New analgesic in the management of pain in this millennium recent perspectives-flupirtine
1. NEW ANALGESIC IN THE MANAGEMENT OF PAIN
IN THIS MILLANEUM – RECENT PERSPECTIVES -
FLUPIRTINE
Prof. A.V. SRINIVASAN,
MD, DM, Ph.D, F.A.A.N, F.I.A.N.
Emeritus Professor
The Tamilnadu Dr. M.G.R. Medical University
Former Head
Institute of Neurology, Madras Medical College
3. 3
Rationale
Analgesics are used in clinical practice for a variety of painful conditions
NSAIDs are the most commonly used analgesic-anti-inflammatory drugs, but have GI ADRs
Opioid analgesics are also used in moderate-severe painful conditions, but have their own
limitations due to unwanted side effects
Flupirtine is an amino-substituted pyridine derivative, centrally-acting, but non-opioid analgesic
Molecular structure and mechanisms do not resemble any other currently available analgesic
agent
“The True Art of Memory is The Art of Attention” - S.Johnson
4. 4
Presentation Points
“ We Sometimes think we have forgotten something when
in fact we never really learned it in the first place”
Imp.Your Memory Skills
5. 5
Pain Sensation
Pain is an unpleasant sensation that originates from ongoing or impending tissue damage
Management of different types of pain (acute, postoperative, inflammatory, neuropathic, cancer-
related and chronic) is the most frequent problem encountered by clinicians
Drug therapy is the first line of approach for the treatment of pain
Through Action You Create your Own Education - D.B. ELLIS
6. 6
Pain Sensation
Acute pain >> normal and predictable physiologic response to adverse chemical, thermal, or
mechanical stimulus; it is associated with surgery, trauma, or acute illness and is usually
experienced for a limited and defined period of time
Chronic pain usually present for a period exceeding 3 weeks and usually associated with
neuropathic pain, cancer-related pain and certain types of arthritis (OA and RA)
Thought is the labour of the intellect
Reverie is its pleasure
7. 7
Pain classified according to underlying
mechanisms
Nociceptive caused by tissue injuries and damage
Inflammatory pain
Neuropathic caused by nerve injuries
Imagination is more Important than Knowledge
8. 8
Management
1. Anti-inflammatory drugs
2. Skeletal muscle relaxants
3. Physiotherapy
4. Back exercises
5. Support belt
6. Surgery for severe cases
A open foe may prove a curse ; but a pretended friend is worse
9. 9
Low Back Pain
Annually 15-45% of adults suffer from low back pain
Lifetime prevalence is at least 70%
Most prevalent among adults 35-55 yrs old
Associated with substantial disability
Economic impact
Absenteeism
Increased utilization of health care resources
It is a great misfortune not to possess sufficient wit to
speak well
10. 10
Low Back Pain
Frequently due to minor problems
1.Poor posture
2.Mild cases of PID
3.Muscular strain (lumbago)
You are what you think and not what you think you are
12. 12
Frozen Shoulder
Inflammation of tissues surrounding shoulder
joint
1. Degenerative process
2. Muscle tear
3. Bursitis
Also called scapulohumeral periarthritis
A great many people think they are thinking when they are merely re
arranging their prejudices
W. James
13. 13
Post-operative Pain
Millions of surgeries are performed on an annual basis, necessitating the frequent use of acute postoperative
pain management
There are many types of surgery and, with few exceptions, all are painful
More than 80% of patients experience post-operative pain
Important issues in managing post-operative pain
Optimizing pain management for the individual patient
Ensuring safety
Minimizing side effects
Maintaining ease of use for staff and patients
Reducing complications
Many Ideas grow better when transplanted into another mind than in
the one where they sprang UP
O.W. Holmos
14. 14
Post-operative pain still undermanaged
1
Apfelbaum JL, et al. Postoperative pain experience: results from a national survey suggest postoperative pain continues to
be undermanaged. Anesth Analg, 2003
A woman’s desire for revenge outlasts all her other emotions
15. 15
Presentation Points
Every discovery contains an irrational element or
4 creative intuition
16. 16
Nociceptive Pain Pathways
I have never let my Medical schooling interfere with my education
Mark Twain
17. 17
Low Back Pain
Lifting even smaller weights in the wrong
way can cause low back pain
Sitting for long hours with poor postures places
strain on back muscles
We learn by thinking and the quality of the learning outcome is determined
by the quality of our thoughts
R.B. Schmeck
18. 18
Mediators involved in pain mechanisms
When they tell you to grow up, they mean stop growing
Piccaso
19. 19
Different target sites for analgesics
A medical school should not be a preparation for life.
A school should be life
20. 20
Limitations of Opioids and NSAIDs
Opioids Drugs
NSAIDs
“Social Isolation is in itself a pathogenic
Factor for disease production”
22. 22
Flupiritine Spectrum of Activity
1
Friedel and Fittion, Drugs 1993/ 2Schuster, CNS Drugs 1999/3Sheridan et al. Neurology 1986/4Schwarz, et al. J Neurol
Transm, 1996
Serious, sincere, systematic study surely secures supreme success
23. 23
Flupirtine: Mechanisms are different from opioids
I. Flupirtine does not show any relevent affinity for opiate receptors
• Structurally different from morphine
• Analgesic activity is not altered by opiate antagonist naloxone
II. Flupirtine does not show any relevent influence on 5HT receptors
• Analgesic activity is not altered by 5HT receptor antagonist cyproheptadine
III. Does not influence the BDZ receptors or the α-1 or α-2 adrenergic receptors or nicotinic or
muscarinic receptors
IV.Low potential for drug abuse, drug dependence, tolerance or withdrawal symptoms1
Ringe JD, et al. Analgesic Efficacy of Flupirtine in primary care of patients with osteoporosis related pain. Arzneim.-Forsch./Drug
Res. 53, No. 7, 496−502 (2003)
Discipline Weighs ounces Regret
weighs Tons
24. 24
Flupirtine indirectly influences NMDA receptors
Mechanism of action has yet to be fully explained: evidence that flupirtine interacts with
glutamatergic N-Methyl-D-Aspartate (NMDA) receptor1,2.3,4,5
Not possible to demonstrate direct effect on NMDA receptor: all findings point to indirect influence
on NMDA receptor (functional NMDA antagonism)
1
Block F, et al. NeuroReport 1994/2Rupalla K, et al. Eur J Pharmacol 1995/3Perovil S, et al. Neurodegeneration
1995/4Osborne NN et al. Brain Research 1994/ 5Schwarz M, et al. NeuroReport 1994
Experience can be defined as
yesterday’s answer to today’s
problems
25. 25
Glutamate Receptors
Glutamate receptors
Glutamate receptors
Ionotropic receptors Metabotropic receptors
NMDA AMPA Kainate Gr I Gr II Gr III
The secret of walking on water is Knowing where the stones are
28. 28
Flupirtine as a SNEPCO
Flupirtine
KCNQ
Stabilizes membrane: inhibits
incoming pain signals
G-protein NMDA-receptor with Mg+2 block
K+ ↓ Ca+2 increase after excitotoxic
stimulation
Interaction with G-protein-activated inwardly rectifying K+ channels (GIRK) >> opening of which
leads to stabilization of RMP of neuronal cells >> causes an indirect inhibition of NMDA receptor.
At therapeutically relevant concentration, flupirtine is a selective neuronal potassium channel
opener (SNEPCO)1
1
Kornhuber J, et al. J Neural Transm 1999; 106: 857-867
Science is below the mind; Spirituality is beyond the mind
29. 29
Analgesic Activity: Animal Studies
Methadone
Methadone Flupirtine
Flupirtine Dextroproxyphene
Dextroproxyphene
Buprenorphine
Buprenorphine > > Codeine
Codeine
Morphine
Morphine Pentazocine
Pentazocine Phenacetin
Phenacetin
Paracetamol
Paracetamol
• Max analgesia reached at 30 min post-dose
• Duration of effects: at least 75 min
• Flupirtine classified as medium to strong analgesic with onset/duration similar to codeine
Jakovlev V, et al. Arzneimittel-Forschnug 35: 30-43; 1985
Nickel B. The antinociceptive activity of flupirtine: a structurally new analgesic. Postgrad Med Journal 63(Suppl 3),19-28, 1987
Success is a prize to be won. Action is the road to it.
Chance is what may lurk in the shadows at the road side.
30. 30
Flupirtine Indications
Available as 100 mg capsules
Indicated for use in acute and chronic pain conditions such as
painful musculoskeletal conditions with or without spasm
pains after traumatic/orthopedic/general surgical/gynecological operations and injuries
stress headaches
cancer-related pain
dysmenhorrhea
neuropathic pain
NATURE, TIME AND PATIENCE
are the 3 great physicians
31. 31
Pharmacokinetic Data
• Studies included both young and elderly healthy volunteers
• Studies included patients with mild/mod renal impairment, liver disease
and epilepsy
Parameter Data (200 mg flupirtine maleate orally)
Bioavailability 90% (Freely soulble in water and undergoes rapid gastric absorption and
appears in plasma in 15-30 min)
Cmax 1.98 mg/L (Plasma concentrations are linearly related over the dose range from
50-300 mg)
Tmax 2 hr
Half-life ~ 9.6 hr (Drug accumulation not observed after oral admin of 100 mg)
Vd 1.16 L/kg
Protein binding ~84 %
Metabolism Hepatic [2 active metabolites with 20-30% of analgesic activity of parent
compound]
Excretion 72% renal and 18% fecal excretion
Memory, Pity and Beauty are short lived in life;
But tinged with emotion persist in life
32. Pharmacokinetic Data in Special
32
Populations
Parameter Data (100 mg flupirtine maleate orally)
Healthy volunteers Hepatic Impairment Renally impaired
18-35 yrs 66-83 yrs ClCr = 44-99 ml/min
Cmax 0.77 mg/L 1.12 mg/L 1 mg/L 0.72 mg/L
Tmax 1.6 hr 1.8 hr 2.5 hr 1.8 hr
Half-life 6.5 hr 14 hr Not reported 9.8 hr
Total body clearance 16.5 L/hr 9.7 L/hr Not reported 15.8 L/hr
Mean elimination half-life of flupirtine was higher in elderly patients than in younger normal subjects, and this was
associated with an increased maximum serum concentration and reduced clearance
Abrams SM, et al. Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment.
Postgrad Med J. 1988 May;64(751):361-3.
It is the disease of not listening, the malady of not marking,
that I am troubled withal - Shakespeare
33. 33
Flupirtine Dosage
100 mg, three to four times daily
For severe pain, 200 mg three times daily (daily dose exceeding 600 mg not advisable)
The sign wasn’t placed there
By the Big Printer in the sky
34. 34
Flupirtine Dosage in Special Populations
For elderly patients: 100 mg twice daily initially, increased to thrice daily if needed
For patients with impaired renal function: 100 mg thrice daily (with careful monitoring)
For patients with impaired hepatic function: use carefully with monitoring of liver enzymes
Pediatric patients: adequate trials have not been conducted in these patients
Pregnancy and Lactation: safety and efficacy studies have not been conducted
Flupirtine can be excreted into breast mik in lactating mothers
The art of medicine is caring for the heart of the patient
35. 35
Flupirtine Contraindications
Patients with a risk of a hepatic encephalopathy
Patients with cholestasis
Patients with myasthenia gravis
Patients with pre-existing liver disease and alcohol abuse
In patients with hypersensitivity to flupirtine maleate or any other ingredient of this formulation
Every thing should be made as simple as possible; but not simpler
36. 36
Flupirtine Precautions
May cause sedation: patients should not undertake driving vehicles or operation machinery
More care if alcohol is also consumed
Speak obligingly even if you cannot oblige
37. 37
Flupirtine Drug Interactions
Flupirtine can intensify the action of alcohol and medicines which exhibit sedative or muscle-
relaxing properties
Flupirtine may displace warfarin from its protein binding and thus increase the anticoagulant
effect necessitating dosage changes of warfarin
Flupirtine with paracetamol or carbamazepine should not be used
Develop the heart; art comes automatically
38. 38
Flupirtine Adverse Effects
Rare
↑ in liver
enzymes,
hepatitis
Knowledge without action is useless;
Action without knowledge is foolish
39. 39
Analgesic Activity: Human Studies
Author Dose Test Results
Hummel 50-100 CO2 application to Linear dose-related reduction in
(1991)1 mg nasal mucosa pain intensity
Kobal (1988)2 200 mg CO2 application to Pain threshold ↑ within 30-60 min
nasal mucosa with max effect 1.5-2 hr postdose
Bromm (1987)3 IV 80 mg Evoked cerebral Equivalent analgesia with flupirtine
potentials in response and pentazocine
to phasic pain stimuli
Gatto (1886)4 Thermal stimulation of Flupirtine superior to placebo
tooth pulp producing ↑ pain threshold within
15 min and lasting up to 45 min
1
Hummel T, et al. Dose-related analgesic effects of flupirtine. Br Journal of Clin Pharmacol. 32; 69-76; 1991
2
Kobal G, et al. Effects of flupirtine on pain-related evoked potential and spontaneous EEG. Agents and Actions. 23: 117-19; 1988
3
Bromm B. Assessment of analgesia by evoked cerebral potential measurements in humans. Postgrad Med J. 63: 9-13; 1987
4
Gatto R. et al. Study on the analgesic effect of flupirtine in dentistry. Quadeni di Odontostomatologia. 3: 71-82: 1986
40. 40
Post-op pain in general Sx setting
Analgesic efficacy of flupirtine versus placebo in 28 patients undergoing general surgical procedures
Pain intensity measured on a 5-point scale (no pain – unbearable pain)
Dose used: 100 mg orally single dose
Assessments at baseline and 3 and 6 hr post-dose
Reduction in pain intensity
Reduction in pain intensity
percent
Borgognone A, et al. A new non-opioid analgesic (flupirtine) in the treatment of postoperative pain. Therapeutika 1986; 86: 1-
41. 41
Post-op pain in orthopedic setting
Analgesic efficacy of flupirtine versus codeine in 66 patients undergoing hip replacement Sx
Pain relief measured on 5-point scale (0 = none and 4 = unbearable)
Dose used: FLU 100-200 mg orally as required (min interval of 4 hrs between doses)
PENTAZOCIN 50-100 mg orally as required (min interval of 4 hrs between doses)
Patients (n) in each severity grade on d1
Patients (n) in each severity grade on d1 Patients (n) in each severity grade on d4
Patients (n) in each severity grade on d4
Galasko CSB, et al. Current Medical Research and Opinion, 1985, vol 9: 594-601
42. 42
Post-op pain in orthopedic setting
FLU group: time taken for pain relief gradually decreased from 52 min to 32 min
PENTAZOCIN group: small progressive increase from 42 to 48 min
No significant differences between groups
Time taken for pain relief after drug administration (min)
Time taken for pain relief after drug administration (min) Complete pain relief after drug administration (%)
Complete pain relief after drug administration (%)
Galasko CSB, et al. Current Medical Research and Opinion, 1985, vol 9: 594-601
43. 43
Post-op pain in orthopedic setting
Higher proportion of patients reported being satisfied with flupirtine than with pentazocin
Patients satisfied with analgesia (%)
Patients satisfied with analgesia (%)
Galasko CSB, et al. Current Medical Research and Opinion, 1985, vol 9: 594-601
44. 44
Post-op pain in orthopedic setting
Galasko CSB, et al. Current Medical Research and Opinion, 1985, vol 9: 594-601
Teachers are reservoirs from which, through the process
of education, the students draw the water of life
45. 45
Post-op pain in orthopedic Sx setting
Analgesic efficacy of flupirtine versus diclofenac sodium for post-op patients in elective orthopedic
Sx settings (n = 40)
Dose used: 100 mg orally single dose (FLU) x 4 doses (max/day); n = 20
50 mg orally single dose (DIC) x 4 doses (max/day); n = 20
Assessments made 30 and 60 min post-dose and 1 hrly for 6 hrs on 100 mm VAS (0 = no pain and
100 = max conceivable pain)
Pain relief measured on 100 mm VAS (0 = no pain relief and 100 = total relief)
Overall Clinical Assessment (values = number of patients)
Therapy Excellent Good Moderate Useless
Flupirtine (n = 20) 4 2 8 6
Diclofenac (n = 20) 1 4 4 11
Mastronardi P, et al. J Int Med Res, 1988; 16: 338-348
It is not your position that makes you happy or unhappy
It is your disposition
46. 46
Post-op pain in orthopedic Sx setting
Analgesic effect of first administration of FLU or DIC (mean VAS scores)
Mastronardi P, et al. J Int Med Res, 1988; 16: 338-348
A good teacher is a perpetual learner
47. 47
Post-op pain in orthopedic Sx setting
Analgesic effect of third administration of FLU or DIC (mean VAS scores)
* * * * * * *
* Statistically significant between groups
Mastronardi P, et al. J Int Med Res, 1988; 16: 338-348
Learn to adapt, adjust and accommodate
Learn to give, not to take and learn to serve not to rule
48. 48
Post-op pain in orthopedic Sx setting
Mastronardi P, et al. J Int Med Res, 1988; 16: 338-348
Hate screeches, fear squeals; conceits trumpets
but love since lullabies
49. 49
Post-op pain in gynecological Sx setting
Analgesic efficacy of flupirtine versus dihyrdrocodeine for post-op patients with abdominal
hysterectomy (n = 50)
Pain intensity measured on a 4-point scale (0= no pain – 3 = severe pain)
Dose used: 100 mg orally single dose (FLU); n = 25
60 mg orally single dose (Dihydrocodeine); n = 25
Assessments made twice daily x 3 days post-op
Pain intensity and relief scores
Pain intensity and relief scores Total analgesic and antiemetics interventions
Total analgesic and antiemetics interventions
Moore RA ,et al. Br J Anaesth. 1983; 55: 429-432
50. 50
Post-op pain in gynecological Sx setting
Moore RA ,et al. Br J Anaesth. 1983; 55: 429-432
Reputation is made in a moment; character is built in a life time
51. 51
Clinical experience with flupirtine in US
1300 pts evaluated (episiotomy, surgical or dental procedures) at 26 study sites
Placebo evaluations or versus paracetamol 650 mg, codeine 60 mg, pentazocin 50 mg or oxycodone
10/paracetamol 650 mg
FLU 100-300 mg (max 600 mg/d)
Total Pain Relief (TOPAR) scores
Total Pain Relief (TOPAR) scores
McMahon FG, et al. Postgrad Med Journal , 1987; 63: 81-85
52. 52
Clinical experience with flupirtine in US
McMahon FG, et al. Postgrad Med Journal , 1987; 63: 81-85
Character gets you out of bed commitment moves you to
action faith, hope and Discipline follow through to
53. 53
Phase IV study in 869
patients
Max dose 600 mg/d
Duration: 2-90 days
VAS 10 pt scale:
0 = none
10 = maximum pain relief
54. 20 patients had 29 AEs (2.4%)
20 patients had 29 AEs (2.4%)
19 AEs rated as drug-related
19 AEs rated as drug-related 10 AEs rated possibly not drug-related
10 AEs rated possibly not drug-related
1.3% CNS related
1.3% CNS related
1.1% GI related
1.1% GI related
no drug dependency
no drug dependency
no tolerance
no tolerance
no withdrawal symptoms
no withdrawal symptoms
25 of 29 AEs resolved by study end
25 of 29 AEs resolved by study end
wisdom to listen - Hodly’s
to speak and it is the privilege of the
It is the providence of the knowledge
54
55. 55
Efficacy of flupirtine in osteoporosis pain
Ringe, et al. Arzneim Forschung, 2003
Opinion is ultimately determined by the feelings
and not by the intellect
56. 56
Low Back Pain: Comparison with Tramadol
209 patients with moderate-severe subacute LBP randomized to either flupirtine or tramadol
Flupirtine 100 mg x 3 times/d x 5-7 d (n = 105)
Tramadol 50 mg x 3 times/d x 5-7d (n = 104)
Assessment on Numerical Rating Scale 0 = no pain to 10 = worst pain imaginable
Pain Relief Rates
Pain Relief Rates
Li C, et al. Current Medical Research and Opinion 2008, 24(12): 3523-3530
57. 57
Low Back Pain: Comparison with Tramadol
Mean LBP Intensity Scores
Mean LBP Intensity Scores ADR events and ADR related dropouts (%)
ADR events and ADR related dropouts (%)
p = 0.02
59% 56% p < 0.001
Li C, et al. Current Medical Research and Opinion 2008, 24(12): 3523-3530
A great many people think they are thinking when
they are merely re arranging their prejudices
W. James
58. 58
Low Back Pain: Comparison with Tramadol
Li C, et al. Current Medical Research and Opinion 2008, 24(12): 3523-3530
The Truth is fear and immorality are two of the
greatest inhibitors of Performance to progress
59. 59
Efficacy in Musculo-Skeletal Disorders
7,806 pts with musclo-skeletal disorders (cervical/lumbar spine pain, myofascial pain, tension
headache, muscle spasm associated with arthritis) evaluated
Flupirtine 100 mg (2-3 doses/d) max dose 600 mg/d
Assessment on pain scale: 0 = no pain to 4 = very severe pain
G.Mueller-Schwefe. Progress of Medicine 121 Jg.- Original No.1/2003, Pg.11-18
A true commitment is a heart felt promise to yourself from
which you will not back down -
D. Mcnally
60. 60
Efficacy in Musculo-Skeletal Disorders
% patients with response (improvement by at
% patients with response (improvement by at % patients with continuous pain at beginning
% patients with continuous pain at beginning
least 1 step) at end of 1 wk
least 1 step) at end of 1 wk and end of 4 wks Rx
and end of 4 wks Rx
G.Mueller-Schwefe. Progress of Medicine 121 Jg.- Original No.1/2003, Pg.11-18
Serious, sincere, systematic
studies,
surely secure supreme success
61. 61
Efficacy in Musculo-Skeletal Disorders
% patients with response (improvement by at least 1
% patients with response (improvement by at least 1 % patients with response (improvement by at least 1
% patients with response (improvement by at least 1
step): reduction of muscle spasm
step): reduction of muscle spasm step): restriction of daily activities
step): restriction of daily activities
G.Mueller-Schwefe. Progress of Medicine 121 Jg.- Original No.1/2003, Pg.11-18
God is a comedian performing before an audience
that is afraid to laugh
62. 62
Clinical experience in migraine
47 pts with migraine evaluated
Flupirtine (n = 24) 100 mg (up to 4 doses/d x 5 d)
Paracetamol (n = 23) 1 gm (up to 4 doses/d x 5 d)
60 % patients unable to work
20 % patients confined to bed
50 PAR
PAR
40
% pts % pts 10
30 FLU
20
10
FLU 0
0
1 2 3 4 5
1 2 3 4 5
Million R, et al. Current Medical Research and Opinion, 1984; vol 9 (no 3): 204-212
63. 63
Clinical experience in migraine
Mean VAS scores of pain severity during migraine attack
70
60
50
40
Score
30
PAR
20
FLU
10
0
Time (d)
1 2 3 4 5
Million R, et al. Current Medical Research and Opinion, 1984; vol 9 (no 3): 204-212
64. 64
Clinical experience in migraine
Million R, et al. Current Medical Research and Opinion, 1984; vol 9 (no 3): 204-212
Man is made by his beliefs; as he beliefs, so he is
65. 65
10 patients with tumor/chemoRx/radioRx-related neuropathic pain not controlled with opioid drugs
Flupirtine 100 mg x 4 times/d x 8 d (max dose 300 mg x 4 times/d)
Opioid Rx was continued during trial
Assessment of pain relief by Wisconsin Brief Pain Questionnaire (0 = no pain to 10 = worst pain)
* *
* Patient # 1 and 10 could not understand the questionnaire and hence values are not available
67. 67
71 patients with cancer-related pain not controlled with opioid drugs
Flupirtine 100 mg x 4 times/d x 4 wks (max dose 100 mg x 6 times/d); n = 35
Tramadol 50 mg x 4 times/d x 4wks (max dose 50 mg x 6 times/d); n = 36
Assessment of pain relief by scale (1 = pain free to 5 = severe pain)
Pain Intensity Differences after 4 wks
Pain Intensity Differences after 4 wks
No Pre-Rx Successful Pre-Rx Not successful Pre-Rx All patients
In any field, find the strangest thing and explore it
68. 68
% pts with pain alleviation after 4 wks
% pts with pain alleviation after 4 wks
54 %
36 %
There are sixty trillion cells in the human body
69. 69
Presentation Points
“Men of Genius Admired:
Men of Wealth envied
women of power feared but only
women of character are trusted”
A- Friedman
70. 70
Summary
Flupirtine is a centrally acting,non-opioid analgesic that exhibits additionally muscle relaxing
activity
Has been used in Europe for 20 years in treatment of pain states such as post-Sx, arthritis, and
muscular pain syndromes
Flupirtine has been found in clinical trials to be safe and well tolerated 1,2,3,4
Free of the opioid-related respiratory depression, dependence potential, and constipation4,5
Devoid of cardiac effects in humans during prolonged exposure5
Useful adddition alone and in combination with NSAIDs to control pain
1
Scheef W. Analgesic efficacy and safety of oral flupirtine in the treatment of cancer pain. J Postgrad Med 1987;63(suppl 3):67–
70
2
Galasko CS, et al. Trial of oral flupirtine maleate in the treatment of pain after orthopaedic surgery. Curr Med Res Opin
1985;9(9):594–601
3
Heusinger JH. Efficacy and tolerance of flupirtine and pentazocine in 2 multicentre trials. J Postgrad Med 1987;63(suppl 3):71–9
4
Riethmuller-Winzen H. Flupirtine in the treatment of post-operative pain. Postgrad Med J 1987; 63(suppl 3):61–5
5
Scheef W, Wolf-Gruber D. [Flupirtine in patients with cancer pain]. Arzneimittelforschung 1985; 35(1):75–7
73. READ not to contradict or confute
Nor to Believe and Take for Granted
but TO WEIGH AND CONSIDER
THANK YOU
My sincere thanks to SUN-SOLARIS
Notas do Editor
NMDA receptor is one of the main mediators of excitatory neurotransmission. The binding of both glutamate and glycine activates this receptor. The receptor is a ligand gated ion channel, which permits the movement of calcium, sodium and potassium across the post-synaptic membrane
NMDA receptor is one of the main mediators of excitatory neurotransmission. The binding of both glutamate and glycine activates this receptor. The receptor is a ligand gated ion channel, which permits the movement of calcium, sodium and potassium across the post-synaptic membrane
NMDA receptor is one of the main mediators of excitatory neurotransmission. The binding of both glutamate and glycine activates this receptor. The receptor is a ligand gated ion channel, which permits the movement of calcium, sodium and potassium across the post-synaptic membrane
NMDA receptor is one of the main mediators of excitatory neurotransmission. The binding of both glutamate and glycine activates this receptor. The receptor is a ligand gated ion channel, which permits the movement of calcium, sodium and potassium across the post-synaptic membrane
NMDA receptor is one of the main mediators of excitatory neurotransmission. The binding of both glutamate and glycine activates this receptor. The receptor is a ligand gated ion channel, which permits the movement of calcium, sodium and potassium across the post-synaptic membrane
NMDA receptor is one of the main mediators of excitatory neurotransmission. The binding of both glutamate and glycine activates this receptor. The receptor is a ligand gated ion channel, which permits the movement of calcium, sodium and potassium across the post-synaptic membrane
PPID = peak pain intensity difference SPID = sum of pain intensity difference