transduction

Transmission
Pain transmission

Perception

Modulation
Transduction

Transmission
Stages of Nociception

4. PERCEPTION Net result of three events – the subjective experience of pain

Process by which impulse travel from the brain

back down to the spinal cord to selectively inhibit
(or sometimes amplify) pain impulses
3. MODULATION

Communication of the nerve impulse from

2. TRANSMISSION the periphery to the spinal cord, up the
spinothalamic tract to the thalamus and
cerebral cortex

1. TRANSDUCTION

Conversion of noxious, or
harmful stimuli (mechanical,
thermal, chemical) into nervous
impulse, or action potential
 Endorphins &  Opioid Receptors
Pain signal through Substance P

Presynaptic
Opiate

neuron
Endorphin Pain signal
Receptor from periphery

Substance P
in the synapse

Substance P
Receptor (NK1)

Postsynaptic
neuron

Pain signal
to brain
 Endorphins &  Opioid Receptors
Opioids block secretion of Substance P
through opiate receptor

Presynaptic
Endorphins Pain signal

neuron
in the synapse from periphery
Termination of
pain signal

Substance P

Signal from
brain to inhibit Opiate
pain signal receptor Substance P
Receptor (NK1)

Postsynaptic
neuron
 Classification of pain

Source Duration Intensity

Nociceptive
Acute
Mild

Neuropathic Chronic Severe

Moderate

Non-Malignant

Malignant
 Classification by Source

Examples of nociceptive and neuropathic pain

Nociceptive pain Neuropathic Pain

(Result of stimulation of peripheral (Result of lesions or dysfunction in
pain receptors by noxious stimuli) the nervous system)

Somatic
Tumor compression or infiltration of
Postsurgical incisional pain peripheral nerves or spinal cord
Musculoskeletal pain
Injury to peripheral nerves or spinal
cord from trauma, infection,
Visceral diabetes and other metabolic
Myocardial infarction disorder, surgery, radiation
Intraperitoneal metastasis
 Classification by Duration

Chronic vs. acute pain

Chronic Pain Acute Pain

Persisting >= 3 months : often
Recent onset ; usual duration 0-7
with less sudden and defined
days
onset

May or may not be the result of Cause usually known ; usually a

tissue damage definable event

More often leads to depression More often leads to anxiety and

and other behavioral changes pursuit of remedy

Pain persists, becoming a disease Pain usually subsides as healing

into itself progresses
 Classifications of pain

Miscellaneous

• Phantom limb pain: Painful sensations referred to the absent

limb

• Complex Regional Pain Syndrome (CRPS), also known as

Reflex Sympathetic Dystrophy, is a chronic neurological
syndrome characterized by:

– Severe burning pain

– Pathological changes in bone and skin
– Excessive sweating
– Tissue swelling
– Extreme sensitivity to touch
 Consequences of Untreated & Undertreated
Acute Pain

Extensive and Persistent cascade of neurochemical mediators triggered

by tissue injury presage long-term, permanent, neurological change that
can lead to
SENSITIZATION
ALLODYNIA
HYPERALGESIA
MAY evolve into chronic pain

Canadian Pain Society - Position Statement on Pain Relief

Canadian Consortium on Pain Mechanisms, Diagnosis and Management
Chronic Pain

• Chronic pain appears Because of an expression of

the presence of central sensitization

• Pain pathways are hypersensitive, geared up to

respond to the slightest touch
Chronic pain

• In chronic pain, dorsal horn neuron can now

be activated by glutamate.

• The activation of the NMDA receptor allows

calcium ion to flow into the cell, beginning a
cascade that leads to the generation of nitric
oxide.

• Nitric oxide also causes the release of

Substance P, which is a promotor of neural
remodeling and hypersensitization.

Brookoff D. Chronic Pain: A New Disease? Hosp Pract (Off Ed) 2000;35:45-
52, 59.
Clinical Implications of Central
sensitization

• Increased response to a noxious stimulus (Hyperalgesia)

• Disproportionate response to pain stimulus (Allodynia)

• Prolonged / Persistent pain

• Referred pain
Clinical Conditions

Central Sensitization plays important role in

• Osteoarthritis
• Fibromyalgia
• Low Back pain
• Neuropathic pain
Assessment of pain
 Pain Scales

Adjective Description Scale

No Pain Mild Pain Moderate Severe Very Worst

Pain Pain severe Possible
Pain Pain

Numeric Pain Scale

0 1 2 3 4 5 6 7 8 9 10

No Pain Worst
Moderate
Possibl
Pain
e Pain

Visual Analogue Pain Scale

 Thermography

• Non-invasive clinical imaging procedure

• It detects and monitors a number of

diseases and physical injuries by
showing thermal abnormalities

• Internal inflammation is vented out the

skin, so the location and patterns of heat
and cold on the skin shown by
thermography provide a visual map of
inflammation and heat irregularities in the
body
Pain management
Non-pharmacologic approaches to pain

• Cognitive behavioral therapy

– Individuals can gain voluntary control over … specific brain region… these
effects were powerful enough to impact severe, chronic clinical pain.”

• Meditation
– Strong evidence for the use of relaxation & hypnosis in reducing pain in a
variety of medical conditions

• Music therapy
– Systematic reviews suggest its benefit in pain management

• Massage and exercise

– May potentially have a positive effect on a number of symptoms in
advanced cancer including pain
Non-pharmacologic approaches to pain

• Acupuncture
– No evidence to support its efficacy in pain management

• TENS (Transcutaneous Electrical Nerve Stimulation)

– Lack of Suitable RCTs to assess the value of TENS in pain management

• Hot or cold
– Applying heat or cold to a painful area can help reduce pain. Both heat and
cold decrease sensitivity to pain

• UV rays
– Ultraviolet light may help alleviate fibromyalgia pain, according to a study
published in the Journal of Alternative and Complementary Medicine
Pain management
 Non opioid analgesics

• Classed according to chemical characteristics (acid or non acid)

• All affect PG synthesis

• NSAIDs (e.g. acetylsalicylic acid, ibuprofen, diclofenac, naproxen)

• Selective COX-2 inhibitors

• Paracetamol

• Metamizole
 Non-opioid analgesics: NSAIDs

• Mainly acting on nociceptive pain

• Mechanism of action:
– Inhibition of cyclooxygenase
prostaglandin synthesis
decreases
– e.g. acetylsalicylic acid

• Side-effects including:
– Gastrointestinal irritation
(erosions and ulcers)
– Impaired renal function
Other non-opioid analgesics: Paracetamol

• Paracetamol
– Aniline derivate
– Analgesic, antipyretic, no anti-inflammatory effects
– Risk of toxic liver damage

• Mechanism of action
– Inhibition of central prostaglandin synthesis
– Believed to inhibit NO
– Not been fully explained

• Maximum permisible dose

– 2.5gm/day
Side effects of traditional NSAIDs

- Gastric toxicity
- Decreased platelet aggregation
- Renal & hepatic dysfunction
- Exacerbation of asthma
- Hyperkalemia
- Fluid retention
- Congestive heart failure
- Hypertension
- CNS symptoms
Facts to note
• Chronic users of NSAIDs are at 3 times greater risk for serious
adverse GI events than non-users

• NSAIDs are responsible for an estimated 1,07,000 hospitalizations a

year in US due to GI complications

• There are approximately 16,500 NSAID related deaths a year in US

• Patients at higher risk of GI ulcers include the elderly patients with a

history of ulcers, those taking higher doses NSAIDs or concomitant
steroids, and those with severe disability from arthritis or heart disease
Traditional NSAIDs
Limitations

• Use is largely for mild to moderate pain only

• Associated with GI bleeding & Ulceration that may be life
threatening
• Antiplatelet effect may be undesirable/contraindicated in some
patients (e.g. surgical patients)
• Associated with kidney impairment, increased blood pressure
• Numerous potential drug interactions
COX – 2 Inhibitors
Limitations
• Use is largely for mild to moderate pain only
• Labeling warns of same potential for GI adverse events as
traditional NSAIDs; more definitive data needed
• Co-administration of celecoxib & aspirin results in increased
incidence of GI effects & complicated ulcers US-FDA recommends
further study to clarify safety of COX-2 inhibitors plus aspirin
• Rofecoxib and celecoxib are associated with more cardiac side-
effects than comparator agents; rofecoxib increases blood
pressure & neither COX – 2 inhibitor is cardioprotective
• Associated with kidney impairment and increased blood pressure
• Numerous potential drug interactions
“Black box" warning on cardiovascular and
gastrointestinal risk - NSAIDs

• "NSAIDs may cause an increased risk of serious

cardiovascular thrombotic events, myocardial infarction,
and stroke, which can be fatal," the boxed warning states.
"Patients with cardiovascular disease or risk factors for
cardiovascular disease may be at greater risk."

• The boxed warning will note that the CV risk "may

increase with duration of use."

• The boxed warning template further states that the

products are "contraindicated for the treatment of peri-
operative pain in the setting of coronary artery bypass
graft (CABG) surgery
All NSAIDs may be linked to MI risk- BMJ 2005,
Vol 330

• Drugs evaluated: selective NSAIDs : Rofecoxib,

Celecoxib, other selcetive :Etoricoxib, Valdecoxib,
Nonselective : Diclofenac, Ibuprofen

• Diclofenac and ibuprofen seem to pose about as much

risk as the COX-2 inhibitor rofecoxib

• Patients taking Ibuprofen had 24% increased risk and

who has been taking it for longer has higher. With
Diclofenac- 55% increased risk.
 Opioid analgesics

• WHO classification
– Weak opioids (e.g. tramadol,
codeine)
– Strong opioids (e.g. morphine,
oxycodone, fentanyl)

• Efficacy
– Mainly effective in nociceptive
pain
– Only partially effective in
neuropathic pain
Opioids

• Analgesics with morphine like activity

• Bind with ,  and  receptors within the CNS
• Most opioids acts on 1 in brain or 2 in spinal cord or both
• Well accepted for use of opioids is in cancer pain & other
chronic unremitting pain associated with life-threatening disease
• Also used on temporary basis in acute non-malignant pain
• Use in non-cancerous pain is less accepted because of the
perceived risk of abuse
 Opioids and addiction…? Myth

Important to note
• Addiction during the course of opioid use for medical reasons is rare
• In a study of approximately 12,000 hospitalized
patients with no history of drug abuse who received
opioid analgesics during hospitalization, only 4 (0.33%) developed an
addiction disorder
(Poter J, Jick J. NEJM 1980;302:123)

• In retrospective reviews of approximately 24,000 patients who

received opioids for pain relief, only 7 (0.029%) could be identified as
having developed an addiction disorder
(Friedman DP. J Pain Sympt management 1980;5(Suppl.1);S2-S5)
Tramadol

• Tramadol is indicated in moderately severe pain

• It has a dual, centrally acting mechanism of action

• Both tramadol and its active metabolite (M1) bind to mu-

opioid receptor sites in the CNS, producing analgesia by
blocking the release of neurotransmitters

• Unlike opioids, tramadol also inhibits the reuptake of

serotonin and nor-ephinephrine in the spinal cord

• These two mechanisms have been shown to act

synergistically in animals and additively in humans to
relieve pain
 Tramadol

• Different from NSAIDs, tramadol does not inhibit

prostaglandin synthesis

• Unlike conventional opioids, it has rarely been associated

with respiratory depression

• Side effects are reduced if lower doses are used initially.

• Tramadol thus has a low abuse potential and is

unscheduled, with no federal restrictions on prescribing
 The Therapeutic action of Tramadol

Tramadol
metabolism

Inhibits the reuptake of CYP2D6

Serotonin and
NorEpinephrine

Increased levels of Serotonin

& NE in descending M1 Metabolite
inhibitory pain pathway
Binds to Mu opioid receptor

Pain Relief Mimics action of Enkephelins

Less prominent action Pain Relief

 Other therapeutic options in pain
management
• Antidepressants, anticonvulsants, antiarrythmics,
corticosteroids, and psychostimulants may be employed
adjunctly or as monotherapy for the relief of pain

• Most are administered orally

• The agent of choice varies with the type of pain

• There is generally a ceiling effect on analgesia of agents

in this category, which varies from patient to patient
Tricyclic Antidepressants (TCA)

• Example: Amitriptyline

• Mechanism of action:
– Inhibition of neuronal reuptake of noradrenaline and
serotonin (5-HT)

• Efficacy in pain:
– Neuropathic pain
– Complex regional pain syndrome
– Tension headache
 Selective Serotonin and Noradrenaline
Reuptake Inhibitors

Mechanism of action:
• Selectively inhibit reuptake of noradrenaline or serotonin or
both
• Analgesia by intensifying descending inhibition
• SSRIs less analgesic than SSNRIs

No affinity to adrenergic, cholinergic or histaminergic receptors

• Fewer side effects than TCAs

Side effects (e.g. Duloxetine)

• e.g. nausea, vomiting, constipation, somnolence
Anticonvulsants

Different mechanisms of action

• Common features: inhibition of neuronal excitation and
stabilization of nerve membranes

Examples:
• Carbamazepine: blocks Ca2+ and Na+ channels
• Pregabalin: Ligand of Ca2+ channel 2 sub-unit in brain and
spinal cord; modulates calcium influx to reduce
neurotransmitter release (including glutamate, substance P)

Side-effects:
• e.g. sedation, dizziness, ataxia, peripheral oedema, nausea,
weight increase
Topical analgesics

Main categories of topical analgesics include:

– Rubefacients: traditional formulations based on salicylate

and nicotinate esters, capsaicin and capsicum extracts and
derivatives

– NSAIDs: diclofenac, felbinac, ibuprofen, ketoprofen,

piroxicam, naproxen, flurbiprofen and other NSAIDs

– A miscellaneous group: including benzydamine,

mucopolysaccharide polysulphate, salicylamide and cooling
sprays
 Pain management
In the management of acute and chronic pain analgesics from
different groups are frequently combined

Benefits of combination of medications:

• By activating multiple pain inhibitory pathways, the

combination analgesics can provide more effective pain
relief for a broader spectrum of pain1

• Combining two analgesics with complementary

mechanisms of action may enhance analgesia and at the
same time reduce the risk of adverse events 2

1.Journal of Clinical Pharmacology & Therapeutics 2001; 26:257-64

2.Drugs 2003; 63(11): 1079-86
Need for Multimodal Pain
Management…
 Combination Analgesics

• In the management of acute and chronic pain analgesics from

different groups are frequently combined.

Such combination can have several benefits:

• By activating multiple pain inhibitory pathways, the combination

analgesics can provide more effective pain relief for a broader spectrum
of pain1

• Combining two analgesics with complementary mechanisms of action

may enhance analgesia and at the same time reduce the risk of adverse
events2

1.Journal of Clinical Pharmacology & Therapeutics 2001; 26:257-64

2.Drugs 2003; 63(11): 1079-86
 Combination Analgesics

Combination analgesia has been recommended by

- WHO1 1996
- The American Pain Society3 1996
- American Geriatric Society2 1999
- The American Medical Directors Association4 1999
- American College of Rheumatology5 2000

1) WHO. Cancer Pain relief with a guide to opioid availability 2nd Ed. Geneva 1996
2) J Amer Geriatr Soc 1998;46:635 – 51
3) Glienview IL. Principles of analgesic use in treatment of acute pain and cancer pain. American Pain Society 1999
4) Baltimore MD.Clinical Practice Guidelines. American Medical Directors Association 1999
5) Arthritis Rheum 2000; 43:1905-15
 Benefits of combination of tramadol and
paracetamol

• More effective than plain tramadol in relieving acute pain

• Rapid pain relief only in 17 minutes as against 51 minutes
with tramadol
• Median time of supplemental analgesia was 302 minutes as
against 122 minutes with plain tramadol indicating a longer
duration of action
• Better tolerated than plain tramadol with significantly less
adverse events
Tramadol + paracetamol

• Tramadol
– Centrally acting opioid analgesic, binds to µ opioid
receptors
– Inhibits reuptake of NE and serotonin within pain
pathways of CNS
– Contribute to enhancing the descending pain inhibitory
pathways
• Paracetamol
– Inhibits cyclooxygenase (COX) in central nervous
system
• Proven efficacy in clinical settings involving central
sensitization
Tram/Para-Mechanism of Action
 Tramadol/Paracetamol combination

Tram/Para has shown to cause

• Synergistic analgesia *

Mcchellen K & Scott LJ. Drugs 2003;

53(11):1379-86

Thus the dose of tramadol in ULTRACET is 25%

lower per tablet than the dosage of plain
tramadol, yet provide effective pain relief of
moderate to moderately severe pain
*Synergy in mice
 Tramadol + paracetamol –
Central sensitization

Inhibits reuptake of Inhibits release of

Binds to Mu opiods NO
Serotonin and NE

Mimics the effects More in qty at the Reduce the effects of

Encephalins synapse Sub P

Reduce the effects of Reduce the effects of

Sub P Sub P Reducing the intensity
of the pain signal to
brain
Reduce the intensity of Reduce the intensity of
the pain the pain
Pain relief
Pain relief Pain relief

Inhibits afferent
Enhances descending inhibition pain signal
Tramadol/Paracetamol combination

Internationally approved and

acclaimed
Tramadol/Paracetamol
Clinical trial evidence
Tramadol/Paracetamol Key Publications

Conclusion
Sr no. Study Journal - year Study design No of patients

1 Tramadol/Paracetamol Clinical 4 Week, 462 Tramadol/Parac

Combination Tablets and Therapeutics - randomized, etamol
Codeine/Paracetamol 2001 double-blind, combination is
Combination Capsules parallel-group, efficacious in
for the Management of active-control, adult patients
Chronic Pain: A double dummy, with chronic low
Comparative Trial multicenter trial back pain,
osteoarthritis or
William S. Mullican et al both.
Tramadol/Paracetamol Key Publications

Conclusion
Sr no. Study Journal - year Study design No of patients

2 Tramadol/Paracetamol Clinical 3 month, 318 3 month

Combination Tablets for Therapeutics - multicenter, therapy of
the Treatment of Chronic 2003 outpatient, Tramadol/Parac
Lower Back Pain: A randomized, etamol
Multicenter, double blind, combination in
Randomized, Double- and placebo chronic LBP
Blind, Placebo- controlled study offers a
Controlled Outpatient significant
Study reduction in
pain.
Gary E. Ruoff et al
Tramadol/Paracetamol Key Publications

Conclusion
Sr no. Study Journal - year Study design No of patients

3 Analgesic efficacy and The Journal of 91 day, 336 Both patients

safety of Tramadol/ Rheumatology - multicenter, and
Paracetamol 2004 outpatient, investigators
combination tablets randomized, were more
(Ultracet) in treatment of double blind, satisfied with
chronic low back pain: and placebo Ultracet than
a multicenter, outpatient, controlled study placebo.
randomized, double
blind, placebo controlled
trial

Paul M Peloso et al
Tramadol/Paracetamol Key Publications

Conclusion
Sr no. Study Journal - year Study design No of patients

4 The efficacy of Clinical 12 week, 143 Ultracet as add-

Tramadol/ Paracetamol Rheumatology - randomized, on, significantly
combination tablets 2012 multicenter, reduced pain in
(Ultracet®) as add-on open patients with
and maintenance comparative NSAID-
therapy in knee study refractory OA
osteoarthritis pain pain or flare of
inadequately controlled OA pain.
by NSAID

Kyung-Su Park et al
Tramadol/Paracetamol Key Publications

Conclusion
Sr no. Study Journal - year Study design No of patients

5 Randomized study of Current Medical 66 day, 312 Tramadol/Parac

Tramadol/ Paracetamol Research & multicenter, etamol
versus placebo in Opinion – 2007 randomized, combination is
painful double-blind, effective in the
Diabetic Peripheral placebo management of
Neuropathy (DPN) controlled painful DPN
parallel-group with good
Roy Freeman et al trial tolerability.
Tramadol/Paracetamol Key Publications

Conclusion
Sr no. Study Journal - year Study design No of patients

6 Tramadol and American 91 day, 313 Tramadol/

Paracetamol Journal of multicenter, Paracetamol
Combination Tablets in Medicine – double-blind, combination is a
the Treatment of 2003 randomized, safe, effective,
Fibromyalgia Pain: A placebo- and well-
Double-Blind, controlled study tolerated
Randomized, Placebo- treatment for
Controlled Study fibromyalgia
pain and related
Robert M. Bennett et al symptoms.
Tramadol/Paracetamol Key Publications

Conclusion
Sr no. Study Journal - year Study design No of patients

7 Tramadol/Paracetamol Clinical 12-week, 60 Tramadol/Parac

combination as add-on Rheumatology - randomized, etamol
therapy in the treatment 2012 double-blind, combination
of patients placebo- has additional
with ankylosing controlled study effect to non-
spondylitis steroidal anti-
inflammatory
Jhi-Kai Chang et al drugs in the
treatment of
patients with
ankylosing
spondylitis.
Tramadol/Paracetamol Key Publications

Conclusion
Sr no. Study Journal - year Study design No of patients

8 Impact of Fibromyalgia American 91 day, 313 Treatment with

Pain on Health-Related College of multicenter, Tramadol/Parac
Quality of Life before and Rheumatology - randomized, etamol
After 2005 double-blind, significantly
Treatment with placebo improved
Tramadol/Paracetamol controlled study moderate to
severe
Robert M. Bennett et al fibromyalgia
pain.
Tramadol/Paracetamol Key Publications

Conclusion
Sr no. Study Journal - year Study design No of patients

9 Comparison of the Diabetic 6 week, Open, 163 Tramadol/Parac

efficacy and safety of Medicine - 2010 Randomized, etamol
Tramadol/Paracetamol comparative treatment is as
combination therapy and study effective as
gabapentin in the gabapentin for
treatment of painful the treatment of
diabetic neuropathy painful diabetic
neuropathy, not
S.H. Ko et al only in terms of
pain control but
also in the
improvement of
sleep
disturbance and
quality of life.
Tramadol/Paracetamol Key Publications

Sr Journal - Conclusion
Study Study design No of patients
no. year

10 A 2-Week, Clinical 2-week, 250 Ultracet semi can

Multicenter, Therapeutic multicenter, be started as low
Randomized, s - 2007 randomized, dose
Double-Blind, double-blind, Tramadol/Paraceta
Double-Dummy, Add- double-dummy, mol combination.
On Study of the add-on study The dose can be
Effects of Titration on increased
Tolerability of subsequently (then
Tramadol/Paracetam continue with
ol Combination Ultracet) for better
Tablet in Korean patient
Adults with Knee compliance.
Osteoarthritis Pain Upward titration of
dose will lead to
Chan-Bum Choi et al lesser adverse
events.
Conclusion
• Recent data and regulatory statements support limiting use of
NSAIDs/Coxibs

• The target population for pain management is expanding due to ageing

populations, and these patients are likely to have an increased GI
and/or cardiovascular risk.

• Increasing need for effective and safe pain medications, particularly in

special populations

• Greater appreciation of NSAID sparing multi-modal analgesia,

particularly the combination of paracetamol + tramadol for moderate to
severe pain

• The combination paracetamol plus tramadol has emerged as a

particularly useful candidate for pain management
Thank you